Takeda Pharmaceutical Co., Ltd.

Topas Therapeutics, a small German biotech company attempting to quell overactive immune systems, has revealed the first data from a study of its “tolerance induction” therapy for celiac disease. The results, to be presented at the Digestive Disease Week conference on Monday, come more than six months after Topas first declared success in the study via a press release , without divulging any data. The company discussed the therapy and shared the data with Endpoints News in an exclusive interview ahead of the conference, though many questions remain about the results. The 38-person trial focused on the safety of the company’s experimental nanoparticle treatment over seven weeks, its ability to steer immune cells toward a less inflammatory state, and patient-reported changes in gastrointestinal symptoms. Topas executives told Endpoints that the therapy was successful against those goals, even though granular data on safety and patient outcomes was missing from the presentation. They conceded that bigger and longer studies are still needed, but added that any relief from celiac disease would be a breakthrough. “There is both very much a medical need and big commercial opportunity in celiac,” Topas CEO Hugo Fry told Endpoints. Celiac disease is caused by an unwanted immune reaction to gluten, which is abundant in food. There’s no treatment or cure for the condition that, by some estimates, may affect as many as 1 in 100 people. Despite that, there are relatively few drug developers working on treatments. Topas is one of three companies, along with Anokion and Takeda, developing a potential immune tolerizing therapy in a Phase 2 study. Rather than merely tamping down on inflammation, the efforts aim to retrain the immune system to ignore triggers like gluten. “Tolerization is at that disease-modifying, almost curative end of the spectrum,” Fry said. It aims to do so by presenting nanoparticles decorated with tidbits of peptides that resemble the problematic parts of proteins that set off the immune system, known as antigens. For the celiac therapy, dubbed TPM502, the company uses three nanoparticles, each with a different antigenic peptide from the gluten protein. In many ways, the goal is opposite to that of a vaccine, which presents antigens to build the body’s reaction and create an immune response. Instead, Topas’ infused nanoparticles target specific cells in the liver that serve as a calming zone for T cells, where they learn to live peacefully alongside antigens that don’t warrant being attacked. “That’s the body’s natural hub of induced tolerization,” Fry said. “And it pushes them through that natural route.” Celiac was a good place to start looking for signals that the tolerization approach was working because doctors can easily provoke the immune system to flare up by having participants consume gluten, said Topas chief medical officer Cristina de Min. The company tested four doses of its nanoparticle therapy, ranging from 0.72 micromolar to 7.2 micromolar, in 26 patients. The other 12 patients got a placebo. Participants got the drug or placebo on day 1 and day 15 of the study and then consumed gluten a week later. De Min said that “the drug was remarkably safe,” largely resulting in side effects that resemble gluten consumption in celiac disease, including headache, pain, nausea and vomiting in 27 patients. But the company didn’t break this safety data down by side effect, or between participants who got the drug versus placebo. The company also said that there were three “grade 3” adverse events, the second highest severity, but didn’t say what they were. To get an idea of whether the treatment was working, Topas measured the release of the inflammatory immune protein IL-2 in response to being “challenged” with gluten. Only the highest dose of the therapy resulted in a significant decrease in IL-2 release. But when studying the gene expression of T cells before and after the therapy, the company found that all dose levels helped turn on genes that tamped down on inflammation and reduced genes that promoted inflammation. Topas also asked patients to rate their gastrointestinal symptoms before and after the treatment. The company said that people who got higher doses of the therapy had reduced symptoms, but the presentation was light on specific details. Topas emphasized that the study was not designed to test for efficacy. Another major caveat was the study’s strict inclusion criteria. Topas screened 391 people and recruited only one-tenth of them. Many prospective participants were excluded because they didn’t produce high enough levels of IL-2 in response to gluten consumption. “We wanted to make sure that only patients with measurable response would be involved,” de Min said. Even more patients were excluded because they didn’t have the certain immune system genotype that Topas focused on in this study. Topas is planning a Phase 2b study that will include a broader range of immune genotypes, accounting for 85% to 90% of people with celiac disease. Topas also wants to develop a tolerization therapy for type 1 diabetes, Fry said. But doing so will require more funding, and Fry is setting out to raise a €70 million Series D round. The company is currently funded through 2026 and isn’t planning to start a new study before then, he said.

