How much does a year of Humira cost? I would be willing to bet that you and the other rheumatologists around you would struggle to answer that questions. There are a few reasons this is difficult:

1. The price varies depending on who is paying, whether that is Medicare, Medicaid, the VA, or, whosie-whatsit-evil-PBM.

2. Price tags don’t exist. There’s no list somewhere that tells you how much anything is going to cost.

3. The price is constantly changing. Every year it goes up a little (or a lotta) bit and, depending on where you live, it may be higher or lower by many orders of magnitude.

A spicy recent paper in JAMA highlights some of these problems. Among 643 drugs in the analysis, median launch prices rose from $38,857 for products launched in 2008 to 2013 to $254,213 for those launched in 2020 to 2025. Thats a big difference, to put it mildly. As much as I would love to have a JAMA publication, I would much rather post all the prices in some transparent and coherent way so you can look at them whenever you want to reference them.

So I built that! The rheumatology Drug Price Tracker. You can check individual drug prices at launch and compare prices over time. You can compare prices in the USA to prices abroad (trigger warning; its shocking). You can compare prices within classes organized by diseases and you can dig into the changes wrought by biosimilars. It is all pretty self-explanatory and intuitive, so I encourage you to just go to the website and check it out.

If you’d like me to tell you some of the things that I learned, read on!

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Lesson 1: JAMA was Right

I’m sure this will surprise no one, but the article in JAMA was completely correct. The launch price of rheumatology drugs has gone up steadily over time. I graphed all of these by their annual cost at launch in 2025 dollars for clarity. You can see that there’s been a steady trend upwards, but it has followed a remarkably narrow distribution, with a few notable outliers.

The outliers all appear to be in areas where there was rare-disease indications with limited approved options. Recent launches for brepocitinib (dermatomyositis), inebilizumab (IgG4-RD), IVIG (dermatomyositis), and avacopan (AAV) are the small dots to the right. To put it succinctly; launch prices in uncontested markets for rare diseases are much higher. On the one hand, this makes a lot of sense. The price of goods generally tracks scarcity, and in those areas we have had a scarcity of treatments for many years. On the other, it’s not like any of our diseases are common?

Lesson 2: Prices Go Up

All of the prices that I display are adjusted for inflation, so you don’t need to go back and try and figure things out. They’re all annualized by year as well, so every price reflects a full year of therapy. In that context, prices have gone up by 62% Since 2014, even above inflation. That’s a pretty big change, but honestly, a little bit less than I would have expected.

If you want to see this for each individual drug, I graphed all of the various prices from all the various sources for each of them. Krystexxa is an interesting place to start if you want to mosey on over. Its initial list price was $2,300 per 8 mg vial, with commercial availability beginning in December 2010. At one infusion every two weeks, that works out to $59,800 for 26 infusions, which sounds pretty reasonable by today’s stanards.

With steady growth over time, however, the average list price in 2025 annualizes to $789,900 at the same dose and frequency. That is a 13.2-fold increase, or approximately ninefold after inflation adjustment. The latest captured increase, effective June 25, 2026, brings the annualized figure to $854,600. The nice thing about my dashboard is that you can see the prices from all of the various sources. There are differences by who is paying, but across the board, it is high.

Before building this I had a vague sense that a single year of Krystexxa would be quite a bit more expensive than a single year of allopurinol, but I did not realize “more expensive” meant “a pretty nice lake house and a boat” per year of difference.

Lesson 3: Some Drugs are Pretty Good Value?

Given the staggering prices of recent launches, I had a suspicion that obinutuzumab would be a pretty ridiculous number. Somehow it just isn’t? Using the tracker’s captured 2026 nominal prices, Gazyva comes to $18,900 for a maintenance year. For a fancy new B-cell-depleting agent, that is really a pretty remarkable value

I have generally been favoring belimumab on the erroneous theory that it must be cheaper beacause it has been around for awhile, but that is actually not true. This gets a little complicated with loading and dosing (my tracker assumes an 80kg adult for all cases). If you include loading, the gap narrows. During the initial 52 weeks, excluding the dose due at week 52, drug list costs are approximately $37,800 for Gazyva and $61,600 for IV Benlysta. These calculations use Genentech’s disclosed vial price and the Texas price filing for Benlysta, so there is some substantial uncertainty by where you are and who is paying. That said, “Newer Approval = Way More Expensive” does not appear to be true in all cases.

Lesson 4: America Is Getting a Really Really Bad Deal

Other countries give us a way to question whether American prices are necessary. In a RAND analysis using 2022 data, US manufacturer gross prices for brand-name originator drugs were 4.22 times those in 33 comparison OECD countries. It compared matching drug presentations, weighted to US use. Unbranded generics went the other way: US prices were 0.67 times comparator prices. In some sensitivity analyses RAND saw the ratio fall to 3.08 after estimating US rebates, which I suppose is good? Take a look at my comparisons and I think the situation is pretty clear.

For some reason, Australia has the best comparison data. It’s a rough read. The same drugs cost anywhere from 5x to 20x as much money in the United States. Take Rinvoq, for instance. At 15 mg daily, AbbVie’s published US list price annualizes to $86,270. The same brand and daily dose, using Australia’s September 2026 PBS supplier price, comes to A$14,241, or US$10,008 at the tracker’s September 25 exchange rate. Perhaps there is some twiddling at the margins that may make that seem less-bad - ie rebates and such. I doubt it will make it “$76,262 less bad.”

Optimistically, this may be improving? CMS is now allowed (crazy they weren’t before) to negotiate prices on a select list of drugs. The prices of those drugs has fallen precipitously (38%–79% below 2023 list prices), suggesting that a more rational set of public policies could have a pretty remarkable impact in a short period of time.

One quick note on this particular point. Pharmaceutical companies get a lot of shade for drug pricing. At the end of the day, I think the blame rests almost entirely on politicians. If you went to your mechanic and told them you wanted a new set of tires, but that the federal government would pay whatever they asked, I would bet you walk way with a five- or six-figure bill. You can’t ask a company with shareholders in a capitalist economy to charge rates below their competitors or below market value. You can expect your politicians to do a reasonable job of setting rational public policy. For many decades they have failed.

Lesson #5: None of this is good “Value”

You would be surprised how little additional benefit much of this spending buys, relative to conventional therapy. Even compared to placebo, most of our therapies have a surprisingly high cost per life changed.

There have been some studies on this. In RACAT, 353 patients with active disease despite methotrexate were randomized to triple therapy with methotrexate, sulfasalazine and hydroxychloroquine, or etanercept plus methotrexate. At 48 weeks, triple therapy met the prespecified noninferiority criterion for improvement in DAS28. Both strategies allowed switching at week 24 for inadequate improvement, and 27% of each group switched. The result supports trying a conventional combination as a treatment strategy after methotrexate failure, but the majority of us (including myself) typically go straight to a TNF.

How much does that decision cost? An economic analysis estimated that starting etanercept first would produce 0.15 additional lifetime quality-adjusted life-years at an additional cost of $77,290, yielding $521,520 per QALY. Yikes! Decisions you are likely making every day have a remarkably high cost-per-life affected.

I wanted to get at this with the tracker, but QULY analysis is pretty difficult. Instead, I built out a narrower comparison between the annual drug list cost per additional trial responder. I think this provides some useful and interpret-able context for the cost of decisions you make on a regular basis. It’s not really a fully fledged economic analysis, but offers a rough benchmark. I’ll be building out more diseases and more therapies as new studies come along!

Where This Leaves Us

1. Rheumatology is expensive! My take-home point from a lot of this was just that what I do on a daily basis is remarkably expensive. I do think a lot of our therapies really do change lives, but I think I could probably do a better job of picking which therapies in which situation.

2. We need more comparative effectiveness studies of csDMARDs. When I started this project, I hoped to compare conventional synthetic DMARDs to their fancy biologic and targeted alternatives. I mostly gave up. There is just not enough comparative effectiveness data to make meaningful choices in the vast majority of cases.

3. Public policy is the reason. The more I learn about this, the more infuriating I find the system our politicians have designed. Other countries get these therapies for a pretty good value. The fact that nobody pays the rates we pay tells you everything you need to know.

Disclosure: I prescribe many of the medications I discuss in this newsletter. I also participate in clinical trials, unbranded educational activities, advisory boards, and consulting for multiple therapies, many of which are discussed in this newsletter. I also run BoardsBank.com, which is supported by industry sponsors. Views my own, not those of my employer.

It has been five months since the last real Pipeline Monitor, so I felt like we were due for an update. There’s been quite a lot of movement in the “just approved, about to approved, and maybe-going-to-be-unapproved-soon” spaces. Send me a note if I missed anything!

Avacopan is on Borrowed Time

Amgen / Avacopan (Tavneos) in ANCA Vasculitis

I actually opened the first Pipeline Monitor discussing the surprising move by the FDA to propose pulling avacopan from the market. At the time the specifics were unclear; much has changed. We now know that ChemoCentryx was (allegedly, but also un-refutedly) guilty of data manipulation and the NEJM has retracted the ADVOCATE study. This precipitated a rush to the exits by the rest of the world. Health Canada told prescribers to stop starting new patients in July, the European Commission revoked the EU authorization outright on August 4th, and on September 1st the UK’s MHRA suspended avacopan use for new patients. The UK verbiage reflecd that of the FDA: the data are “no longer sufficiently reliable to support a positive benefit-risk balance.”

In the US, the byzantine bureaucratic process is marching forward. Amgen requested a hearing on June 1st and submitted supporting materials in late July. Amgen also published the results of a blinded re-(re?)-adjudication from Duke, which more or less confirmed the gist of the ADVOCATE study (68.1% vs 67.1% in remission at week 26, 61.4% vs 52.4% in sustained remission at week 52). It also more or less confirmed the gist of the FDA’s central complaint; without the suspicious re-adjudication, ADVOCATE did not meet the critical week 52 superiority endpoint.

As before, that puts me in the strange position of thinking avacopan works (steroid sparing, GFR benefits, PROs) AND thinking the FDA would be well within its rights to pull it. Maybe leaving it on the market and sending the guilty parties at Chemocentryx to jail would be a nice compromise? Letting this slide without repercussions seems untenable, but it also feels a shame to lose a drug that I continue to think has benefits for real people in the real world. From a doctoring perspective, I have been explaining the situation to all my patients and only really continuing avacopan in cases where a patient explicitly requests it.

Rating: SELL. I still think avacopan works, but the FDA (and other agencies) are rightly furious by what Chemocentryx pulled.

Another Positive Myositis Study? TIS the Season!

argenx / Efgartigimod (Vyvgart) in Myositis

In the brepocitinib Regulatory Breakdown I mentioned that I was looking forward to FcRn data in the necrotizing myopathies. In August Argenx announced that ALKIVIA met its primary endpoint. The trial randomized 264 patients (175 in the phase 3 portion) to weekly subcutaneous efgartigimod or placebo for 52 weeks, with a mandatory steroid taper. For the immune mediated necrotizing myopathy (IMNM) and dermatomyositis groups combined, the mean Total Improvement Score (TIS) was 48 vs 33, something like a 15 point delta (NNT ~ 7) (p=0.001). IMNM on its own also hit (45 vs 30, p=0.005) but dermatomyositis by itself did not (52 vs 37, p=0.11), which is likely just statistical noise.

That lands pretty close to the 15 point delta that just got brepocitinib approved and is overall pretty similar to IVIG in the PRODERM study. The IMNM part of this is the main novelty. I think these may be the first humans with IMNM randomized to a therapy, which is a nice step forward. I have already been using rituximab and IVIG for refractory SRP and HMGCOA people, so a treatment targeting IgG recycling (it’s a very funky mechanism, but apparently may be a good one?) is on brand. Curious to see how safety plays out (better than RTX? worse?) and how well this performs in other indications (SLE, SjS, & SSc in the docket).

Rating: BUY. IMNM just got its first positive phase 3 and rheumatology got a new way to attack the mal humors. Will be interesting to see where this lands in the evolving B cell landscape.

A Deluge of Data in Sjögren’s Disease

Amgen / Dazodalibep in Sjögren’s Disease

On September 22nd, Amgen announced that OASIZ 301 met its primary endpoint, change in ESSDAI at week 48, in a large trial of 620 patients with moderate-to-severe systemic Sjögren’s Disease. Dazodalibep is a CD40L antagonist, a similar mechanism to dapirolizumab pegol in SLE. This is the second CD40L in rheumatology to run a trial that (so far) appears to have dodged the thromboembolic complications that tanked the first generation of CD40L therapies. Unfortunately we know very little about how well this worked, aside from efficacy “emerging” at week 4. The press release was pretty light on numbers and heavy on business speak.

The bigger story here is Sjögren’s disease, which has gone from graveyard of therapies to a traffic jam. Ianalumab has breakthrough designation and we’re expecting read outs from the NEPTUNUS studies anyday. Nipocalimab has its own breakthrough designation, and the aforementioned efgartigimod is expected to read out next year. After decades of nothing, Sjögren’s is having something of a renaissance. One cautionary note; the actual magnitude of benefit from therapies to date has been pretty marginal. Whether any of them pop beyond ESSDAI (my least favorite outcome measure, and that’s saying something) remains to be seen.

