SELLAS: Why The Bear Case Might Not Hold Up

The REGAL trial hinges on control arm mOS. Of all BAT maintenance options, only venetoclax might plausibly push it beyond historical norms.

Leukemia (AML), Dr. Lance Liotta Laboratory, March 1988 (Public domain, via Wikimedia Commons)

Disclosure: The author holds a beneficial long position in SELLAS Life Sciences Group, Inc. (NASDAQ: SLS). This article is provided for informational and educational purposes only and is not financial advice. Although the author is a Medical Doctor, this content represents a personal analytical perspective and does not constitute medical advice, a diagnosis, or a treatment recommendation. The author receives no compensation for this article and has no business relationship with the company. Please see the full “Legal Information and Disclosures” section below.

Article Update (March 13, 2026):
Thank you to all my readers for the discussion! Several have pointed out that this article does not discuss the VIALE-M trial. This is a fair point, and I want to address it in this update.

VIALE-M was a Phase 3 randomized, double-blind trial designed to evaluate whether adding venetoclax to oral azacitidine improves relapse-free survival as maintenance therapy in AML patients in first CR or CRi after intensive induction and consolidation. Both arms received oral azacitidine; the question was whether venetoclax on top of an already active maintenance backbone adds benefit. As far as I know, the trial was closed by the sponsor without reporting results. "Closed" is not "failed." Strictly speaking, the reasons for closure are unknown and may be commercial. However, this was the sponsor's own trial, designed to extend the venetoclax franchise into the maintenance market, the natural commercial follow-on to VIALE-A. If the data looked promising, the sponsor had every incentive to continue enrollment or report results. So closure without publication may be more consistent with disappointing data.

As far as I know, the only published venetoclax maintenance data come from Bazinet et al. (Lancet Haematology, 2024), a single-center, single-arm Phase 2 at MD Anderson that enrolled 35 remission patients (predominantly CR1/CRi) and closed early due to slow accrual. Median overall survival was not reached. I want to be fair about these results: they are a real signal that venetoclax-based maintenance can keep AML patients in remission for a long time, not merely a demonstration of tolerability. The pessimist case does not require that venetoclax is proven in CR2 maintenance, only that it is plausible enough that some REGAL BAT investigators will use it and some of those patients will do well. Bazinet provides biological plausibility for that scenario. There is no control arm, so the observed survival cannot be attributed to venetoclax rather than to patient selection or the natural history of remission at a world-class institution. But it should not be dismissed.

The population is not the same: Bazinet enrolled predominantly CR1/CRi patients, whereas REGAL enrolls CR2 patients whose disease has already demonstrated resistance to prior therapy. And the treatment context differs: a protocol-specified, closely supervised regimen at a single elite center versus heterogeneous investigator-choice prescribing across approximately 110 sites. Beyond these differences, the critical issue is the biological distinction between CR1 and CR2. In CR1, residual leukemia cells have never been exposed to selective pressure from relapse and salvage therapy. In CR2, the leukemic clone has already survived prior therapy, evolved, and been beaten back a second time. These residual cells are a selected, resistant subpopulation, frequently enriched for resistance mutations such as TP53 and RAS pathway alterations. This matters for venetoclax specifically because common resistance mechanisms include upregulation of MCL-1 and BCL-XL, which bypass BCL-2 inhibition, and TP53 mutations, which disrupt apoptosis upstream of BCL-2. Bazinet’s own data may illustrate this: patients with adverse ELN risk had a median relapse-free survival of just 4 months on venetoclax maintenance, with 0% surviving relapse-free at two years. CR2 patients are likely enriched for exactly these adverse features because relapse selects for them. The specific resistance biology of relapsed AML may undermine the specific mechanism of venetoclax.

