Trehalose

iStock/ dickcraft Misses from amyotrophic lateral sclerosis hopefuls Denali Therapeutics and partners AbbVie and Calico Life Sciences mark the latest setbacks for the controversial platform trial, the results from which have largely mirrored the dismal success rate in ALS overall. Launched in 2020 to expedite the development of an effective medicine for amyotrophic lateral sclerosis, the HEALEY ALS Platform Trial suffered two more disappointments this week as candidates from Denali Therapeutics and AbbVie and Calico Life Sciences missed the study’s primary endpoint, failing to significantly slow disease progression. Funded by Sean M. Healey—who died from amyotrophic lateral sclerosis (ALS) in 2020—and his global asset management firm, the HEALEY trial generated new hope for patients with the intractable neurological disease. Platform trials are a fairly new phenomenon, however, meaning successes have been limited and investigators are still refining the methodology. In a Monday investor note, Stifel analyst Paul Matteis called the trial “a very high-risk/high-reward option.” As with any novel venture, HEALEY has experienced challenges. In an earlier interview with BioSpace , Clene Nanomedicine CEO Rob Etherington noted certain inflexibilities in the trial’s protocol in addition to a six-month timeframe that is “too short of a window to prove efficacy.” For some drug developers, it is also an attractive business proposition. The HEALEY team recruited the first biotechs to the trial by covering some of their costs. “The good news was they paid for the drug, so we didn’t have to raise money for [that],” Prilenia Therapeutics CEO Michael Hayden told me in September. A platform trial also has the advantage of being patient-centric, using a shared placebo group between all regimens to boost the total number of patients receiving a potentially efficacious drug. But nearly five years on, the HEALEY trial has yet to produce a definitive success, instead serving up a string of failures. Hopefuls from Clene, Prilneia, Biohaven , UCB and Seelos Therapeutics all failed to hit the trial’s primary endpoint, and of these, only Prilenia and Clene saw enough positive signals to move their treatments forward. The other programs have all been terminated—a devastating development for the ALS community. It has also been hard, of course, on these companies. Seelos filed for bankruptcy in November after trehalose’s failure. That same month, Massachusetts General Hospital (MGH), which runs the HEALEY trial, sued Seelos over the company’s alleged failure to fully pay for the work MGH conducted on its candidate trehalose. Seelos, which has expressed disagreement regarding the data from its regimen in the HEALY trial, particularly concerning the use of Amylyx’s Relyvrio by some participants, is allegedly withholding payment as a result—to the tune of $2 million, according to the lawsuit. In a March 2024 update , Seelos stated that while the study did not meet statistical significance in the primary and secondary endpoint across all participants, it showed a potential signal of efficacy in a pre-specified subgroup not taking Relyvrio. These patients saw a 22% improvement in slope of change in the ALS Functional Rating Scale-Revised (ALSFRS-R) assessment adjusted for mortality, with an 89% success probability, at 24 weeks, according to the press release. “The HEALEY platform is designed to detect signals of efficacy and we believe the observed signal and success probability is competitive to other recently FDA-approved therapies for ALS which also failed to achieve statistical significance when measured for function and mortality on similar primary and efficacy endpoints,” Seelos CEO Raj Mehra said in the March statement. Relyvrio received approval in September 2022 as only the third-ever treatment for ALS. Given its subsequent withdrawal from U.S. and Canadian markets in April 2024 after failure to show efficacy in a Phase III trial, it would have been interesting to see how trehalose would have performed under different circumstances. Signals of Hope For followers of the HEALEY trial—and the ALS space in general—pulling signals of efficacy from the rubble is a familiar tune. For Prilenia and Clene, positive biomarker data supported moving their respective programs forward. In Prilenia’s case, a subgroup of patients with early-stage ALS who were rapidly declining had “substantially less decline” on the ALSFRS-R total score compared to the placebo group. Prilenia submitted a Marketing Authorisation Application to the European Medicines Agency that was accepted in September 2024. Certainly, there is precedent for moving a program forward based on patient subgroup data. “[ALS] is heterogeneous, and sometimes it’s really important, even when a drug doesn’t work in everybody, to look at if there’s a subset that might have benefited,” Merit Cudkowicz, director of the Healey & AMG Center for ALS, told me in 2021. Cudkowicz noted that results of the first trial for Radicava, developed by Mitsubishi Tanabe and approved by the FDA in May 2017, were also negative across the overall trial population. However, a subset of early fast progressors did respond, “and when they repeated the studies just in that group, it was positive and that led to marketing.” And embattled Israel and New York–based biotech BrainStorm Cell Therapeutics has consistently pointed to analysis from its Phase III trial of NurOwn showing that a prespecified subgroup of patients with early-stage disease, as determined by an ALSFRS-R baseline score of 35, saw a meaningful response across all primary and secondary endpoints. BrainStorm is now gearing up for a Phase IIIb study that president and CEO Chaim Lebovits said would be focused on these early-stage patients. After a 2024 campaign filled with disappointment, this is a space that desperately needs a break. ALS is uniformly fatal, typically claiming its victims within five years of diagnosis, and the disease continues to confound researchers. Given the dire need for effective treatments, patients, drug developers and journalists alike could be forgiven for celebrating signals of hope. As for the HEALEY trial, Cudkowicz shared that the team is currently considering amending the protocol based on learnings from the first five regimens. “My sense is that it is not a perfect clinical trial. It has its flaws,” Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told me . “But I think they’re trying to fix the situation at HEALEY.”