Rating: HOLD. Good news for CD40L, but the devil’s in the details. Waiting to see how big the benefits were and whether they actually improved patient reported outcomes.

Secukinumab Hopes to Hop the Pond

Novartis / Secukinumab (Cosentyx) in PMR

On September 18th, the CHMP recommended approving secukinumab for polymyalgia rheumatica, with a final European Commission decision expected in about two months. The EC typically follows the CHMP, so I would expect approval in the later part of this year. Novartis has also filed in the US and Japan, which I expect will follow suit in late 2026 or early 2027.

I covered REPLENISH in the EBR Journal Club back in June. I think it’s a real but modest benefit in a trial that was bigger and cleaner than SAPHYR. Sustained remission at week 52 was 41% on either 300 mg or 150 mg as compared to 20% on placebo, so a NNT ~5. Steroid sparing was fine - about 500 mg less prednisone over the year - but it’s hard to compare that to SAPHYR because the prednisone tapers differed substantially between trials. For a variety of reasons, I think I would prefer an IL-17 inhibitor over an IL-6 inhibitor in PMR. The dosing is marginally easier and I think the safety is a bit better, one case of cryptococcal meningitis notwithstanding.

What to do for new-onset PMR is a much bigger and potentially more impactful question. JAK-SPARE, a small Lilly-sponsored trial of baricitinib in 46 patients with new-onset PMR, reported steroid-free remission at week 16 of 65% vs 17%. Lilly clearly did not read my newsletter. There’s really no point to running such a small study for a drug with thousands of prior randomized patients. More on that at the PMR Year in Review at ACR Convergence this year, which I will be giving!

Rating: BUY. I would marginally favor an IL-17 over an IL-6 in PMR. Hoping we see more soon about what to do for new-onset disease.

CAR-T on Thinner Ice than Before

Novartis / BMS Pause CAR-T Studies

Shortly after I posted my CAR-T Reality Check Dashboard (check it out!), Novartis reported three deaths from immune effector cell-associated hemophagocytic syndrome. IEC-HS is distinct from the cytokine release syndrome (CRS) that often happens in close proximity to CAR-T therapy. Think of it as a delayed-onset instance of HLH. Responding to this, Novartis voluntarily paused eight of it’s CAR-T autoimmune studies, five of which included patients with rheumatic diseases. The same day, BMS voluntarily paused its own autoimmune CAR-T program over “transient and reversible inflammatory events.”

All of this landed at a tough time for Kyverna, who just this week released data about their CAR-T program in myasthenia and stiff person syndrome. The most notable finding was a durable benefit over 12 months post therapy in over 90% of patients. They responded immediately to the Novartis and BMS news with a statement noting no cases of IEC-HS and no high-grade CRS or ICANS. They are still planning to launch outside of rheumatology in 2027, but these updates are putting a damper on the CAR-T enthusiasm.

Rating: HOLD (down from BUY). CAR-T is still exciting, but at least for me the shine has worn off. To be fair, I’ve always been skeptical. Curious to see how the FDA handles the data in light of these safety signals.

Other News and Notables

JAKs had a rough EULAR. Lilly’s RA-BRIDGE and RA-BRANCH safety trials randomized 3,640 RA patients with at least one VTE risk factor to baricitinib or a TNF inhibitor (open-label). Similar to the miss in ORAL-SURVEILLANCE, baricitinib missed its VTE noninferiority margin. Serious infections were also higher (HR 1.32), though MACE was not (HR 1.06). This does not necessarily answer the critical “Does JAK selectivity matter?” question, but it certainly reinforces concerns about the class.

TYK2 in lupus took a hit: Envudeucitinib missed its primary endpoint, BICLA at week 48, in a 408-patient phase 2b. Again, people should stop running phase 2 studies (if they can). They’re focusing on interferon-high patients only, which also seems kind of silly. It’s a longer conversation, but the interferon signature from the TULIP trials really did not seem to matter very much. Unfortunately I think the TYK2 class is going to underperform.

The money is moving to T-cell engagers. UCB just dropped $2 billion upfront for Candid, whose BCMAxCD3 engager has a foothold across a basket of autoimmune indications. I’m still long on the BiTEs. If they can capture some of the magic and shed most of the logistics, I think they may ultimately win the CAR-T derby.

The Regulatory Breakdown covers updates from the FDA or EMA, explaining development programs, trial data, and the implications for both clinical practice and the market.

On August 27th the FDA approved brepocitinib (Lisraya) for adults with dermatomyositis, making it the first oral drug approved for any idiopathic inflammatory myopathy and, for dermatomyositis, only the second approved therapy of any kind. I covered the VALOR study a few months back, which landed in the “refreshingly solid” zone. I have also been complaining about the lack of development in myositis for many years and am glad to see so much happening here. Where will this fit and for whom should you be using it? Read on to find out!

The Better Part of VALOR

Brepocitinib is a first-in-class, oral, selective TYK2-JAK1 inhibitor. Think upadacitinib + deucravacitinib? That hits a lot of useful cytokines, including the interferon signaling that seems critical in SLE/dermato type rashes. Brepocitinib was approved on the back of the VALOR trial, which I covered back in April. VALOR randomized 241 adults with dermatomyositis to receive brepocitinib at two doses or placebo. Everyone had already failed at least one drug, 3/4 were on glucocorticoids, and roughly 1 in 4 had tried IVIG.

VALOR met the primary endpoint (Total Improvement Score of 46.5 versus 31.2, 15-point delta) and all nine secondaries. The number needed to treat was around 4 people to get a moderate response and around 5 people for a major response, which is broadly similar to TNFs in rheumatoid arthritis. Not bad! The NNT was around 4 to bring about cutaneous remission, which again is a pretty nice response. Brepocitinib even improved the pesky dermato-itch that drives people crazy. That may have contributed to the PROs, which cleared MCID thresholds. Exciting to see a connective-tissue disease trial that actually makes people feel better! Overall I think the headline numbers were very good.

Nothing comes free. Brepocitinib increased serious infections (NNH ~11), which is a bummer. Although you would expect an immunosuppressive therapy to increase infection risk, in many of our studies (TCZ for GCA, for instance) the reduction in steroid exposure actually cancels out the harms of the DMARD itself. Part of that may be the real-but-underwhelming steroid sparing in VALOR. Patients randomized to brepocitinib received around 400mg less prednisone over the year-ish long study, which is good but not great. I suspect part of that is trial design, with patients coming in at a lower dose (20mg) and identical tapering strategies by arms. Both forces likely put a cap on how much steroid progress could have reasonably been expected. All the same, I pitch DMARDs in GCA as an infection-reducing strategy; you cannot say that here.

Worth noting that the MACE and malignancy signal decided not to show up at all. There were zero thromboembolic events or cancers in the brepocitinib arms, one nonfatal cardiovascular event, and no deaths. Like the phase 3 studies of tofacitinib, VALOR was not powered to detect a small-but-meaningful safety signal. Brepocitinib will carry the full suite of JAK-class warnings, which you will have to explain to every patient before prescribing. I think this is appropriate. Emerging observational data (including an abstract of my own at ACR 2026!) has been somewhat reassuring, but it would take an ORAL-SURVEILLANCE-like effort to truly exonerate the JAK class.

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At the ARTS Meeting in Chicago this coming August 28th and 29th, I am participating in a panel discussion about CAR-T. Although I believe CAR-T will be a big deal in rheumatology, I am also a long-term skeptic of it’s role in rheumatology and am annoyed by the ratio of CAR-T-hype to CAR-T-evidence. While preparing my talk I realized that some fundamental questions are remarkably difficult to answer. How many patients have receied CAR-T? Do outcomes differ over time or by disease? How strong is the quality of CAR-T evidence?

In an effort to answer these questions, I scraped the entire medical literature, all of the abstract reports from recent rheumatology meetings, and clinicaltrials.gov. It’s a lot of data and required a lot of deduplication, which itself became a notable finding. All that hard work now lives in a handy dashboard, which you can explore by clicking here! I strongly recommend just doing that yourself, but if you want some quick hits for my high level takes, here are some thoughts!

Lots of Nonsense Trials, Mostly in China

ClinicalTrials.gov lists 150 registered CAR-cell trials in rheumatic diseases, which exploded from 8 in 2023 to nearly 50 per year from 2024 to 2026. That sounds like a healthy scientific effort, but the pipeline itself is remarkably skewed and immature. For one, there is only one registered Phase 3 study out of the entire bunch, which is shocking to me. Running 100 studies of 8 patients is dramatically less useful than 8 studies of 100 people. It increases your Type 2 error rate, because each of those bites at the apple represents another opportunity for an errneously positive p value. It also increases your Type 1 error rate, because none of those studies of 8 patients each is truly powered to assess anything other than dramatic differences.

For two, nearly all of the registered trials (82%) are occurring in China. China is obviously a larger country than the United States and has had a commendable run of increasing scientific productivity. That still feels like an unhealthy balance. Somehow there are only 8 studies registered in the United States. For reference, there are nearly 10 times that many studies of just upadacitinib, and that’s just one JAK inhibitor and just one company. If this is the next big thing, shouldn’t we be studying it as such?

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On July 31st of 2026, Novo Nordisk announced the failure of the ZEUS trial, which investigated ziltivekimab, a monoclonal antibody against the IL-6 ligand. The trial randomized 6,300 people with atherosclerotic disease, chronic kidney disease, and an hsCRP of at least 2 mg/L to receive ZIL or placebo. The drug did what it was designed to do; IL-6 dropped and hsCRP fell. As far as we know (the main study is not published yet) there were no novel safety signals, an uptick in serious infections notwithstanding. The drug also completely failed to improve cardiovascular death, non-fatal MI, or non-fatal stroke, with a hazard ratio for the primary outcome of 0.99.1

I want to talk about this today because I would have bet against this working. I would also bet against it working in the future with a different drug or a different mechanism or a different cardiovascular target. I am officially planting my flag on the “immune drugs will not fix cardiovascular-anything” hill, because I have seen this movie many times before. When you block a cytokine to prevent cardiovascular events, the effect is either marginal or nonexistent, and the benefits never outweigh the risks. So why does pharma keep spending gobs of cash on this? Hoping to unpack this today and - if you share this with enough people - perhaps we can encourage companies to divert these funds elsewhere.

Peas Pass the Punnett Square

The case for immunology in cardiology is pretty strong if you believe in pathophysiology and epidemiologic associations.

For as long as we’ve been looking at plaques under microscopes, we have known they are full of macrophages and T cells and inflammatry schmutz. Cholesterol crystals activate the NLRP3 inflammasome, which cleaves IL-1β, which drives IL-6, which drives hepatic production of the CRP. That gives you a tidy linear pathway from the lipid everyone agrees is causal to the biomarker everyone can measure. On top of that, hsCRP predicts cardiovascular events independent of LDL, statins lower hsCRP as well as LDL, and the patients whose hsCRP falls the most on a statin seem to do the best. The basic sciency side of this is not a hard sell.

The case for IL-6 is even a bit stronger. In addition to the aforementioned pathophysio-woo-woo, IL-6 inhibitors passed muster in a Mendelian randomization study. This one probably needs a brief explainer. The logic of Mendelian randomization is that you are assigned your genotype at conception, more or less at random with respect to everything else about your life. Theoretically, some variant that partially disables some drug target could function as a lifelong natural experiment. If people “randomized” at birth to some hobbled version of a receptor get less disease, then perhaps that’s not only observational evidence for some purported association, but also causal evidence for that association. It’s an elegant and testable hypothesis.

It turns out that the IL6 receptor has just such an experiment. The p.Asp358Ala variant blunts IL-6 receptor signaling, essentially producing the same biomarker fingerprint as tocilizumab. An interesting study that was published in big Lancet evaluated 25,458 coronary heart disease cases against 100,740 controls and found an odds ratio of 0.95 per allele. A companion paper in the same issue, pooling 82 studies, found a 3.4% reduction in coronary heart disease risk per copy of the variant. Separate Mendelian randomization work on CRP variants themselves has repeatedly failed to find a causal effect, which makes the IL-6 finding particularly alluring. I will also never fault someone for running a massive randomized controlled trial, so kudos to Novo Nordisk for taking that information and running with it.

Call me Maybe

It makes for an exciting story, but one that is incomplete without acknowledging the many prior failures in this space.

The hopes that immunosuppression will improve cardiology conditions are as old as TNFs themselves. The ink was barely dry on the 1999 rheumatoid arthritis approval of infliximab when the ATTACH study launched. ATTACH randomized 150 patients with an ejection fraction under 35% to infliximab at 5 mg/kg, infliximab at 10 mg/kg, or placebo, on the theory that TNF drives the progression of heart failure. Patients with CHF randomized to infliximab not only failed to improve, but the 10 mg/kg group actually did worse, with a hazard ratio of 2.84 for death or heart failure hospitalization. RECOVER and RENAISSANCE then randomized over 2,000 patients to etanercept or placebo, again expecting great things. Both studies were stopped early for futility.