There is an important nuance working in the opposite direction, however. Bazinet’s cohort was mixed: some patients had prior venetoclax exposure while others did not, and the study analyzed relapse-free survival based on previous venetoclax exposure. Most CR2 patients in REGAL may never have received venetoclax at all, for two reinforcing reasons. First, venetoclax is approved for newly diagnosed AML in patients who are 75 or older or unfit for intensive chemotherapy, while REGAL enrolls patients fit enough for intensive induction and then intensive salvage; standard salvage regimens for these fitter patients are typically cytarabine-based. Second, the timing matters: venetoclax received accelerated FDA approval in November 2018 and full approval in October 2020, while REGAL enrolled from 2020 to April 2024. Because REGAL patients are in CR2, they went through initial induction, CR1, relapse, and salvage therapy before enrolling, a journey that typically takes a year or more. Many REGAL patients, especially those enrolled in the earlier years of the trial, may have begun their first-line treatment before venetoclax was widely adopted into clinical practice. For these likely venetoclax-naive patients, the venetoclax-specific resistance mechanisms would not have been selected for. Venetoclax might still retain meaningful activity against their residual cells. The broader clonal resistance argument still applies, since relapse selects for generally resistant biology regardless of the specific drug used, but this point may strengthen the pessimist case: for what may be the majority of REGAL BAT patients, venetoclax could be a genuinely active drug they have never seen before.

To summarize: to the best of my knowledge, no controlled evidence exists that venetoclax maintenance improves survival in any remission setting. VIALE-M’s closure may suggest it does not add sufficient benefit even in CR1. Bazinet provides a real but uncontrolled signal whose relevance is likely undermined by the resistance biology of CR2, though this argument is weaker for the potentially large fraction of REGAL patients who are venetoclax-naive. In the context of a sponsor that had every reason to generate controlled evidence and chose not to report it, the absence of that evidence may be more informative than it might first appear. This is consistent with my article’s broader argument: the case for a dramatically elevated control arm mOS depends on assumptions about both venetoclax access and venetoclax efficacy that do not hold up well under scrutiny.

Some responses I received are worth reflecting on. I wrote a rather optimistic article and received backlash because the article was apparently not optimistic enough. There is never guaranteed success in biotech. Therapeutic cancer vaccines, and GPS is one, have historically almost never succeeded. I believe in the science behind GPS, but do I not also want to believe in it? That is an inherent bias. Being able to identify and overcome this kind of bias is what we all should strive for.

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In my article “Monte Carlo Simulation Of Elicio’s Phase II AMPLIFY-7P Study Favors Vaccine Efficacy”, I used Monte Carlo simulation to map the delayed readout of Elicio’s AMPLIFY-7P trial onto combinations of control-arm survival and vaccine hazard ratio. After running similar simulations for SELLAS’ Phase 3 REGAL trial of galinpepimut-S (GPS) in CR2 acute myeloid leukemia, I found that this approach adds rather little insight here. SELLAS (NASDAQ: SLS) has disclosed far more information than Elicio, to the point where the analysis largely collapses into a single question: what is the median overall survival in the control group?

If the best available therapy (BAT) arm achieves an mOS of around 8 months, consistent with historical benchmarks for non-transplant-eligible AML patients in second complete remission, you do not need any simulation at all. Trial success would be highly probable given that fewer than 50% of enrolled patients had died at a median follow-up of 13.5 months, meaning the pooled median survival had not yet been reached and, by SELLAS’ own estimate, exceeds 12 months, and the positive IDMC recommendations in January and August 2025 to continue without modification.

Those benchmarks deserve a brief note on sourcing. The GPS Phase 1/2 study reported an mOS of 5.4 months in a matched historical cohort of CR2 patients receiving standard of care. SELLAS itself cited 6 months in the January 2025 interim analysis press release. Dr. M. Yair Levy, Director of Hematologic Malignancies Research at Texas Oncology Baylor University Medical Center and a REGAL Steering Committee member, put the figure at around eight months, though his estimate explicitly includes treatment with HMAs and/or a BCL-2 inhibitor. All three sources are company-adjacent rather than independent registry data, but they bracket a range of roughly 5 to 8 months that is consistent with the generally poor prognosis described in the broader relapsed AML literature.