Roberto Caricchio has studied lupus for nearly three decades. Hes witnessed steady, but slow, progress in how the frustratingly complex autoimmune disease is understood and treated.The past few years have been different. Promising early research from a team of German scientists has shown that cellular medicines can drive lupus into remission in ways other drugs cant. The findings have sparked a surge in industry interest, leading to the start of about a dozen clinical trials. Many more are on the way.Its unprecedented, said Caricchio, head of UMass Chan Medical Schools rheumatology department. Sometimes I have to sit down and take a deep breath.The latest evidence was on display last week, when leading scientists and physicians in autoimmune disease research gathered in Austria for the European Alliance of Associations for Rheumatologys annual meeting. Georg Schett, whose team at Friedrich Alexander University, Erlangen-Nurnberg in Germany set off the current bonanza, opened the meeting with new results from his teams study. The data show cell therapy continued to benefit almost all treated participants with several autoimmune conditions. Some remissions have lasted three years.Im very excited, said Schett, during a press conference Friday. When we started this three years ago, we did not know where it would go.A bevy of companies, including Kyverna Therapeutics, Cabaletta Bio and Novartis, aim to show that Schetts findings are just the start. At the meeting, they shared updates from clinical studies of these so-called CAR-T therapies in lupus and other autoimmune conditions, like myositis and systemic sclerosis.The new results are from small clinical trials and represent very early steps in what will likely be a yearslong effort to prove these treatments engineered from a patients own cells and proven against certain cancers can rewire the immune systems of people with inflammatory diseases. They hint at the approachs potential, but also the high bar drugmakers will have to clear to succeed.For instance, Cabaletta said that, of the first two people it treated with CAR-T therapy, one no longer needs other drugs and the other is weaning off steroids. Kyverna, which has accumulated the most data of any company in the field so far, reported similar results in six of seven lupus patients given CAR-T, some of whom were treated more than six months ago. Another, with the disease myasthenia gravis, hasnt had evidence of disease or needed other medications for one year following treatment.We are showing that this story about an immune reset is taking some shape and form, said Kyverna CEO Peter Maag, in an interview.Similarly encouraging responses to CAR-T were reported in other tests by Novartis as well as biotechs iCell Gene Therapeuticsand JW Therapeutics.Across these trials, participants have mostly experienced mild forms of the immune and neurological side effects associated with CAR-T a relief to researchers as patients risk tolerance in autoimmune disease is lower than in people with deadly cancers.Before beginning testing in 2021, we were pretty scared by potential safety issues, Schett, who serves on Kyvernas and Cabalettas scientific advisory boards, said on Friday. Now we are much more relaxed.Still, effective autoimmune disease treatments already exist, so the bar is higher to introduce cell therapy. And CAR-T drugs remain costly, complex to manufacture and largely only available at specialized treatment centers. Its unclear whether long-term health issues, such as the secondary malignancies that have been reported in rare cases among cancer patients whove received CAR-T, will also occur in people with autoimmune disease.Cell therapy is very promising, but I'm not sure that I would use it as my first, second or even third option, said Daniel Wallace, chief of rheumatology at City of Hope and Cedars Sinai Medical Center. He isnt involved with any of the companies currently conducting autoimmune cell therapy research.The therapies are only worth it if we can put somebody who has life-threatening organ disease in remission for years, he said.To that end, analysts are watching how well these therapies free people from needing the many immunosuppressive drugs they typically take. At EULAR, Schett revealed one myositis patient relapsed after 18 months of follow-up, while Kyverna said one lupus patient treated with its therapy relapsed after five months. Nine people who received Kyvernas therapy across trials in different diseases, including that lupus patient, are still on some sort of immune medicine. They have either experienced recurrence or have more advanced disease. In the latter case, it may take longer for CAR-T therapy to show benefit, said Chief Medical Officer James Chung.Cabaletta reported some symptom improvement in the two treated lupus and myositis patients, but neither are disease free yet.Wall Street analysts were generally impressed by the results. Jefferies Kelly Shi said Cabalettas data fulfilled the goal of replicating Schetts results. Thomas Smith, of Leerink Partners, noted the majority of patients treated with Kyvernas therapy have had a significant response, and the numbers could improve with time. Yet shares of both companies fell double digits Friday, with Kyvernas stock plummeting by 34%.Kyverna claims the one reported relapse was partly due to the lower dose level the participant received. Maag also noted how, in lupus patients, often multiple things are going on that require therapy. Some investigators prefer to keep their patients on a low dose of an oral steroid and they are allowed to do so in Kyvernas trials. With more time, more patients may eventually stop taking other drugs, Maag said.Ultimately, the goal is to taper people off of steroids completely, he said.We will have side effects, said Cabaletta CEO Steven Nichtberger, on a conference call with analysts on Friday. We will have failure to treat effectively in some patients, and that's fine, as long as what we have is at least as good, if not better, than any other company in the industry.There are still many unanswered questions about autoimmune cell therapy. Caricchio, of UMass, notes the treatments havent been tested in many Black people, who are more likely to have aggressive forms of lupus. He pointed out that people with particularly significant kidney damage, a hallmark of the condition, may not respond as well. And infections observed in testing, while mild so far, bear watching, he said.Personalized cell therapies are also being joined in clinical trials by treatments made from donor cells or natural killer cells, as well as by dual-targeting antibody drugs called T cell engagers. All are seen as more convenient and easier-to-manufacture options that some analysts think could challenge CAR-T therapy. A similar pattern has played out in oncology, where enthusiasm for CAR-T has been tempered by success with other technologies.This is the first CAR-T approach. Its a proof of concept and shows this can work in systemic autoimmunity, said Caricchio. I do truly believe that the next decade will be a life-changing experience for physicians and for patients. '