I wrote about all of this at length last summer, and the conclusion I came to then holds up: I can say with a high degree of confidence that TNF inhibitors do not help heart failure. The case for harm is shakier and not the subject of this newsletter. What I’d rather focus on now is how thoroughly the pathophysiologic story convinced everyone in advance. TNF is elevated in heart failure, pilot studies observed substantial benefits, and everyone loves giving rheumatology drugs to cardiology patients. The investigators who powered ATTACH assumed infliximab would raise the proportion of patients with improved clinical status from 45% to 75%, a lofty thirty percentage point absolute gain.

ATTACH and co were discouraging enough to end TNF development in CHF, but investigators next shifted to coronary vascular disease. The most-positive study in this area was the CANTOS study, which recruited over 10,000 patients with prior MI and elevated hsCRP to receive placebo or the IL-1β inhibitor canakinumab at various doses. The multiplicity adjusted primary endpoint (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was met at the 150mg dose but not for the 300mg dose, though a quick glance sure looks like the 300mg dose has some juice. Success? Not so much.

The effect itself was pretty small - something like half a percent reduction over a 3-5 year period. You would have to treat at least a hundred and fifty people with canakinumab for many years to move the needle. Moreover, there was no difference in all cause mortality. I suspect this is because giving canakinumab was also associated with a small but significant increase in fatal infections or sepsis. In short, the benefits were marginal and the risks likely cancelled them out. All this at roughly $64,000 per patient per year, which modeling put at about $3.5 million per quality-adjusted life year, even after (perhaps erroneously) crediting an incidental lung cancer signal. To get canakinumab under a $100,000 per QALY threshold you would have to cut the price by more than 98%. The FDA rightly refused to approve it.

The concurrent CIRT trial investigated our favorite conventional synthetic DMARD, methotrexate, in a publicly funded study of nearly 5,000 patients with prior MI or multivessel disease. The CIRT study was stopped early for futility, failed to reduce inflammatory markers, and increased the risk of skin cancer. Again, the benefits were nonexistent, and in this case the risks make this a clearly-bad idea. In the discussion of CIRT the investigators said this:

Thus, although abundant data indicate that inflammation contributes critically to atherothrombosis, an important provisional hypothesis deriving from these two contemporary trials is that reducing the risk of cardiovascular events may depend on the pathway targeted

That may be true, but it is a cheeky statement to make in the wake of back-to-back failed randomized controlled trials. It also kept the dream alive. Reframing the failure of methotrexate as a failure to inhibit the right pathway and viewing CANTOS as a quasi-success meant that more studies needed to be done. That is not unreasonable, but I think it was the wrong take home lesson from CIRT and CANTOS.

We Already Tested IL6, Which Successfully Failed

ZEUS was not even the first IL-6 study of cardiovascular outcomes. The post-marketing study ENTRACTE, published in 2020, randomized 3,080 patients with seropositive RA and at least one cardiovascular risk factor to the IL-6 inhibitor tocilizumab or the TNF inhibitor etanercept. ENTRACTE followed patients for a mean of 3.2 years and had a primary outcome of MACE. To be fair, heart failure and MACE are not the same outcome. If IL-6 had a cardiovascular benefit, though, I would have expected it to emerge here. Instead, there were 83 MACE events in those randomized to IL-6 and 78 MACE events in those randomized to etanercept, with hazard ratio of 1.05. Tocilizumab failed to improve MACE against TNFs and raised LDL by 11%.

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The EBR Journal Club Companion applies my adapted version of the JAMA approach to critical appraisal to an important RCT in rheumatology. Each review covers four domains: Does this apply to my patients? What is the risk of bias? How great are the benefits and harms? And what didn’t they show me? Feel free to use this in your own journal clubs! This edition: PHOENYCS GO (dapirolizumab pegol in SLE).

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TRIAL: PHOENYCS GO (NCT04294667)

DRUG: Dapirolizumab pegol (a PEGylated, Fc-free anti-CD40 ligand fragment). Blocks the CD40-CD40L handshake that B cells use to get licensed, class-switch, and make the malhumors

DISEASE: Moderate-to-severe active SLE

DESIGN: Phase 3, randomized 2:1, double-blind, placebo-controlled, 177 sites, 25 countries, N=321 (208 DZP / 107 placebo), 48 weeks, adjunctive on standard of care

JOURNAL: Big Lancet, May 29, 2026

SPONSOR: UCB and Biogen

PRIMARY ENDPOINT: BICLA response at week 48. MET

THE TAKE: Dapirolizumab pegol just became the fourth biologic (after belimumab, anifrolumab, and obinutuzumab) to post a positive phase 3 primary in SLE. The key hierarchical secondary endpt at week 24 missed, so (as per usual for SLE) the analysis will be complicated. I suspect it gets approved but will struggle to gain traction in an increasingly crowded market.

Does This Apply to My Patients?

Who they enrolled: Mean age ~42, 93-94% female (unsurprising, still worth saying every time). Mean SLEDAI-2K 10.7-11.2, nearly all with BILAG grade A in one organ or grade B in two or more (~97-99%). Baseline TJC ~11-12, SJC ~6-7, CLASI-A ~6-7. This is an arthritis-and-skin study

Diversity: Race/region breakdown shades to Latin Amewrica (28-34%), only 1 in 5 came from North America and Black or African American representation ranged from 5-8% . Globally representative and solid on Latin America, but less-so for our typical American SLE population

Who they excluded: Patients with an isolated acute flare and no other risk factor for relapsing disease were kept out unless they had at least one enrichment criterion (prior flare, low complement plus anti-dsDNA, African American race, age under 25). Sensible design, meant to avoid enrolling spontaneous remitters who’d make placebo look artificially good.

Background therapy: Everyone had to be on a stable dose of glucocorticoids, antimalarials, or immunosuppressants at baseline, and mandatory glucocorticoid tapering kicked in by week 8, targeting ≤7.5 mg/day by week 24

Bottom line: This is a joint-and-skin lupus population with mandated steroid tapering. Pretty standard for a non-SLE study

What Is the Risk of Bias?

Randomization: 2:1, stratified by region, chronic-active vs acute-flaring, and baseline SLEDAI-2K (<10 vs ≥10). All reasonable enough

Blinding: Unblinded pharmacist prepped the infusion in an opaque bag; labs that could unblind (autoantibodies, Ig subtypes, complement, PK) were kept from investigators.

RED FLAG: Hypersensitivity reactions occurred exclusively in the dapirolizumab arm (6/213, all treated, none hospitalized) and infection rates ran meaningfully higher on drug. Smaller unblinding than some of our other drugs

Comparator: Placebo plus standard of care. At some point we need to mandate active comparators in this space. I suppose fine for regulatory purposes but not-so-much for me deciding the critical clinical question; how does this stack up against belimumab or anifrolumab?

Attrition: Completion was slightly better on dapirolizumab (85% vs 80%), which is a nice tell against a drug with a rough tolerability story. Non-responder imputation for the primary is the conservative choice (bueno)

Sponsorship: UCB and Biogen funded the trial, had a role in design, analysis, interpretation, and writing, and paid medical writers to assist. Typical modern drug development stuff

Bottom line: The mechanics are clean, but tapering got weird (placebo patients tapered slower). Remember - randomization is magical, but it only happens once. Post-baseline changes have a big impact on the week-24 miss

How Great Are the Benefits and Harms?

Primary endpoint (BICLA at week 48): 50% (103/208) vs 35% (37/107). Δ 14.6 (95% CI 3.3-25.8), p=0.011. NNT ~7. In the “not bad!” zone, but not revoluationary either.

Key secondary endpoint (BICLA at week 24, NOT MET): 47% vs 38%. Δ 7.9 (-3.6 to 19.4), p=0.18. This would be ignore-able, but it also closed the multiplicity gate. Every endpoint after this is nominal, not alpha-protected

Everything after the gate (all descriptive, not confirmatory): Severe BILAG flares through week 48, 12% vs 23% (~50% relative reduction, would have been a nice win run if not for the week 24 BICLA failure). LLDAS in ≥50% of visits, 24% vs 16%. DORIS remission at week 48, 19% vs 8% (more than double!). SRI-4 response, 60% vs 41%. Glucocorticoid taper to ≤7.5 mg/day among those starting above it, 72% vs 53%.

Benchmarks: That SRI-4 spread (60% vs 41%) sits in roughly the same neighborhood as anifrolumab’s TULIP-2 result and belimumab’s BLISS-52 result. Roughly. I’m not going to cross-trial-compare too hard (I did on the podcast lol, couldn’t help myself) because trials handle estimands and intercurrent events differently.

Safety: TEAEs 83% vs 75%, but serious TEAEs actually favored dapirolizumab numerically (10% vs 15%). Infections overall higher on drug (62% vs 52%), almost entirely driven by mild infections; severe infections were rarer on drug (1% vs 4%). Hypersensitivity in 3% (6/213), including 3 anaphylactic reactions meeting Sampson’s criteria; all resolved, none hospitalized, four discontinued. There was one adjudicated MI in a 53-year-old with triple-positive antiphospholipid antibodies and one death from gangrene-related sepsis, which was 57 days after the last dose of the study drug. Two cases of ophthalmic herpes zoster plus one herpes ophthalmic case, all in the drug arm

Bottom line: Mostly successful trial, but failing to run the board on hierarchical secondary endpoints is a bummer. This trial basically ran the table on “wierd 1 person safety signals that make me uneasy,” including MI, VTE, anaphylaxis, sepsis death, and funky viral things.

What Didn’t They Show Me?

All the secondary endpoints! It’s not their fault, but we run hierarchical endpoints for a reason. They failed to run it and now we won’t know whether secondary endpoints were significant or not.

RED FLAG: No statisitcal analysis of BICLA-48, LLDAS, DORIS remission, SRI-4, or glucocorticoid tapering

Patient Reported Outcome Measures: I’m not sure why, but SLE trialists seem particularly averse to telling us whether or not their drug met patient reported outcome measures. I suspect there are multiple reasons for this. For one, these studies use an astonishing number of outcome measures. The typical alphabet soup includes SLEDAI-2K, BICLA, SRI-4, SRI6, BILAG, DORIS, LLDAS, and CLASI. For two, medical therapy just does not work very well in SLE. If they routinely hit MCIDs for SF36, you would hear about it. And finally, I think SLE investigators are just not that into PROs.

The trial I wish I had: So many. For starters, a head-to-head against belimumab or anifrolumab feels necessary at this point. A SLE-LN trial is also an obvious omission. I assumed we would see that coming soon, but there are currently no registered SLE-LN trials of the drug. We also probably need a relatively large phase 4 study to evaluate safety. The PHOENYCS FLY study (NCT06617325) is already enrolling and the long-term extension (PHOENYCS GLIDE NCT04976322) will carry the safety story forward.

Practice Points

1. Dapirolizumab pegol works! It hit on its primary endpoint, but the missed key secondary at week 24 means the downstream numbers (DORIS remission more than doubled! steroid tapering way better!) are descriptive.

2. First-generation anti-CD40L antibodies got shelved over thrombotic events tied to Fc-receptor cross-linking… and we did see one adjudicated MI in a high-risk patient. That isn’t terrible, but we need to see more data (FLY and GLIDE incoming!)

3. This is an arthritis-and-skin trial population, not a renal one, and I don’t see a renal one on clinicaltrials.gov. That + softer efficacy + OK-but-huh?-safety will put it behind BEL, ANI, and OBI in my prescribing tree.

EBR Journal Club accompanies the Evidence Based Rheumatology Podcast. Disclosure: I prescribe many of the medications I discuss in this newsletter. I also participate in clinical trials, unbranded educational activities, advisory boards, and consulting. Views my own, not those of my employer.

On June 29^th of 2026, the New England Journal of Medicine (NEJM) retracted the ADVOCATE study, which described a phase 3 randomized controlled trial of the C5a receptor inhibitor avacopan (Tavneos) as compared to a prednisone taper. This marks the first time in the >200-year history of NEJM it has retracted a registrational study that served as the basis for regulatory approval. It also marks the first time it retracted a rheumatology trial.

This will be a pivotal moment for rheumatology, but I hope folks outside of rheumatology are also paying attention. This is not just a story about avacopan. It is a story about how the normal systems of sponsor oversight, contract research organization (CRO) data handling, peer review, regulatory approval, and post-publication scrutiny failed to detect a shocking case of data manipulation.

Re-Re-adjudicating Avacopan

For a full rundown of what happened, please read my recent substack on Re-adjudicating Avacopan or grind your way through the 24 page notice of opportunity for a hearing documentation that lays out the case in exhaustive detail. Here’s a brief summary:

ADVOCATE was a 52-week randomized controlled trial that pitted avacopan against a prednisone taper in patients with ANCA associated vasculitis. The company that owned avacopan at the time, ChemoCentryx, reported positive headline results in November of 2019, and the drug was approved in October of 2021. In January of 2026, the FDA asked for it to be withdrawn voluntarily. Amgen, which had acquired ChemoCentryx in 2022, declined.

In April the FDA published the notice of opportunity for a hearing (NOOH) that lays out its case. According to the FDA, when ADVOCATE was designed, the FDA told ChemoCentryx that approval would require superiority at week 52. After enrollment finished, the database was unblinded and two company employees, the chief medical officer (Dr. Pirow Bekker) and the director of biostatistics (Dr. Huibin Yue), saw the results. The critical week 52 superiority outcome had not been met (p = 0.1025).