It is worth noting, however, that these historical benchmarks derive from heterogeneous patient populations that include patients who would never have been fit enough to enroll in a clinical trial. REGAL required patients to have achieved CR2 and to meet performance status criteria for enrollment, which enriches the study population for fitter, biologically more favorable patients. This selection effect alone could elevate both arms’ survival above historical norms, independent of any treatment effect from venetoclax or GPS.

The real question is whether an mOS of 14, 16, or even more months is plausible in the BAT group. And that is something no Monte Carlo simulation can answer.

Consider the timeline. The final analysis requires 80 events. As of December 26, 2025, SELLAS reported 72. Today is March 11, 2026. More than ten weeks have passed and no announcement of the 80th event has been made. Enrollment completed in April 2024 with 126 patients randomized. The company itself noted that survival times appear longer than expected, which they framed as potentially positive. Given the historical benchmarks discussed above, the fact that 8 remaining events have not accumulated in over ten weeks among the 54 patients recorded as alive or censored as of that date tells you something about the tail of the survival curve. Some patients are living longer than expected. The question is whether it is the GPS arm, the BAT arm, or both.

It should be noted that some of the slowdown could also reflect operational factors: CRO event-verification lag, reduced site activity during the holiday period immediately surrounding the December 26 cutoff, or delays in death certificate processing across six or more countries. These explanations are not mutually exclusive with a genuine slowing of events, but they caution against overinterpreting the precise timing.

The IDMC data offer partial answers. The committee reviewed unblinded data at the interim analysis, triggered by 60 deaths, and confirmed that GPS exceeded the predetermined futility criteria. This means the data did not demonstrate that GPS is futile; it does not mean the IDMC found positive evidence of efficacy, and the distinction matters. No safety concerns were identified. They recommended continuation without modification. A subsequent review in August 2025 reached the same conclusion. The trial was neither stopped for futility nor for efficacy.

Why neither? This is actually consistent with the mechanism of a therapeutic vaccine. GPS works by training the patient’s T cells to recognize and kill WT1-expressing leukemic cells. Unlike a small molecule that acts immediately, a vaccine needs time to mount an immune response, and that response is inherently heterogeneous across patients. There will be non-responders whose outcome might even be worse than the control arm, since BAT patients might receive active treatment while non-responders get a vaccine that does not work for them. The responders, on the other hand, could show sustained, durable survival if the immune system successfully establishes long-term surveillance against WT1-positive residual disease. SELLAS disclosed that 80% of randomly selected GPS patients showed a specific T-cell immune response, surpassing the Phase 2 results. But that still leaves 20% who did not respond.

There is a scenario worth flagging here that sits between the bull and bear cases. What if GPS works for the 80% of immunologic responders, producing a genuine survival benefit, but the blended hazard ratio across all patients, diluted by the 20% non-responders, comes in at 0.70 or 0.75 rather than the more dramatic separation the trial may have been powered to detect? In that scenario, a real GPS effect exists but the trial fails to reach statistical significance on its primary endpoint.

The bimodal pattern of responders and non-responders would produce a rather late meaningful separation of the survival curves and an effect that is not dramatic in either direction at any single point in time. Early on, the curves would overlap because the vaccine has not yet primed the immune system. Then the non-responders would start relapsing and dying at rates similar to or worse than BAT, while the responders would diverge upward. At an interim look, this could easily look like a modest, non-significant trend. Only as follow-up lengthens and the responder tail stretches out would the full effect become visible. One could try to model this with a Monte Carlo simulation, but you would have to bake in assumptions about the responder fraction, the immune priming delay, and the differential hazard rates for responders versus non-responders. Each assumption biases the simulation considerably. I do not see how we gain information with an MC here that we cannot get from simply reasoning about the clinical reality of the control arm.

So instead of modeling event trajectories, let me reason about whether the bear case holds up.