Welcome back to Endpoints Weekly, our roundup of the top headlines in biopharma. Earnings season continued this week, with more comments from pharma executives on the potential impact of tariffs, new details around Pfizer and Moderna’s cost-efficiency efforts, and more. Read below for a recap of the top news out of this week’s earnings calls. We’ve also got a summary of data out of the American Association for Cancer Research’s annual meeting, where Lei Lei Wu reported from Chicago. And Endpoints News’ Andrew Dunn welcomed Arc Institute co-founder Patrick Hsu to our special Slack channel to discuss all things AI. Stay tuned next week as more companies, including BioNTech, Novo Nordisk, Takeda and more, report their earnings.  — Nicole DeFeudis 💲 More pharma companies reported their Q1 earnings this week, including AstraZeneca, Novartis, Pfizer, GSK, Eli Lilly, Moderna and Amgen. Tariffs were a central theme during earnings calls, as drugmakers provided some detail on the potential impact to their business. “Our goal, as I mentioned, is to have 100% of our products produced in the US for the US,” Novartis CEO Vas Narasimhan said during a first-quarter earnings call with the media Tuesday. AstraZeneca CEO Pascal Soriot said the company “can actually move the manufacturing of products that are made in Europe, move it to the US for supply to the US. And we can also potentially do the other way around.” Here’s what else our reporters tracked: The privately-held biotech Stealth BioTherapeutics said its rare disease drug was delayed this week. A person familiar with the situation said the company hadn’t been asked to run more trials or provide more data, that the FDA hadn’t identified any safety concerns, and that the agency hadn’t raised manufacturing issues, Endpoints’ Max Gelman reported. The apparent delay comes amid upheaval at health agencies, though several companies have said in earnings calls and interviews in recent weeks that they aren’t seeing an impact on their interactions with the FDA so far. The agency made decisions on time for two other drugs this week: Johnson & Johnson’s rare disease drug Imaavy and Satsuma Pharmaceuticals’ migraine drug Atzumi. The agency also hit PDUFA dates for other big-name medicines in recent weeks, like Dupixent, Amvuttra, Uplizna and Eylea. Stealth’s drug had an original decision deadline in January, but the company said the FDA requested more time to review supplemental material. Max examines lingering questions around the situation here . AACR recap: Data from GSK, Merck and more 🔬Scientists descended on Chicago this week for the American Association for Cancer Research’s annual meeting. Some in attendance, including cancer scientists, former NIH leaders and patient advocates, spoke about how cuts to science funding could impact cancer research. “It is a time to be clear-eyed about what is happening and to decide what role each of us is willing to play,” Yale oncologist Patricia LoRusso said during a panel. Read more here . Elsewhere, GSK presented data showing that its PD-1 inhibitor Jemperli induced a 100% complete response rate in 49 patients with a specific type of rectal cancer after six months. Even though the results were excellent, Endpoints’ Elizabeth Cairns reported that they are unlikely to have major commercial implications. Jemperli is already approved in this cancer type, known as mismatch repair deficient (MMRd) solid tumors, though only after the patient has progressed on prior treatment and has no further options. The new data could move the product into the neoadjuvant setting for dMMR cancers, but it’s still a tiny patient population. Only around 3% of solid tumors carry the dMMR biomarker. Merck also impressed with Keytruda data in head and neck cancer, showing that adding Keytruda before and after surgery cut the risk of disease recurrence or death by 27%. Patients in the study remained disease-free for more than four years at the median. 🌎 The US’ drug infrastructure has historically been robust, making it an attractive country in which to run clinical trials. But some companies say uncertainty is driving them to look elsewhere for their studies. Jared Whitlock examined this phenomenon in a story this week . Of note, companies find FDA Commissioner Marty Makary’s comments on rare disease approval pathways and animal testing largely promising. “Since we are in the ultra-rare disease space, Makary’s words on creating paths for rare [diseases] creates hope, and we are looking forward to learning more about his plans,” Mahzi Therapeutics CEO Yael Weiss said. While overseas trials have limitations, agencies in Europe, Canada, Australia and the UK have worked in recent years to harmonize guidelines with the FDA. 🎤 Endpoints’ Andrew Dunn welcomed Patrick Hsu to the newsroom’s Slack channel earlier this month to share his thoughts from the frontlines of the AI bio space. Hsu co-founded the Arc Institute in 2021, a Palo Alto, CA-based nonprofit research organization that has spearheaded some leading AI biology research. “I think AI will become a universal copilot that we use for everything,” he said during the interview. Read more here . DON’T MISS:

Vertex is pulling back on its genetic medicine research, ending all work related to adeno-associated viruses, or AAVs — the viral vectors commonly used to deliver gene therapies into the body, the company confirmed to Endpoints News . The cuts impact Vertex’s collaborations with at least two biotech startups: the AAV design company Affinia Therapeutics and tRNA therapy company Tevard Biosciences, which uses AAVs. It also calls into question Vertex’s work on CRISPR therapies for genetic muscle diseases. Several bigger pharmaceutical companies, including Biogen , Pfizer , Roche and Takeda , have cut or pared back on AAV gene therapy research in recent years. And several gene therapy biotech companies have trimmed their pipelines and staff as private and public investors sour on the field. This change of fortune was seemingly unimaginable a few years ago. AAV technology ushered in a new era of gene therapy investment and led to several commercial products for diseases, including Roche’s Luxturna for childhood blindness, Sarepta Therapeutics’ Elevidys for Duchenne muscular dystrophy, and Novartis’ Zolgensma for an otherwise fatal neurodegenerative condition in infants. But a panoply of challenges — including costly manufacturing, multimillion-dollar drug prices, slow progress in improving targeted delivery and lingering safety issues — has raised questions about the future of AAV medicines. Vertex did not have any AAV gene therapies in clinical development, despite work on the technology stretching back to at least 2019 when it acquired Exonics Therapeutics for its early-stage CRISPR therapies for two muscle diseases: Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). Exonics relied on AAV vectors to deliver its therapies to muscles. Vertex has shared few updates on the program since its acquisition. The approach was essentially a permanent version of the commercial exon-skipping therapies for DMD, meaning it wouldn’t fully restore the dystrophin protein that’s broken in people with the disease. A Chinese biotech called HuidaGene has developed a similar CRISPR therapy and has already treated two boys, Endpoints reported last month . The first patient had modest improvement in his walking ability three months after the treatment. It is unknown why Vertex’s own CRISPR therapy has seemingly lagged behind. It is possible that the company is holding out for a more curative approach. It may also have been spooked by multiple deaths in people who received the high doses of AAV needed to reach the body’s many muscles, including two from Pfizer’s experimental therapy , one from Sarepta’s approved drug and one from a custom CRISPR therapy . Heather Nichols, a spokesperson for Vertex, confirmed that the company has discontinued its AAV work, but in an email said that the company’s “commitment to cell and genetic therapies remains strong” and that other investments in DMD and DM1 continue. The company declined to provide further comment on its AAV cuts or make an executive available for an interview. The need for better AAVs, ones that could deliver more of the therapy at lower doses, has been clear for years. Vertex struck a partnership with Affinia in 2020 worth up to $1.6 billion for access to the startup’s viral vectors designed to better target the muscles for treating DMD and DM1 and target the lungs to treat cystic fibrosis, the disease responsible for most of the company’s $11 billion revenue last year. Affinia CEO Rick Modi told Endpoints in an email that his company regained the rights to its muscle-targeting viruses from Vertex in March. He said the earlier work on cystic fibrosis ended in 2022 and rights to those programs were returned then. The startup is currently focused on finishing preclinical studies and designing a clinical trial for its lead candidate, for a heart condition called BAG3 dilated cardiomyopathy. Modi said that Affinia received “the maximum amount of milestone payments” for the research phase of its DMD and DM1 collaboration with Vertex, but he wouldn’t specify the amount. He added that Affinia is looking to license its newly-regained muscle capsids to other companies. Vertex’s step back from AAVs also impacts Tevard Biosciences. The small startup, which is housed in Eli Lilly’s genetics-focused research center that opened in Boston last summer, struck a four-year partnership with Vertex in February 2023 to develop a new class of genetic medicines known as tRNA therapies. In nature, tRNA molecules are part of the machinery that cells use to translate genetic code into proteins. Tevard is one of a few companies developing synthetic versions of these molecules to help skip over genetic mutations that prevent cells from making fully functional proteins. Tevard believes its approach could help restore the vital dystrophin protein missing from the muscles of the 15% of people with DMD whose disease is caused by so-called nonsense mutations. While some companies are trying to package tRNA therapies in lipid nanoparticles, those delivery vessels are not readily taken up by the body’s many muscles, so Tevard planned to use AAVs to deliver its treatment. “We were doing great. The collaboration was going great. But in December, we were informed that they were realigning priorities, and multiple programs were being terminated, including this one,” Tevard CEO Daniel Fischer told Endpoints in an interview. “Two weeks ago, we got the rights back to this program.” Other tRNA companies have also struggled, including HC Bioscience, which shut down in March after “challenges in targeted delivery,” Endpoints previously reported . Fischer said the fate of the DMD program will depend on whether Tevard can find another drugmaker to partner with or raise enough money to move it forward on its own. The company is planning to present data showing that the DMD therapy works in mice at the upcoming American Society of Gene & Cell Therapy meeting later this month.