What happened next is the part the FDA calls data manipulation. Rather than report the null result, the agency alleges, Bekker and Yue worked backward from the answer they wanted. They ran a post-hoc analysis that showed a mere 5 patients flipping their outcome would change the overall results of the trial (the “reverse fragility index” for those interested in this topic). They then identified 9 patients for blinded re-adjudication, which for complicated reasons could only land in avacopans favor. It worked; after re-adjudication, the headline result became statistically significant.

When ChemoCentryx filed for approval, they left out the original (clean) analysis, did not disclose that the data had been re-analyzed, and did not disclose the re-adjudication. The FDA’s notice disclosing these facts is unusually blunt. It accuses Bekker and ChemoCentryx of data manipulation, material omissions, and untrue statements of material fact.

This is serious, but it was also just one notice from one agency. When I wrote my last article, the FDA’s European counterpart (the EMA) was reviewing the data, NEJM still hosted an unblemished PDF of the ADVOCATE study on their website, and Amgen was asserting that the totality of the evidence continued to support approval. Things have changed. The lead authors of the ADVOCATE study, Dr. Peter Merkel and Dr. David Jayne, have now requested retraction, confirming the central fact: endpoint assessments were readjudicated after database lock and unblinding, without their knowledge. The NEJM posted the following:

“The two academic authors of the article by Jayne et al., Avacopan for the Treatment of ANCA-Associated Vasculitis, N Engl J Med 2021;384:599-609,¹ request retraction of the article because, according to an ongoing Food and Drug Administration investigation conducted after publication, and without the knowledge of these two authors, the primary end-point assessments in nine patients were readjudicated after database lock and trial unblinding. This was not disclosed in the article and is inconsistent with proper research conduct. The editors therefore retract the article.”

In short, the core of what the FDA accused ChemoCentryx of doing appears to be true.

Only The Market Always Knows

The reason we discovered this? Aggrieved finance bros.

We only know about this because the 2021 FDA advisory board raised concerns about whether the (already manipulated) efficacy data even supported approval. The advisory board was not aware of the re-adjudication because Bekker and Co did not disclose it. When they split on whether to recommend approval, ChemoCentryx stock collapsed by 80% and furious shareholders sued for securities fraud. In discovery, an expert named Marc Walton produced a report detailing what happened. This prompted the inquiry by the FDA.

That lawsuit was dismissed in August 2025, on summary judgment, without the court ever addressing the manipulation. It was a securities case, which means the question was never whether the trial data were manipulated, it was whether ChemoCentryx had misled investors. As far as I can tell, the court held that the securities-law claims failed. Maddeningly, the alleged misconduct Bekker and Co perpetrated was almost incidental. Had discovery been sealed this may never have come to light.

The one group that seems likely to dodge repercussions is the group of people who are most responsible for this mess. Pirow Bekker and Huibin Yue, for instance, have thus far avoided accountability for regulatory misconduct with multibillion-dollar repercussions. We do not know how much they personally profited from this, but securities plaintiffs alleged that ChemoCentryx CEO Thomas Schall sold roughly $40 million in stock while telling investors the company’s FDA interactions had been “straightforward and routine.” The gulf between “straightforward and routine” and “unprecedented NEJM retraction” is about as wide as you can get.

One of a Kind(ish)

The retraction of any paper is an embarrassing event. It is hard on the scientists who contributed to the paper, whose reputations may be tarnished. It is bad for the journal itself, suggesting inadequacies in their editorial process. It hurts the scientific establishment, which already struggles with a trust-problem.

That does not mean we should avoid retracting questionable studies. If anything, we need more retractions, not fewer. Retractions reflect a healthy scientific process, which is willing to correct itself when it errs. That said, they are objectively bad for everyone involved.

They are also remarkably rare. NEJM has published most of the best medical science since 1812; in the half-century PubMed has tracked it, the journal has logged only 27 retractions over roughly 88,000 papers. That’s an incredible record, something like 0.03%, or one retraction for every 3,300 published articles. It is rarer-still if you count only original research, and it is completely unprecedented if you look at randomized controlled trials that informed regulatory approval. As far as I can tell, this is the first time in the journal’s history that something like this has happened.

Prior retractions have mostly been driven by individual investigators who fabricated data. John Darsee, a Harvard cardiologist, faked data across over 80 papers and abstracts before his 1983 retractions. His hospital became the first institution forced to repay the NIH over research fraud ($122,371), and the scandal helped create the federal Office of Research Integrity. Anil Potti published genomic-signature work that was used in Duke cancer trials but later discredited; those trials were halted, and patients and families sued. Piero Anversa built a career on a cardiac stem cell that probably doesn’t exist, had 31 papers flagged, and cost his institution a $10 million federal settlement.

None of these high profile retractions approach the scope and implications of this one.

The Fallout Snowballs

The FDA led the charge on demanding action, but the momentum is building. The European Medicines Agency recently reached its own verdict, and on June 26, the EMA’s CHMP recommended revoking avacopan’s EU authorization. Like the FDA and now the NEJM, the EMA agrees that ADVOCATE cannot be relied upon. In Europe a CHMP recommendation goes to the European Commission, which typically follows CHMP recommendations.

In January of 2026 when the FDA first requested voluntary withdrawal, most of us did not know the details. That includes myself, most (all?) of my friends in the vasculitis community, and even many (most?) of the people at Amgen. In April when the FDA published the NOOH and laid out their rather shocking case for revoking authorization, I upgraded my concern to “probably will be withdrawn, but we’re not sure if the FDA is correct and perhaps there is more to the story.”

The NEJM retraction changes everything. The study would not have been retracted if the accusations of scientific malfeasance were demonstrably false, and Amgen has yet to refute the accusations leveled by any of the regulatory agencies. I suspect it’s all true. Bekker and Co appear to have cooked the books to cheat the system. The FDA and the EMA and probably the NEJM are furious about this. I am upgrading from “probably will be withdrawn” to “on borrowed time.”

From a medical perspective, I still think avacopan works for ANCA associated vasculitis. I outlined the case for that in my last substack. That said, it is hard to imagine starting any patient on avacopan at this point, and nearly every patient I have explained this to has discontinued it. This is unfortunate, because I do think some patients would benefit from receiving it. It may also be necessary from a public policy perspective. The FDA said it best:

“Withdrawing a drug under these circumstances is critical to protect the public health and the integrity of the drug approval process.”

The Tip of the Iceberg

The biggest question I have after reviewing all of this is a simple one: what if Thomas Schall was being honest? What if manipulating trial data so you can extract billions of dollars from the American public is, in fact, “straightforward and routine?”

That sounds hyperbolic, but consider this: we rely on a system where corporations that stand to make billions of dollars from regulatory approval run the very studies that result in regulatory approval. They fund the institutions that run the studies and they fund the companies that manage the data, help with recruitment, and hire medical writers to write the papers. They also buy reprints, pay open-access or publication charges when applicable, and participate in a publishing economy that benefits from high-profile industry trials.

Remarkably, the system appears to function reasonably well. We have established randomized controlled trials as a (mostly) required step for regulatory approval. Pharmaceutical companies generally run high quality randomized controlled trials, which generally deliver high quality scientific information. This process has brought about hundreds of revolutionary therapies that have saved millions of lives. I know beyond a shadow of doubt that TNF inhibitors work great for rheumatoid arthritis and that rituximab works great for ANCA associated vasculitis, because I see the results every day. Objectively, something about this system works great.

I would also note here that everyone I know in the pharmaceutical industry has been shocked by the details of this. Contrary to what some believe, most of the employees of pharmaceutical companies genuinely want to make the world a better place. Many of them are scientists or doctors who felt like they could have a bigger impact by building new drugs. All of them work in a regulatory environment that causes them to be remarkably cautious, over-indexing on compliance to a degree that would likely be surprising to the lay public.

That slows progress, but it is also good, because all of this requires an enormous amount of trust. We trust that the companies running these studies do not have the capacity to change the outcome of enrolled patients when they see something they do not like. We trust that any protocol deviations will be disclosed at submission and available to the relevant advisory committees. We trust the ostensibly independent trial oversight apparatus to catch deviations like this and report them. The entire regulatory process we have created depends on us placing a remarkable amount of trust in people like Bekker and Yue to behave ethically.

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TRIAL: INDIGO (NCT05662241)

DRUG: Obexelimab (no brand name yet) - bifunctional monoclonal antibody that co-engages CD19 and FcγRIIb to inhibit B-cell activity without depleting B cells

DISEASE: Active IgG4-related disease

DESIGN: Phase 3, double-blind, randomized, placebo-controlled; 194 patients (97 per arm); 52 weeks; mandatory GC induction then protocolized taper to discontinuation by week 8; subcutaneous 250mg injection weekly

JOURNAL: N Engl J Med, June 2, 2026.

SPONSOR: Zenas BioPharma (BLA submitted to FDA May 28, 2026)

PRIMARY ENDPOINT: Time to first adjudicated flare requiring rescue therapy - MET (HR 0.44, 95% CI 0.28-0.71, P<0.001; 27% vs. 55% flared)

THE TAKE: Obexelimab works! Whether it works well enough to earn a preferred slot alongside the already-approved inebilizumab or the likely-much-cheaper rituximab is a harder question. In a disease where most patients do well, perhaps less-B cell destruction is the way forward?

Does This Apply to My Patients?

Who they enrolled: Mean age 59, 67% male - jives with my clinical practice. 67% had recurrent disease, which is common for those on prednisone monotherapy but rare among those receiving any B cell depletion/inhibition. 93% had two or more organs involved. About 12% had prior rituximab (all > 6months prior), and median baseline IgG4 was ~625 mg/dL, so active serologically-supported disease.

Diversity: 57% Asian, 34% White, across 19 countries - reasonable global representation for a disease more prevalent in Asia. Worth noting: the obexelimab arm skewed more Asian (61% vs. 53%) and the placebo arm more White (40% vs. 28%). The authors flag this as a potential generalizability concern, which is fair. I’m not worried about it; like math, B cells are the same in every country1

Who they excluded: Active infection, prednisone >60mg within 4 weeks, B-cell-depleting therapy or other immunomodulators within 6 months. All reasonable.

Background therapy: Protocolized GC induction for all patients, then mandatory taper to discontinuation by week 8. Concomitant immunosuppressants prohibited throughout. This taper is likely faster than you’d use in the real world, which is common in trials these days (need people to flare to show a benefit)2

Bottom line: Applies well to the steroid-dependent relapser who hasn’t failed B-cell depletion, which is going to be the majority of patients. Less clear for patients already on background immunosuppression or for those who failed rituximab or inebilizumab.

What Is the Risk of Bias?

Randomization: 1:1, stratified by organ count and disease status (newly diagnosed vs. recurrent). Baseline characteristics were well balanced except for the racial imbalance noted above. Methodologically clean.

Blinding: Double-blind with matching subcutaneous placebo. The main unblinding risks are arthralgias (19.6% vs. 11.3%) and urticaria (6.2% vs. 1.0%) - both visible enough that patients could piece together their assignment. They tried to mitigate that (the primary endpoint required agreement between the treating investigator AND an independent adjudication committee) but unblinding is unblinding.

Comparator: Placebo plus the same mandatory GC taper, with rescue steroids permitted for confirmed flares. The placebo flare rate (~55%) is consistent with the natural history of IgG4-RD and matches the MITIGATE placebo arm (~60%), so the control group performed as expected. There’s no active comparator arm, which was OK when this was designed but probably not-ok going forward

Attrition: 88.7% completed 52 weeks. Adverse-event-related discontinuations were three times higher in obexelimab than placebo (9.3% vs. 3.1%).

Sponsorship: Fully sponsor-funded; Zenas BioPharma employees as co-authors; sponsor-funded medical writing. Standard for a Phase 3 registrational trial. Noted.

Bottom line: Credible approach. Dual-adjudication is nice but doesn’t entirely fix unblinding, which is a relatively small issue here. I think this generalizes well and is a reasonable design.

How Great Are the Benefits and Harms?

Primary endpoint (time to first adjudicated flare, 52 weeks): 27% vs. 55% flared; HR 0.44 (95% CI 0.28-0.71), P<0.001. NNT ~4. Impressive for a disease that had no approved therapy until 14 months ago! Kaplan-Meier separation began around month 3, which makes sense; steroids work great, but when you take them away flares are common.

Key secondary endpoints (all MET hierarchically):

• Annualized adjudicated flare rate: 0.34 vs. 0.70/year; rate ratio 0.48 (P<0.001)

• Complete remission at week 52: 37.1% vs. 19.6%; NNT ~6 (P=0.005)

• Cumulative GC rescue dose: 329.5mg vs. 929.8mg; 65% reduction (P=0.004)

• GTI Cumulative Worsening Score: 28.2 vs. 39.6; difference 11.4 points (95% CI 1.7-21.1)

That last one deserves a note: the MCID for the GTI-CWS is 15 points. The observed difference (11.4) didn’t reach it, but I bet it would if you compared typical-steroids to minimal-steroids+OBEX.