To understand why this matters, a brief primer on the patient population. REGAL enrolled AML patients in second or later complete remission (CR2/CRp2) after second-line salvage therapy who are ineligible for or unable to undergo allogeneic stem cell transplantation. These patients have already relapsed once after initial treatment and then responded to a second round of aggressive chemotherapy. Their disease has demonstrated its ability to overcome prior therapy. The leukemic stem cells that survived induction and consolidation have proven themselves resistant. There is no approved maintenance therapy for these patients.

The permitted BAT options in REGAL include observation (with hydroxyurea if needed), a hypomethylating agent (azacitidine or decitabine), venetoclax, and low-dose cytarabine, or combinations thereof. Observation is the historical default. Low-dose cytarabine is an old, essentially palliative therapy with no meaningful survival impact in this setting. Injectable azacitidine and decitabine as maintenance agents have been studied but have not demonstrated significant survival benefit. The QUAZAR AML-001 trial did demonstrate an OS benefit for oral azacitidine (Onureg) in first-line maintenance, but that is a different formulation that is not bioequivalent to injectable azacitidine and was studied in CR1, not CR2. Oral azacitidine is not listed among the REGAL BAT options.

In routine clinical practice, the vast majority of transplant-ineligible CR2 patients are simply observed. There is no approved or guideline-recommended maintenance therapy for this population. The relevant question is whether the fraction of BAT patients who do receive active treatment could shift the control arm’s median enough to matter in a 126-patient study.

That leaves venetoclax as the only BAT component that could plausibly push the control arm’s mOS far beyond historical norms, assuming it is used at all. Venetoclax received accelerated FDA approval for newly diagnosed AML in November 2018 and full approval in October 2020, making it a relatively recent addition to the AML treatment landscape. This is exactly why this bear case exists: if enough BAT patients would receive venetoclax-based maintenance regimens instead of observation, which is the standard of care, the control arm might achieve an unprecedented mOS that narrows or eliminates the survival gap GPS needs to demonstrate.

But how realistic is this scenario?

First, venetoclax is not approved for the REGAL setting anywhere. The FDA granted approval for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults who are age 75 years or older, or with comorbidities precluding intensive induction chemotherapy. The European Commission’s approval is similar in scope: venetoclax in combination with a hypomethylating agent for newly diagnosed AML in adults ineligible for intensive chemotherapy. Neither covers CR2 maintenance, which is the REGAL population. Using venetoclax in this setting is off-label everywhere, including the United States. The VIALE-A trial demonstrated a median overall survival of 14.7 months for venetoclax plus azacitidine versus 9.6 months for azacitidine alone, but those patients had active, newly diagnosed disease where venetoclax plus azacitidine served as the primary antileukemic regimen. REGAL BAT patients are already in complete remission after salvage chemotherapy and would receive venetoclax as maintenance to prevent relapse in disease that has already demonstrated resistance to prior therapy. There is no controlled evidence that venetoclax-based maintenance in CR2 reproduces anything close to the frontline survival benefit.

Second, the geographic composition of the trial matters. REGAL enrolled 126 patients across approximately 110 sites. The trial launched in 2020 with sites in the U.S. and Europe only; Asian sites in India and China were added later, with China endorsed by the IDMC in April 2023, relatively late in the enrollment period. Among the European countries, the trial included sites in France, Germany, Greece, Hungary, Poland, and Serbia. SELLAS has stated that the U.S., Greece, and India were the top three enrolling countries, and Dr. Panagiotis Tsirigotis at the National and Kapodistrian University of Athens has been identified as the investigator who enrolled the highest number of patients in the study. Critically, study sites in the U.S. and Europe accounted for approximately 75% of patients enrolled, with the U.S. representing the single highest enrolling country. The remaining roughly 25% came from India and China.

Now consider venetoclax access across these geographies. In the United States, off-label use of oncology drugs is relatively common, and insurance coverage for off-label cancer treatments is more flexible than in most other countries. Some American investigators in the trial could plausibly prescribe venetoclax to their BAT patients.