Benchmarks: MITIGATE (inebilizumab, NEJM 2025) - the first Phase 3 trial in IgG4-RD - found 10% vs. 60% flare rates (HR 0.13, NNT ~ 2-3). Cross-trial comparison is fraught, but we always do it. This also makes sense with my priors. Killing all the CD19 B cells with inebiliuzmab is likely more effective than simply (mostly?) suppressing them. I would also bet that it is more toxic.

Safety: Overall AE rates similar (98% vs. 96%). Serious AEs were lower in obexelimab (10.3% vs. 18.6%), which is directionally reassuring and probably reflects efficacy + steroid sparing more than safety per se. More common with obexelimab included arthralgias, hypersensitivity, diarrhea, urticaria, pyrexia. I suspect that is people just receiving less steroid and so feeling more symptoms, which is a win? I think? There were no deaths and I do not think the 3 cancers in the OBEX group are related to the drug (squamous-cell carcinoma, prostate cancer, and a renal-cell carcinoma).

Bottom line: NNT of ~4 for flare prevention is good! The numerical comparison with inebilizumab is less flattering from an efficacy standpoint. The cancer signal is likely noise

What Didn’t They Show Me?

RED FLAG: No patient-reported outcomes. The GTI gives us something on steroid toxicity, but where did my PROs go? Knowing 37% achieved complete remission is useful; did that (and the steroid sparing effect) actually improve their quality of life?

The trial I wish I had: Obexelimab vs. inebilizumab vs. rituximab. The pitch for each is pretty clear; rituximab is dirt cheap, inebilizumab kills all the things; obexelimab works with less killing. I would also love to see a study about withdrawing this among patients who develop bad infections. Can we actually “stop the drug” in a way that matters? For both RTX and INE, you’re just in it to win it. Being able to pull back could be a real feature, if it’s real.

Other gaps: 52 weeks of blinded data for what will be a years-long maintenance therapy. No data after prior B-cell depletion. No data with concomitant immunosuppression. And while the ongoing 3-year open-label extension will fill some gaps, OLE data in a self-selected, monitored cohort always looks better than real-world durability. From published protocols it does not look like we’ll get re-randomization.

Bottom line: Solid study with some interesting implications. IgG4-RD has moved into the “only comparative studies are ethical from here forward zone” remarkably quickly. Curious to see the PROs and we’ll probably have to leave it to RWE to see how these stack up against each other.

Practice Points

1. Obexelimab has a real, clinically meaningful effect in active IgG4-RD. An NNT of ~4 for flare prevention and a 65% reduction in rescue GC exposure are compelling numbers. I would expect FDA approval

2. The central clinical question isn’t whether obexelimab works; it’s where it fits relative to inebilizumab and rituximab. Cross-trial inference suggests inebilizumab is more potent (HR 0.13 vs. 0.44), but that cuts both ways. It is also likely more toxic. This may be a particularly good option for folks with infection history, hypogammaglobulinemia, or those who really need their vaccinations (ie older, frailer).

3. I do not think patients should receive csDMARDs for IgG4-RD. The data for B cell depletion across two trials and lots of RWE strongly favors RTX, INE, or OBEX.

EBR Journal Club accompanies the Evidence Based Rheumatology Podcast. Disclosure: I prescribe many of the medications I discuss in this newsletter. I also participate in clinical trials, unbranded educational activities, advisory boards, and consulting. Views my own, not those of my employer.

TRIAL: REPLENISH (NCT05767034)

DRUG: Secukinumab (Cosentyx): a fully human monoclonal antibody against IL-17A, already approved across psoriasis, PsA, axSpA, and a handful of other indications

DISEASE: Relapsed polymyalgia rheumatica

DESIGN: Phase 3, double-blind, 1:1:1 randomized, placebo-controlled; N=381 (127/arm); 52 weeks; 148 sites, 28 countries

JOURNAL: NEJM, June 3, 2026 (NEJMoa2602567)

SPONSOR: Novartis

PRIMARY ENDPOINT: Sustained remission at week 52 (SEC-300 vs placebo). MET (SEC-150 met it too)

THE TAKE: PMR finally has a second mechanism, and I think I would favor it over an IL6 inhibitor. REPLENISH was bigger and cleaner than SAPHYR with a real but modest benefit (NNT ~5). Surprisingly, 150 mg is enough and I would favor that dose. Fungal infections were a known problem beforehand and will be an ongoing concern after. Regardless, I expect FDA to approve

Does This Apply to My Patients?

Who they enrolled: Relapsing PMR, so another “not necessarily upfront” trial. Entry required a relapse while tapering prednisone (≥5 mg/day) in the prior 12 weeks, plus an elevated CRP or ESR. Mean age 70, ~70% women, median 1.2 years since diagnosis. Very similar to SAPHYR, the comparison-begging trial in this space

Diversity: ~70% White, ~13% Asian, ~16% other.

Who they excluded: Anyone with a whiff of GCA (roughly 1 in 8 patients with PMR will have GCA, so this is “pure” PMR). They also excluded prior IL-6 inhibitor failures, so we don’t know whether secukinumab rescues a sarilumab non-responder. “Refractory-ish” is my vibes.

Background therapy: Stable methotrexate (≤15 mg/week) was allowed and about a third of patients were on it, balanced across arms. FWIW I don’t think MTX works in this disease, really at all. All three arms got the same protocolized 24-week prednisone taper from 10 or 15 mg, depending on their dose at entry

Bottom line: If your patient keeps bouncing on the taper (and has no GCA features - more on that in the next podcast), this trial is for them.

What Is the Risk of Bias?

Randomization: 1:1:1 to SEC-300, SEC-150, or placebo, stratified by region and baseline prednisone dose. 474 screened, 381 randomized, arms well balanced.

Blinding: Double-blind, placebo-controlled, matched injection schedules. Critically important issue to note: ESR and CRP were concealed from investigators and left out of the primary endpoint, designing out the unblinding-by-biomarker problem that haunts IL-6 trials (and drives me crazy)

Comparator: Placebo plus a 24-week taper. I think this is still reasonable and ethical in 2026. We haev options, but most of my relapsing patients still get steroid monotherapy (more and more getting IL6 or leflunomide as well)

RED FLAG: No active comparator. We now have two working mechanisms in PMR (IL-6 and IL-17A) and exactly zero head-to-head data. The trial answers “is secukinumab better than nothing?” not “What’s the best DMARD to add?”

Attrition: 76% completed treatment, with higher dropout in the placebo arm (32% vs 17-21%), generally what you’d expect when placebo patients flare and bail for rescue. Discontinuers were counted as non-responders and a tipping-point analysis didn’t tip (some nice graphs in the supplement). Reasonably robust and if you’re going to have high dropout, you want it to be in the placebo group.

Sponsorship: Novartis funded it, designed it, and ran the analysis; the first and last authors drafted the manuscript. Standard pharma-sponsored phase 3.

Bottom line: Internal validity is good, design is a skosh better than SAPHYR, depending on how you feel about the steroid tapers

How Great Are the Benefits and Harms?

Primary endpoint (sustained remission at week 52): SEC-300 41.2% vs placebo 20.4% (Δ ~21 points, NNT ~5); SEC-150 40.6% (NNT ~5). Both P<0.001. Not bad! And the two doses are interchangeable (41.2 vs 40.6), a theme that repeats on every endpoint. (Favor 150.)

Compared to SAPHYR? REPLENISH’s primary left CRP/ESR out (correct); SAPHYR’s required CRP normalization (aggravating) but reported CRP-less results as well (still worked). So the primary isn’t apples-to-apples with the sarilumab data. The matched endpoint (complete sustained remission including biomarkers): SEC-300 28.2% vs placebo 4.7% (NNT ~4). That 28% lands right on sarilumab’s 28% in SAPHYR, albeit against a much lower placebo (4.7% vs 10%). The low placebo rate is likely due to a lower taper (ie 24 weeks in REPLENISH vs 52 in SAPHYR), hard to interpret. You should never compare between trials, but we kind of always do. I see these as roughly similar based on this?

Steroid sparing: Adjusted annual cumulative prednisone 1604 mg (SEC-300) vs 2093 mg (placebo), ~489 mg/year less, about 20%. This is much less than SAPHYR, but SAPHYR required a much-faster taper for the treatment group. I like that because it’s a high bar; I don’t like that because it confounds the “steroid sparing” claim (ie maybe people were just forced onto less steroid?). The steroid sparing in REPLENISH is helpful but not transformative; the Glucocorticoid Toxicity Index agreed, GTI-AIS of 32 vs 84.

Escape/rescue and PROs: Half the secukinumab patients still needed escape or rescue treatment (51% vs 76% placebo; HR 0.5). Fatigue and function both favored secukinumab (FACIT-Fatigue ~6 points, HAQ-DI ~0.44), clearing usual minimal-important-difference thresholds, which is a big deal to me.

GCA? This trial excluded people with GCA, but it is notable that virtually nobody developed GCA either. I honestly would not have expected much of that - I’m skeptical of the GPSD business - but I think it is worth noting that people who start steroid +/- an IL17 rarely ‘progress’ to GCA.

Safety: The reassuring part: serious infections were flat across arms (~3%), serious AEs were flat (13.5/15.9/14.2%), and fewer secukinumab patients discontinued for AEs than placebo. As expected, fungal infections ran higher on secukinumab (6-10% vs 3%, the expected IL-17 candida tax). One SEC-150 patient died of cryptococcal meningitis, which is pretty disturbing… but perhaps somewhat idiosyncratic? The investigators pinned it on 15-plus years of steroid immunosuppression and called it “potentially related” (See page 26 of the supplement for that little gem). I’m torn. I haven’t seen that with SEC, but also a fatal opportunistic CNS fungal infection isn’t a great look. Hypersensitivity was up as well (14% vs 9%), all nonserious.

Bottom line: A genuine, modest, dose-independent benefit with a fair steroid-sparing signal, shadowed by a fungal-infection story that may carry outsized weight

What Didn’t They Show Me?

RED FLAG: No efficacy data beyond 52 weeks and no withdrawal data. Re-randomization at week 52 should be required for pretty much any study that could ethically do it.

The trial I wish I had: Secukinumab versus sarilumab, head-to-head, same taper. Also, secukinumab upfront for newly diagnosed PMR. Oh also secukinumab vs leflunomide. Honestly there are an infinite of needed-trials in PMR. I’ll take a nice phase 3 any day, but long term we need to know (1) which steroid sparing is best and (2) which patients actually need it.

Other gaps: No signal on who responds; 59% didn’t sustain remission and nothing predicts the 41% who did. Nothing on the IL-6-blocker-failure patient. And nothing on the PMR-GCA overlap, by design.

Bottom line: They proved secukinumab beats steroids alone over one year for relapsing patients. Lot’s more to do, but happy to see a big phase 3!

Practice Points

1. Secukinumab works in relapsing PMR (sustained remission 41% vs 20%, NNT ~5) and is the first non-IL-6 mechanism to do so. It’s steroid-sparing (~20%, ~489 mg/year), not steroid-eliminating; half of treated patients still needed rescue.

2. The 150 mg and 300 mg doses are indistinguishable on every single endpoint. If and when this is approved, there’s no efficacy case for 300 mg. I would not have run a trial with both doses (seems wasteful), but the FDA was right and I’d use the 150mg dose to (hopefully) cut down on toxicity.

3. Watch fungal infections in your elderly, steroid-exposed patients. Serious infections weren’t elevated overall, but a fatal cryptococcal meningitis plus a 6-10% incidennce (up from 3% in placebo) is notable

4. I’m not sure where this stands? I would rather take an IL17 than an IL6 myself, so I think I would favor this over sarilumab going forward. I’d expect approval for PMR in the near future.

In late July the FDA’s Pharmacy Compounding Advisory Committee will spend two days deciding whether a handful of “peptides” should move one step closer to legal compounding. The headliner is “BPC-157,” a substance whose PubMed footprint now runs north of two hundred papers. Those publications include fewer than 40 actual humans, there is no identified high-affinity receptor for BPC-157 in the human body, and no randomized trial has ever demonstrated any evidence that it works. So why is the FDA spending time on this topic?

Mostly because it’s “having a moment.” BPC-157 has been a frequent guest on the Joe Rogan podcast, receives backing from Gary Brecka (a purveyor of nasal-sprayed BPC-157 for $375 a pop), and got a boost on Andrew Huberman’s popular neuroscience-ish podcast. The formula is pretty simple: health-guru-dude shares a personal anecdote on a podcast segment, the segment gets picked up and shared through social media, and one of my patients is now spending a small fortune to have their Lyme disease cured by BPC-157.

To date the reporting on BPC-157 has been surprisingly credulous, with a few notable exceptions. This will not be one of those pieces. I think BPC-157 is an expensive placebo being shilled for cash on the back of anecdotes and vibes. It is pseudoscientific nonsense of the first order. Despite that, your patients (and the FDA) will be talking about this a lot. This one turned into a wild ride - hope you enjoy!

What’s a peptide and why is it so peppy?