But what about patients enrolled outside the U.S.? In India, venetoclax access remains limited and costly for indications beyond its approved label. Indian patients can only obtain it through cumbersome channels at substantial expense. For an off-label maintenance indication without guideline support, the probability of Indian BAT patients receiving venetoclax is very low. Greece, one of the trial’s top three enrolling countries and home to the single highest-enrolling investigator, has well-documented constraints on oncology drug spending following years of austerity. Off-label venetoclax maintenance in CR2 is extremely unlikely to be reimbursed there. In Poland, venetoclax reimbursement is restricted even for certain approved indications. The bar for off-label AML maintenance reimbursement would be even higher. Hungary has some of the most stringent population restrictions for venetoclax access in Europe, even for approved indications. Serbia has limited oncology drug access overall. Germany and France offer the strongest healthcare systems among the European participants, and off-label venetoclax use is more plausible at their academic centers, but still not guaranteed for a CR2 maintenance indication that lacks any guideline recommendation.

The picture that emerges is this: the U.S. is the only geography where off-label venetoclax use in CR2 maintenance is realistically common. A significant share of the BAT patients come from the U.S. and could in theory receive venetoclax. But a substantial portion come from countries where venetoclax access ranges from restricted to nonexistent, even for approved indications. And as noted, Greece and India, two of the trial’s three largest enrollment contributors, are among those countries. For those patients, “best available therapy” most likely means observation or HMA monotherapy, therapies that have not demonstrated meaningful survival improvements in this population.

Even within the U.S. contingent, it is not obvious that all or even most BAT patients would receive venetoclax. These are CR2 patients already in remission. Venetoclax combined with a hypomethylating agent carries real toxicity: severe cytopenias, risk of tumor lysis syndrome, and serious infections including fatal sepsis. For a fragile, already depleted patient currently in remission, an investigator might reasonably choose observation over an aggressive, toxic, off-label regimen. The decision to use venetoclax-based maintenance in a transplant-ineligible CR2 patient is not automatic, even at a major U.S. cancer center.

So what does the blended BAT arm likely look like? A mix of some venetoclax-treated U.S. patients and a larger number of patients on observation or HMA monotherapy from the U.S. and elsewhere. That blend might produce an mOS closer to historical benchmarks than the critics fear.

I want to be careful not to overstate this. Clinical trials produce surprises with remarkable regularity. The history of oncology is full of studies that failed or succeeded for reasons no one anticipated. There is also the Hawthorne effect to consider, amplified by the open-label design: investigators who know their BAT patients are not receiving an experimental vaccine might compensate by treating more aggressively, selecting therapies they would not have chosen outside a trial context. In an open-label trial, this effect operates in both directions. Investigators may work harder for their BAT patients precisely because they feel those patients are missing out on a potentially beneficial experimental therapy. And it is even theoretically possible that the BAT group performs better than the vaccine group. GPS is an immunotherapy, and immune responses are variable. The 20% non-responder rate alone could dilute the treatment effect enough to erase statistical significance if the BAT arm performs even moderately above expectations.

But return to the timeline. Seventy-two events by December 26, and now more than ten weeks of silence. In a population where 6- to 8-month mOS is the benchmark, the slowing of events is itself data. Combined with two positive IDMC reviews of unblinded data, the predominance of observation in this setting, the geographic reality of venetoclax access, and the limited efficacy of the remaining BAT maintenance options, the specific bear case that the control arm will produce an unprecedented mOS seems to rest on assumptions that do not hold up well.

None of this guarantees that REGAL will succeed. The study could fail for any number of reasons, including a real but underpowered treatment effect diluted by non-responders, better-than-expected BAT performance driven by trial-enrichment for fitter patients, or the inherent variability of immune responses across a 126-patient study. The market started pricing in trial success in recent months, which reflects the fact that at some point any further delay of the readout is more likely signal than noise.

Follow me on X for frequent updates (@chaotropy).

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