Let’s start with the word “peptide,” because I think it’s carrying an outsized amount of weight. “Peptide” is a short and punchy word. “Peptide” rolls off the tongue and suggests it’ll give you a pick-me-up; like Dr. Pepper, it’ll put some pep in your step. Many non-medical people (and apparently some medical people as well) seem to think peptides are some exciting new discovery in the world of medicine. This is ridiculous. Peptides are not some novel biomedical invention. A peptide is just a short chain of amino acids, bigger than a single amino acid and smaller than a full protein. That’s it.

As a drug class, peptides are about as far from fringe as it gets. Notable peptides include oldies-but-goodies like insulin, hospital workhorses like vasopressin, and cancer drugs like leuprolide. GLP1’s like semaglutide and tirzepatide are also peptides, which I suspect adds to the confusion. “Everyone is on peptides now!” These are neither new discoveries nor fringe science; they are some of the most important drugs we have, and they’ve been around for a long time. BPC-157 is just another peptide - a string of 15 amino acids that is selling like hot cakes.

I should note here that being a string of 15 amino acids is also remarkably un-special. Amino acids can be arranged in any order you like, so a chain of 15 amino acids has 20^15 possible sequences, or about 3.3 x 10^19, which is 33 quintillion possibilities. A few of those 33 quintillion might be a blockbuster drug. Some might (probably would*) be carcinogenic or outright poisonous. The vast, vast majority (many quintillions of them) would be completely inert: random strings of amino acids in some incoherent order that your body simply metabolizes back into its constituent parts and repurposes into something that’s actually useful. The word “peptide” tells you nothing about the chemistry of whatever you’re putting into your body, and nothing at all about the evidence for its utility.

Just a Guy with a Dream

BPC-157 existed long before podcasts, iPhones, or really even the internet for that matter. I strongly recommend the recent reporting by Undark if you want the full rundown. The quick summary is remarkably fun and occasionally (unintentionally?) hilarious. In short, in 1975 a medical student in Zagreb named Dr. Predrag Sikiric decided that the stomach, which can be injured by stress, must logically make its own protective anti-stress compound. He set out on a quest to discover this substance, which sounds glamorous and exciting but was really just him subjecting hordes of rats to various smelly liquids he isolated from various gastric juices. After years of effort he eventually isolated what he called “Body Protection Compound 157,” or BPC-157 for short.

When they first isolated it, the scientists in Zagreb did not have the tools to fully characterize it. The 15-amino-acid sequence they eventually settled on (GEPPPGKPADDAGLV) is published and public; what was never published in any reproducible way is a parent protein or the original isolation. Moreover, no gene encoding the peptide’s particular sequence has ever turned up in the human genome or the gut microbiome. Asked recently whether the molecule is even what the original team believed it was, one of Sikiric’s collaborators told Undark, “As long as it works and has no side effects, who cares?”

If you read my work, you know I’m not big for pathophysiology. Listen to my episode a while back about TNFs and heart failure; we went from thinking they would reverse it completely to worrying that TNFs actively cause exacerbations. This is different because the entire case for BPC-157, as far as I can tell, boils down to “I know someone who took it and was cured of something. Also, it’s real science.” Anecdotes are no basis for public policy, and since when do we not care that the origin story of a molecule appears to be nonsense?

Even a cursory read through the established facts is pretty shocking. Fifty years on, three decades of publishing, and still nobody has shown what BPC-157 actually binds. A 2026 biopharmaceutical review in a journal I do not trust said there is no identified high-affinity receptor, no validated molecular target, and a wide disconnect between the tidy preclinical effects and any coherent pharmacology. When even quasi-predatory journals are publishing skeptical think pieces, you should pause a beat.

Almost every peptide we use works by latching onto a specific receptor, the way insulin finds the insulin receptor. The claim that BPC-157 can heal half the body’s ailments without any evidence that it has any actual target in the human body is an astonishing claim. I am usually happy to hold a mechanism loosely and let the data lead. But “we can’t find a receptor, can’t name a target, and can’t find a gene for it in your genome” is just giving up on science entirely.

Speaking of #Science

I would forgive BPC-157 its shady origin story if not for its remarkably shoddy (nonexistent?) clinical development program. Over fifty years of hype, and BPC-157 has never published a single double blind randomized controlled trial. Forget DBRCT - it has never published any controlled efficacy trial of any variety in human beings. As far as I can tell, here is the actual human ledger:

• Two industry trials from the early 2000s, when the Croatian firm Pliva developed BPC-157 for inflammatory bowel disease. They ran a Phase I safety study of rectally administered BPC-157 and a randomized, double-blind, placebo-controlled Phase II enema study in ulcerative colitis. Neither were published and Pliva was so excited about the results it abandoned the drug entirely

• One Phase I safety and pharmacokinetics trial of oral BPC-157, registered in 2015, that has no public results and appears to have been withdrawn or abandoned

• Three small and nonrandomized uncontrolled pilot studies from a single for-profit clinic in Florida, which included a 16-patient knee-pain chart review, a 12-woman interstitial cystitis study, and a small intravenous safety study

• One legitimate entry: a registered Phase 2 trial of BPC-157 for acute hamstring strain. I’m actually curious to see how that one plays out.

My first plan for this topic had been to do a quick podcast on the data behind BPC-157, but there is literally nothing to talk about. There is no data. There are no studies. There is no clinical science, and the “basic science” is remarkably alarming.

You Can’t Fix Perfection

I just alluded to that mountain of papers, almost none of which merit even passing discussion in a journal club. So what, exactly, is all that publishing about? I scraped PubMed in May and June of 2026, discovering 211 BPC-157 records. This included 166 original reports, 45 review articles, and not a single study tagged as a clinical trial. Charted by year, the literature tells the whole story.

BPC-157 PubMed publications by year and study type, 1993 to June 2026 (n = 211)

First, the post-2020 surge in the figure is driven by a proliferation of review articles that recycle the same data from the same rodent experiments. The ratio of review articles to original studies is something like two to one in 2026. We are not seeing an explosion of new research; we are seeing an explosion of hype, repackaging older studies.

Second, the original research seems determined to prove James Heathers’s “In Mice” meme. The majority of the studies (see above in red) are preclinical studies in rodents, the vast majority of which have been done by a single research group in Croatia, which has been rinsing and repeating the same approach for decades. Feel free to click through yourself, but here are some entertaining highlights:

• BPC-157 shortens bleeding time in rats and also boosts platelet aggregation and clot formation.

• BPC-157 treats high blood pressure AND low blood pressure, occasionally in the same rat

• BPC-157 rescues rats from too much nitric oxide AND too little. It reverses the effects of L-arginine (the NO precursor) and L-NAME (the NO blocker). Whatever your nitric oxide problem, the peptide is somehow the answer.

• BPC-157 is an antidepressant in the forced-swim test, anxiolytic in the light/dark test, and active against both the positive-like and negative-like symptoms of schizophrenia. One molecule, the entire psychiatric formulary.

• BPC-157 blocks amphetamine stereotypy and rescues haloperidol-induced catalepsy

• BPC-157 is anti-nociceptive in an incisional-pain model but if you need it in a pinch it counteracts morphine’s analgesia and lithium toxicity

• BPC-157 corrects basically any electrolyte problem in any direction: hyperkalemia, hypermagnesemia, and honestly you should just read this litany of various electrolyte disturbances that BPC-157 handles with ease

• BPC-157 reverses both atropine mydriasis and drug-induced miosis in the same rats and guinea pigs.

• BPC-157 antagonizes thiopental, counteracts lidocaine toxicity, and shortens corneal numbing.

• BPC-157 works in rats, mice, rabbits, dogs, guinea pigs, broiler chicks and - I’m not even kidding - saves honeybee colonies from infestation

The volume, breadth, and audacity of these assertions strain credulity to the breaking point, but somehow they are only the second most incredible thing about BPC-157. The most incredible thing about BPC-157 is that nothing bad (supposedly) has ever happened to any rat (or human or honeybee) who has been exposed to it. I found 34 papers that commented on safety, asserting BPC-157 to be “safe,” “well-tolerated,” or “harmless.” Sikiric’s group has actually claimed that the LD1 dose has not been achieved, essentially asserting that no reasonable quantity of BPC-157 even could be harmful.

This would be an astonishing discovery in the history of science; a highly active molecule with a perfect safety record. It’s a molecule that has a plasma half-life under thirty minutes that nonetheless fixes whatever ails you, in whichever direction you happen to need it fixed, with no side effects whatsoever. And also fixes the bees. It is magic beans or it is pseudoscientific nonsense. I am betting on pseudoscientific nonsense.

Compounding Interest

Why then has the FDA scheduled a hearing to discuss it? The answer has almost nothing to do with science and almost everything to do with the bureaucratic weirdness of compounding laws.

Compounding pharmacies make customized medicines for individual patients, and under section 503A of the Food, Drug, and Cosmetic Act, a pharmacy can compound from a bulk substance only if that substance has an official quality monograph, is a component of an FDA-approved drug, or has been formally added to an approved “bulks list.” BPC-157 qualifies on none of those counts, which is why the FDA placed it in “Category 2” of its 503A bulk-substance review in September of 2023. This is a list of nominated substances that may present significant safety risks in compounding. For BPC-157, the agency cited the potential for immunogenicity, peptide-related impurities, problems characterizing the active ingredient, and a lack of safety data for the proposed routes of administration. Nothing in the published literature has changed.

What is happening this July is that the agency has reopened the question and convened its advisory committee to weigh whether BPC-157, along with six other nominated peptide-related bulk substances, should be added to the 503A bulks list. For BPC-157 the proposed indication is ulcerative colitis, a callback to that abandoned Pliva program. The committee will provide a recommendation, which is not FDA approval or an endorsement of its effectiveness. Even a favorable vote would still require separate, formal rulemaking before anything actually changes.

I suppose a better question is whether that prior determination should have happened at all. It’s not entirely clear to me that BPC-157 is unsafe. If I had to guess, I would say it is a functionally inert string of amino acids with no real safety or efficacy signal at all. This puts me in the strange position of neither believing it works nor believing the FDA is obligated to ban it. On balance I think the FDA should ban it, but the libertarian argument for letting not-obviously-dangerous-things exist seems reasonable.

There is also an upside to allowing legitimate compounding. A large and largely unregulated gray market for BPC-157 already exists. My patients are buying unstandardized and contaminated research-grade vials of who-knows-what off the internet and injecting it into themselves. I have no idea if BPC-157 is safe, but it would be nice to know my patients are actually receiving it from a licensed pharmacy.

Rheum for Doubt

It is fun to point out the madness of BPC-157 in a Substack. It is a lot harder to sit in clinic and discourage someone from using a therapy that their friends and family and favorite podcasters swear by. I have always had three rules for complementary therapies:

1. The therapy is not dangerous.

2. The therapy does not substitute for things I know work.

3. The therapy does not break the bank.

For starters, BPC-157 and the current crop of peptides do not seem to be obviously dangerous, in the way that Diet Coke and Twinkies and acai berries are not obviously dangerous. The unfortunate truth is that big risk signals (let’s say the kind you get from drinking antifreeze) can be spotted from the anecdotal experience of people in the world just trying things, but small-but-serious risk signals (let’s say cardiovascular disease with tofacitinib) are really hard to identify without a proper trial or a proper observational study. Neither of those exist for BPC-157, but I am reasonably confident it is at least safer than drinking antifreeze.

As for pushing out things I know work? This will be highly patient-dependent. I have patients doing peptides on Monday and showing up for their rituximab on Thursday. For those patients, I tend to take a laissez-faire attitude toward complementary therapies that are not obviously-dangerous. It gets more complicated when someone wants to use peptides instead of rituximab in a case where I know rituximab will benefit them. Embracing dual-use in a situation like that may be the right tactic, if for nothing else than to maintain your own credibility. Then of course there is the third group, the one you likely do not meet in your clinic until it’s too late. The people who don’t trust the medical establishment at all and are trying to treat their autoimmune hepatitis with peptides. The tragedy of cases like that fuel a lot of the frustration doctors have with “complementary” medicine.

Breaking the bank is complicated and, again, patient-dependent. The numbers add up fast. Brecka’s nasal spray runs $375, the patch version $575 a month, and almost nobody takes a single peptide. The standard advice is to “stack” BPC-157 with TB-500 and whatever else the podcast of the week pushed that day. None of it is covered by insurance. At least in my experience, the patients most drawn to miracle cures are often the ones least able to afford them. When I hear stories of people skipping vacations to get their BPC-157, I typically provide some gentle pushback.

At the end of the day, doctors can only do so much to oppose pseudoscientific nonsense. If you fight too hard against it, you risk losing your chance to do something useful. Determining what therapies will be available if people want to pursue them is not my job; that responsibility lies with the FDA. We’ll see what they decide.

Where This Leaves Us

1. There is no credible clinical evidence that BPC-157 works. After three decades and more than two hundred papers, there is still no published randomized controlled trial showing efficacy. “Lots of publications” is not the same as “evidence.”

2. If BPC-157 doesn’t trigger your snake-oil antenna then nothing will. It reportedly fixes bleeding and clotting, high and low blood pressure, ulcers and tendons and nerves and tumors, all with no meaningful side effects. That is either one of the great therapeutic discoveries in modern medicine or the too-often melding of shoddy science with the potential for financial gain.

3. I suspect most peptides are safer than the FDA fears, but that is because they just don’t work. Peptides are not magic sauce or a novel invention. They’re just a bunch of amino acids. Most will be harmlessly metabolized away.

4. The FDA meeting is about access, not efficacy, but the grifters will sell the difference. A favorable vote would not make BPC-157 FDA-approved and would not prove that it works; it would clear one compounding obstacle. It will also be seen as regulatory endorsement.

5. If the peptide world is so sure it works, run the trial. Drugs with miraculous benefits require very few patients to meet bars for statistical significance. If this is a parachute, it won’t take much to prove it.

April Showers Bring May TULIPS

Back in October 2021 I wrote my second-ever newsletter (at Figure 1) about the original anifrolumab approval, asking whether we should be excited about them. My answer at the time was a hedged maybe-for-skin: anifrolumab offered an underwhelming but measurable benefit in moderate-to-severe SLE, the signal was concentrated in skin disease and steroid sparing, and there was no convincing role for it in NPSLE or lupus nephritis.

The TULIP trials also pulled a classic endpoint-shenanigans move, deciding to swap one esoteric outcome measure (the SRI-4) for an equally esoteric outcome measure (the BICLA) just prior to unblinding. This is technically permissible and I do believe they did this prior to unblinding. TULIP-2 actually hit on both SRI-4 and BICLA; if they knew the results, they likely would not have pulled any shenanigans at all (it was ultimately an unnecessesary shenanigan). It still kind of gives me the ick and has not aged well =in light of the rather astonishing shenanigans Chemocentryx was pulling around the same time.

On April 27, 2026 the FDA approved a subcutaneous autoinjector formulation of anifrolumab, the “Saphnelo Pen,” for adults with moderate-to-severe SLE on standard therapy. The approval came after a complete response letter in February and was based on the phase 3 TULIP-SC trial, published in Arthritis & Rheumatology in January 2026. I would expect your local specialty pharmacy to have access by late June.

The upside is pretty clear; same drug, same indication, smaller needle, no infusion chair. The trial was pretty clear; anifrolumab SC works about as well as anifrolumab IV. The more interesting question for today is what we have learned over three TULIP trials about not only the drug, but also the pathophysiology of SLE itself.

TULIP-SC: a brief tour

TULIP-SC randomized 367 adults with moderate-to-severe SLE 1:1 to once-weekly 120 mg SC anifrolumab or placebo for 52 weeks, on top of standard therapy. The population was basically the same as TULIP-1 and TULIP-2 in every way that matters: no active severe lupus nephritis, no severe NPSLE, mostly IFN gene signature high at screening (for whatever that’s worth), nearly half the cohort on ≥10 mg/day of prednisone-equivalent at baseline. Same primary endpoint as TULIP-2 (BICLA at week 52).

Not surprisingly, they found about the same result. The absolute difference in BICLA response was about 20%, equating to roughly 1 additional BICLA responder for every 5 patients treated. For a trial in SLE, that’s actually pretty good! The trial also hit on the steroid-tapering endpoint (~20% delta favoring anifrolumab patients; those who started at baseline ≥10 mg/day got to ≤7.5 mg/day and stayed there from week 40 to 52), an effect nearly identical to TULIP-2’s 51.5% vs 30.2%). Similar story for DORIS remission (14% difference favoring anifrolumab), LLDAS (14% difference favoring anifrolumab), and of course the previously-abandoned SRI-4 (~15% difference favoring anifrolumab). CLASI-50 favored anifrolumab (76.9% vs 61.2%) and I’m guessing that’s what drove lots of the BICLA/DORIS/LLDAS differences above.

The failures were similar to the failures from the prior studies. TULIP-SC did not clearly hit on flare outcomes, reflecting the broader TULIP program where flare data has been mixed, although pooled analyses favor anifrolumab and I suspect it works. Safety was also similar, with a little extra herpes zoster for the anifrolumab group (about 1 in 35 patients) and injection site reactions in 1 out of every 6 (likely causing some unblinding). You could quit here and call it a success, which I think is pretty fair. This is a useful drug that now comes in a useful formulation, which brings about statistically significant benefits for various (opaque) SLE measures and clinically meaningful benefits benefits for patients with SLE affecting their skin.

What three TULIPs taught us about lupus biology

Perhaps a more interesting angle on the ongoing TULIP story is what we’ve learned about SLE biology. The original case for anifrolumab was a pathophysiology case. SLE is an IFN-driven disease, the story went. Blocking the IFN receptor should help the patients with the most IFN activation more than the patients with less. Three positive-by-BICLA trials later, that story has not held up.

In the pooled TULIP-1/2 subgroup analysis (Vital et al., Lupus Sci Med 2022), “interferon signature high” patients showed an 18% difference in the BICLA (whatever that is) as compared to a 17% difference in the total population. That’s basically a rounding error’s difference for what was purported to be a central driver of SLE immunopathology. Meanwhile, in the same paper, Asian race (29% treatment difference) and abnormal baseline serologies (23%) showed bigger subgroup signals than the biomarker that’s supposed to identify responders.

Checking interferon signatures is also not something many of us do with any regularity. I suspect AstraZeneca is fine with that, because the drug was not approved for “interferon driven SLE.” It was approved for SLE. The benefit was attenuated among interferon-low subgroups, but those folks still had a (directional) benefit as compared to placebo. The difference was 9.6% for the interferon low group, which tells us very little. Either way, the IFN biology isn’t doing the work the marketing implies it does.

Listeners of my podcast will know I’m skeptical of pathophysiology-driven drug development. The three TULIP trials are exhibit A for why. We developed a drug for a precision-biology-esque hypothesis. The drug actually failed its first trial but has since had two positive trials. If you look at the totality of the data, the thing the drug is supposed to address does not appear to be a strong or meaningful signal, aside from the obvious signal that it does work. At the end of the day, all I can say is that anifrolumab works in SLE - mostly for the skin - and that prescribing should probably be to people with a skin-ish phenotype.

Same drug, same gaps

The other ongoing pattern is missing patient-reported outcomes. PROs were collected in TULIP-1 and TULIP-2 but omitted from the primary publications, which prompted me to write a Letter to the Editor in NEJM in April 2020 making the obvious point: few rheumatologists could name the components of BICLA or SRI, fewer still use them, and a simple clinically meaningful question, “do you feel better?”, could clarify the entire BICLA-vs-SRI methodological debate. Both trials had SF-36, FACIT-Fatigue, and Patient Global Assessment data. AstraZeneca eventually published TULIP-1/2 PROs in 2022 in a paper that treated the PROs as a means to validate the BICLA. PROs exist to tell us whether a drug made people feel better, not to show that people who felt better had better BICLA.

TULIP-SC continues the pattern, though I did find the patient global assessment, buried on page 18 and Table S4. PtGA is a continuous measure and it was statistically significantly different, but the magnitude of effect was marginal at best (-0.23 difference, typically would look for a full 1-1.5 points for minimal clinically important difference).

The other thing the pen doesn’t change is the competitive landscape. Drug development has taken off in SLE and the 2026 pipeline is hot. Telitacicept recently showed a 67% SRI-4 vs 33% placebo response in its phase 3 trial, an NNT of 3. That would put it in a different category from anything else in lupus, though I suspect the FDA is suspicious of the data and may force more trials before approval. In the next year or two I’d expect to see litifilimab, deucravacitinib, upadacitinib, and possibly ianalumab report phase 3 data. After that, we may get CAR-T and bispecific antibodies.

What about the long-term extension (LTE)?

I have a standing position that LTEs are typically worthless: underpowered for safety signals, usually unblinded, almost always analyzed in ways that flatter the original treatment group. The magical part of randomized trials is the randomization and the blinding. LTEs typically have neither, instead functioning as poorly reported case series that get published many years too late to be helpful. TULIP-LTE (Strand et al., Lancet Rheumatology 2025), which reported 4-year PRO data, is a somewhat-notable exception.

Unlike most LTEs, TULIP-LTE was actually run as a double-blind, placebo-controlled, 3-year extension. Patients on anifrolumab in TULIP-1 or 2 continued anifrolumab, while patients on placebo were re-randomized to anifrolumab or placebo at LTE entry. This is great and should be the standard in drug development. If you’re going to follow patients for 4 years, lets learn something useful from it!

Now the problems, all of which the authors flag.

1. Dropout was hugely differential: 52% of placebo patients dropped out over 3 years vs 31% of anifrolumab patients. The repeated-measures model assumes missing-at-random, which is almost certainly not the case; placebo patients who stay enrolled for 4 years are by definition the ones doing well enough to stay. Notably, this may mean the drug was just working, a nod in its favor.

2. The protocol relaxed in the LTE. The mandated glucocorticoid taper from the feeder trials became tapering “encouraged”, and investigators were allowed to adjust background therapy as needed. By year 3 the two arms were on different real-world cocktails.

3. The PRO data are softer than the abstract reads. At week 208 the least-squares mean differences were “numerically greater” across the board for SF-36 bodily pain, mental health, and EQ-5D. “Numerically greater” appears to be the end of that story; confidence intervals for all of them crossed 0 when compared to placebo.

I love that TULIP-LTE maintained blinding and re-randomized patients after the initial trials finished. It answered a real and useful question, but unfortunately the answer was the same one we got with the original trials; anifrolumab works, most likely for skin, and has marginal benefits with respect to quality of life.

The Verdict

1. This does not change much for target populations. My target patient is the same one I described in October 2021: moderate-to-severe SLE with prominent skin involvement and/or a stuck steroid taper, not active severe lupus nephritis or NPSLE, willing to tolerate the herpes zoster risk and ideally vaccinated against it.

2. For existing IV patients on stable disease, I’ll offer the SC switch as a convenience option. The pharmacokinetic bridging data and TULIP-SC’s consistency with TULIP-1 and TULIP-2 passed muster and I will be viewing them as equivalent going forward. Patients who prefer the convenience of home injection have a new option, which is great.

3. I’m not impressed by interferons, interferon signatures, or really SLE-pathophysiology writ large. Interferons certainly matter for SLE, but not enough for them to drive prescribing. I do not send interferons and do not think anyone else on the adult side should be regularly sending them either. I would make an exception for some of the interferonopathies / pediatric SLE syndromes.

4. SLE remains a hot area for drug development. It seems plausible that we will have more new indications for SLE in the next five years than we had in the previous 50. That is a great thing for a patient population that desperately needs better options.

On April 27, 2026, CDER issued a Notice of Opportunity for a Hearing (NOOH) proposing to withdraw approval of avacopan (Tavneos); the Federal Register notice followed on April 30. The FDA’s previously semi-public concerns about endpoint readjudication and hepatotoxicity have now become a formal allegation that ChemoCentryx’s NDA relied on manipulated primary-endpoint data and untrue statements of material fact, which “rendered the results [of the ADVOCATE study] biased and unreliable” and “irrevocably compromises the credibility of the study results.” ChemoCentryx (now an Amgen subsidiary) has until June 1st to request a hearing and June 29th to submit additional data and analysis. Today’s Critical Commentary will run a little long as I am hoping to present the facts as we know them in their entirety.

The FDA’s Case for Withdrawal

To save you the trouble of reading all 24 pages of the NOOH, I’ll summarize the accusations the FDA has made. These are based on internal ChemoCentryx and Medpace documents, contemporaneous emails, and Amgen’s own August 2025 written response to the agency. As of this writing, Amgen has said it “continues to believe that TAVNEOS demonstrates effectiveness and a favorable benefit–risk profile,” but to date they have not refuted the following chronology.

For brief background: the ADVOCATE trial randomized 331 patients with severe ANCA-associated vasculitis to avacopan or a prednisone taper with a background of rituximab or cyclophosphamide. The two primary endpoints were remission at week 26 (non-inferiority) and sustained remission at week 52 (superiority). The latter was non-negotiable; apparently the FDA “informed ChemoCentryx in 2016 that TAVNEOS would not be considered for approval unless the ADVOCATE study demonstrated superiority on week 52 sustained remission.” Put a pin in that; it will matter soon.

According to the FDA, on November 5, 2019, the company managing data for the ADVOCATE study (Medpace) signed off on database lock, which means the previously blinded data could now be viewed. According to the analysis plan, two ChemoCentryx employees (Director of Biostatistics Huibin Yue and Chief Medical Officer Pirow Bekker) were allowed to see the unblinded data for the purpose of conducting a quality control review “for completeness and internal consistency.”

On November 8, the topline efficacy tables were transferred to Bekker. The week 52 sustained remission analysis had failed, with a two-sided p-value of 0.1025. What happened next, in the FDA’s words:

“After being informed that there was nothing wrong with either the data or the analysis, Drs. Bekker and Yue looked for cases that could alter the study results to indicate TAVNEOS achieved a statistically superior outcome on the primary endpoint of sustained remission.”

On November 9, Bekker wrote to Yue:

“Regarding sustained remission at Week 52 it is, of course, of paramount importance that the data are correct (especially the p-value for superiority). Chao and you must verify these results ASAP. We cannot afford to miss a superiority outcome here.”

Three days later, Medpace completed a blinded data quality check that came back “with no findings” and the external statistical consultant validated the analysis. At this point, the data were confirmed correct, the analysis was confirmed correct, and the p-value was confirmed to be 0.1025. Thus far, nothing truly untoward has happened.

The targeted search. On November 12, Yue ran an unblinded query of the database for subjects with a Birmingham Vasculitis Activity Score of zero who had received glucocorticoids in the four weeks before the week 26 or week 52 assessments. This is starting to sound bad. The FDA minces no words when describing this choice:

“In the absence of any evidence of erroneous data, sponsor personnel used unblinded data specifically to find subjects whose readjudication would change the results of the trial. The evidence shows that the goal of this behavior was to alter the results of the original analysis. If the original analysis had been positive, Drs. Bekker and Yue would likely not have searched for subjects to readjudicate.”

The pre-emptive p-value. Their search ultimately identified 9 patients who had were not in remission, 6 from the avacopan group and 3 from the prednisone group. Bekker and Yue (perhaps reasonably!) believed that these patients were wrongly adjudicated. Yue next asked the consultant Chao Wang to rerun the primary endpoint analysis on a hypothetical dataset, where 5 of the 6 avacopan patients and 0 of the 3 prednisone patients somehow flipped their outcomes to sustained remission. On November 13, 2019, Dr. Wang replied that the essential 52 week primary endpoint would be superior, were those patients to flip outcomes. This is starting to raise serious concerns.

A pause for reflection. The asymmetry of the nine selected subjects is worth dwelling on, because including three prednisone-arm cases feels like a sign of good faith. The FDA did not find this convincing. They point out in the NOOH that two of the three control-arm patients had terminated the trial early and the third received glucocorticoids in a way that precluded a remission determination on its own. By construction, the agency notes:

“the three control arm patients selected for readjudication could not have made a difference in the analysis of the superiority claim at week 52.”

The FDA is saying the 3 control arm patients were window dressing. We cannot know this for certain, but they are suggesting that Bekker and Yue chose those control-arm patients because they would not flip their outcomes. The avacopan patients, on the other hand, could change.

The call. On November 14, Bekker and Medpace sent the adjudication committee chair David Jayne a “patient profile” package for each of the nine subjects. According to the FDA, he reviewed each chart and reclassified five of the six avacopan subjects as in sustained remission. None of the three controls were reclassified at week 52, possibly for the aforementioned structural reasons. It is worth noting here that the FDA has not suggested that Jayne knew this was untoward; as far as I know, all parties agree he remained blinded and acted in good faith. The FDA also does not think this salvages it:

“Bias in the selection of subjects for readjudication could not be mitigated by the fact that Dr. Jayne conducted the readjudications in a blinded fashion.”

The FDA is saying that this was all pre-ordained. Whether or not Jayne knew who was in which group was immaterial, because the only way this could land was in avacopan’s favor.

The submission. On November 20, the database was locked for a second time, this time with the re-adjudicated p-value of 0.0132. That p-value, and only that p-value, was submitted to the FDA. When FDA reviewers asked about the timeline in a December 2020 information request, the response described “the freeze of the study database, which occurred on 20 November 2019” as a single event. The November 5 lock, the failed analysis, the unblinded targeted search, and the readjudications were not disclosed. The FDA letter is direct about what this concealment accomplished:

“The applicant never disclosed the readjudications that occurred after the initial database lock and that they were prompted by both an unblinded review of the study database and knowledge that the readjudications would change the study result from not statistically significant to statistically significant.”

On October 7, 2021, the FDA approved avacopan (tavneos). The agency’s account of what its own reviewers were told, and would have done if told the truth, is striking. The Division Director who recommended approval, the letter writes,

“…did not know that the facts on which he was relying were untrue, that absent manipulation, the study results were not statistically significant on the superiority analysis at week 52, and the procedures in place to ensure trial quality were violated. Had the Division Director known these facts, he would not have recommended approval.”

This is all very bad and it feels like the FDA has largely made up its mind about what to do.

Is the FDA right that it doesn’t work?

Let’s put aside the regulatory question for a moment. The broader scientific question of whether avacopan is beneficial in ANCA associated vasculitis is a little more complicated.

Bekker and Yue only flipped a few patients, and we can easily roll back the clock to see what would have happened had they not. If you strip them out and reverse the cosmetic week 26 reclassifications on the prednisone arm, which didn’t affect week 52 anyway, you get a sustained remission rate of approximately 63% on avacopan versus 55% on prednisone, an absolute difference of about 7-8%. That would still favor avacopan, though it may not meet regulatory muster.

I like to share this graphic during talks, which is from a paper I published a few years back. In the paper we broke down the trial by avacopan vs. control and rituximab maintenance vs cyclophosphamide. The benefit appears to be driven by the patients who were randomized to the control group and received rituximab for induction. Those patients did not receive maintenance therapy (at all!) and clearly fared worse than those who did in the other arms. Two conclusions follow from that:

1. Not-treating people from week 20 to week 52 is a bad idea, and probably drove some of the perceived benefit of the drug

2. Giving people avacopan was obviously doing something, because those people would have flared if it did not work

Sustained remission is also not the only metric that matters. I would argue that preventing people from going on dialysis is a substantially more important outcome measure. The ADVOCATE trial was not powered to assess progression to ESRD, but the GFR data that was not altered by Yue and Bekker also suggests a meaningful benefit from the drug. I would put an asterisk on the week 52 data because of the aforementioned problems with maintenance therapy, but I find the week 26 data pretty convincing:

Finally, we also have patient reported outcomes from the ADVOCATE trial. Patients who were randomized to received avacopan had better outcomes at both week 26 and week 52, and as far as we know those data were never touched by Bekker and Yue. An avacopan-based, glucocorticoid-sparing regimen produced better patient-reported outcomes than a protocolized prednisone taper. All of these outcomes matter a great deal, and I still believe avacopan has efficacy in ANCA associated vasculitis.

But is it safe?

So far I have been ignoring the other big story here, which is that on March 31, the FDA issued a Drug Safety Communication describing 76 postmarketing drug induced liver injury cases. Seventy-four involved a serious outcome: 54 patients were hospitalized and 8 died. Seven met criteria for biopsy-confirmed vanishing bile duct syndrome (VBDS), which is a terrifying set of words you’ve probably never seen together in a sentence before this mess emerged.

I prescribe avacopan regularly and have never seen anything like this, but therein lies the problem with rare safety signals. We typically identify them with passive reporting systems, which are complicated to interpret, to say the least. First, they suffer from the classic denominator problem. The FDA has told us all of the cases that have been reported (the numerator), but what should the denominator there be? All the prescriptions that have occurred? All of those that occurred in industrialized countries with active reporting? It’s all very nebulous.

Second, they do not come with a comparator. For all we know, this is picking up on some risk signal that is inherent to ANCA associated vasculitis. I find that difficult to believe, especially given that I have never seen VBDS and rarely see bad liver disease from ANCA associated vasculitis itself. Still, data like this cannot answer the critical question: “What is the magnitude of this risk?”

Additionally, there seems to be a remarkably strong geographic bias for these cases. Of the 76 DILI cases, most were reported from Japan (n=66), followed by the United States (n=5), Europe (n=4), and Canada (n=1). Uptake of avacopan in Japan may have been faster than in the U.S., but given the size of the populations in question it seems very unlikely that uptake and reporting culture could entirely account for it. I suspect there are some pharmacogenomic components to this that have yet to be fully characterized, which would make for a much more nuanced safety assessment (ie similar to allopurinol hypersensitivity syndrome, where some populations have HLA alleles that put them at much higher risk).

I think the jury is still out on safety. It is fair to say the safety profile in 2026 looks materially worse than the safety profile in 2021, and I have been informing all my patients of this risk. So far, nobody who hears “FDA has asked it to be withdrawn from the market” and “vanishing bile duct syndrome” has opted to start therapy with avacopan.

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TRIAL: TOGETHER-PsA (NCT06588296)

DRUG: Ixekizumab (Taltz, IL-17A monoclonal antibody) concomitantly with tirzepatide (Zepbound, dual GIP/GLP-1 receptor agonist)

DISEASE: Active psoriatic arthritis with overweight + comorbidity or obesity

DESIGN: Phase 3b, open-label, randomized 1:1, multicenter (US only), N=271, 36-week interim of a 52-week trial

JOURNAL: Arthritis & Rheumatology, April 2026

SPONSOR: Eli Lilly and Company

PRIMARY ENDPOINT: Simultaneous achievement of ACR50 + ≥10% weight reduction at week 36. MET (31.7% vs. 0.8%, p<0.001). Really though the thing that mattere…

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The Pipeline Monitor covers recent developments in autoimmune disease drug development. This is a themed edition covering the rapidly evolving CAR-T, CAR-NK, and related cell therapy landscape in autoimmune disease. Five spotlights, each with a Buy/Sell/Hold rating.

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Can we cure autoimmune diseases with a single infusion? Three years ago that was an obvious “No.” Today, Kyverna Therapeutics is preparing to file the first-ever BLA for a CAR-T therapy in autoimmune disease, the FDA has signalled williness to lower the bar for approval, and industry has spent roughly $7 billion acquiring startups who can help them join the potential gold rush.

The growth has been staggering. From 1 registered trial in 2018 and a COVID hiatus from 2019-2020, the yearly number of registered CAR-T trials climbed to 5 in 2021, then 8 in 2023, and then exploded to 25 in 2024 (Figure 1). The field is moving fast enough that I thought it warranted a full Pipeline Monitor to map where everyone is and what to watch …

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TRIAL: VALOR (NCT05437263)

DRUG: Brepocitinib — oral, selective TYK2/JAK1 inhibitor (blocks IFN, IL-6, IL-12, IL-23 signaling)

DISEASE: Active dermatomyositis (skin + muscle, treatment-refractory)

DESIGN: Phase 3, randomized, double-blind, placebo-controlled, 1:1:1, N=241, 52 weeks, 90 sites / 20 countries

JOURNAL: NEJM, March 28, 2026

SPONSOR: Priovant Therapeutics (Roivant subsidiary)

PRIMARY ENDPOINT: Mean Total Improvement Score (TIS) at week 52 — MET (30 mg only)

THE TAKE: First targeted therapy to ever succeed in a registrational DM trial. FDA Priority Review with Q3 2026 PDUFA. Will become first-line add-on for refractory DM, b…

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For the most part, rheumatologists have been content to let our pulmonary colleagues take point on managing interstitial lung disease (ILD). I generally feel we should take at least a collaborative role in management, especially because I suspect progressive fibrosis in autoimmune-related ILD is downstream from inflammation. The recent approval of nerandomilast (Jascayd) for both idiopathic pulmonary fibrosis and progressive pulmonary fibrosis straddles both worlds; a drug that will be mostly-prescribed by pulmonologists but appeared to be most-important for rheumatology.

A Competent IPF Approval (And Little More)

I’ll keep the IPF story brief, but it is worth interrogating. FIBRONEER-IPF randomized 1,177 IPF patients to nerandomilast 18mg twice dail…

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TRIAL: ALLEGORY (NCT04963296)

DRUG: Obinutuzumab (Gazyva) — glycoengineered type II anti-CD20 monoclonal antibody

DISEASE: Active SLE (without proliferative/membranous lupus nephritis)

DESIGN: Phase 3, randomized, double-blind, placebo-controlled, N=303 (1:1), 52 weeks

JOURNAL: NEJM, March 6, 2026

SPONSOR: F. Hoffmann-La Roche

PRIMARY ENDPOINT: SRI-4 at week 52 — MET

THE TAKE: Surprisigly solid trial in SLE… perhaps the most solid trial ever? Will easily merit an expanded label at the FDA. Need more data to understand specific use case (what manifestations, exactly, improved here?) but we can say with confide…

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On March 6 of 2026, the FDA approved deucravacitinib (Sotyktu) for adults with active psoriatic arthritis, making it the first TYK2 inhibitor to carry a PsA indication. Bristol Myers Squibb would like you to know this is a differentiated oral option and will likely play up the favorable safety profile. I have a bigger picture question: who, exactly, is this for?

PsA is not a disease starved for therapies. Rheumatologists in 2026 can choose from five TNF inhibitors, IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab), IL-23 inhibitors (guselkumab, risankizumab, and off label tildrakizumab), IL-12/23 inhibition (ustekinumab), JAK inhibitors (tofacitinib, upadacitinib), and apremilast. The explosion of highly efficacious therapies for psoriasis …

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What Just Happened

On February 19, FDA Commissioner Marty Makary and CBER Director Vinay Prasad published a Sounding Board piece in the New England Journal of Medicine announcing that the FDA’s “default position” is now a single randomized controlled trial. This may be combined with confirmatory evidence to support marketing authorization. The two-trial expectation that has anchored drug regulation since the 1960s is, in their words, a “dogma” that “no longer makes sense.”

The statutory authority for this isn’t new. Since 1997, the FDA has been legally permitted to approve drugs on a single trial plus confirmatory evidence. And in practice, it’s been doing exactly that - in 2024, roughly two-thirds of new molecular entities approved by the Center f…

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