TNFR1

Pictured: A person with an irritated gut/Taylor Tieden for BioSpace Twenty-two years ago, a molecule called TL1A was first discovered and isolated. Today, after two decades of research, therapeutics to calm its activity may usher in a new era for the treatment of immune-mediated diseases like inflammatory bowel disease, psoriasis and rheumatoid arthritis. TL1A (tumor necrosis factor-like cytokine 1A) is part of the tumor necrosis factor (TNF) superfamily, a group of cell-signaling molecules that have potent effects on immune function and which have led to anti-TNF antibodies such as AbbVie’s blockbuster Humira (adalimumab). Against this backdrop, two monoclonal antibodies targeting TL1A spurred major biopharma acquisitions in 2023. In June, Merck completed the purchase of Prometheus Biosciences for $10.8 billion. The company’s lead asset, PRA-023—now MK-7240—has shown clinical evidence of “best-in-class” potential for treating inflammation and scarring in the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease, Nature reported. Then in October, Roche paid $7.1 billion for Roivant subsidiary Televant Holdings and its anti-TL1A antibody RVT-3101, also for IBD. That same month, Sanofi and Teva Pharmaceuticals announced a collaboration worth a potential $1.5 billion to co-develop TEV-’574, a TL1A inhibitor currently in Phase IIb clinical trials for IBD. Stephan Targan, executive director of the F. Widjaja Inflammatory Bowel Institute of Cedars-Sinai, Los Angeles, and colleagues carried out much of the research into TL1A and developed the antibody Prometheus purchased. After giving the keynote presentation about TL1A at the Crohn’s & Colitis Congress earlier this month, Targan told BioSpace, “I have never had an audience response like that. There’s a big buzz about this in our field.” What’s All the Excitement About? In an April 2023 note shared with BioSpace, Jefferies analyst Michael Yee wrote that there is a “high unmet need” in IBD. Current treatment options are limited and with modest benefit, Yee explained. Driving part of the excitement around TL1A inhibitors is the hope that they can break the “efficacy ceiling that we see even with the best drugs out there,” Aileen Pangan, a rheumatologist and therapeutic area head of immunology clinical research at Merck, told BioSpace. “We are not getting the remission rates we’d like. And even after remission, there is a considerable loss of response over time, requiring patients to switch to another drug. . . . Some patients may have to try two or three different drugs before they find one that works. We are simply not where we want to be.” In December 2022, Prometheus announced positive results from two 12-week Phase IIa studies of PRA-023, ARTEMIS-UC and APOLLO-CD, in patients with moderate to severe ulcerative colitis and Crohn’s disease who had failed other therapies. In the ARTEMIS study, 26.5% of patients reached the primary endpoint of clinical remission compared to 1.5% of those on placebo. And in APOLLO-CD, a 49.1% clinical remission rate was achieved, compared with a 16% historical placebo rate. Targan called the results “huge,” highlighting the durability of the treatment as a significant improvement over existing treatments. “The therapeutics available today might offer a 20% increase [in remission] over placebo over a 12-week trial, but at the end of a year, only 40% are maintained. That means, of the entire population of Crohn’s sufferers, a given biologic may offer an 8% remission.” But with Merck’s TL1A inhibitor, he said, “Initial remission rates may be over 50% and durability over time could be as high as 90%,” for an overall remission rate of 45%. “That’s never been seen before.” Similarly, Roche’s RVT-3101 showed positive results in the Phase IIb TUSCANY-2 study in moderate-to-severe ulcerative colitis. The results, released in June 2023, led to clinical remission in 36% of patients after 56 weeks of treatment, with endoscopic improvement reaching 50%. Enabling Targeted Treatment These new antibodies could perform very well in targeted patient populations, Targan said, thanks to a novel diagnostic tool that uses genetic testing as well as other genomic markers to inform physicians about how well the molecule will work in a specific patient. “Right now, physicians and patients have to go through trial-and-error steps before they find the right drug,” he explained. But certain genetic variations, called risk alleles, increase the likelihood the patient will respond to the drug. “Risk alleles are very significantly associated with increased expression of TL1A over time,” Targan said. “I predict the Phase III trials will show people doing very well if their diagnostic tests show a strong genetic association with the presence of the TL1A molecule.” He added that he believes the new companion diagnostic will also identify those patients who will see a durable response. He compared this companion diagnostic, which is yet to be approved by the FDA, to those used in oncology, where “to find out what you need to treat a tumor, you evaluate the characteristics of the tumor.” Pangan said the power of this diagnostic was evident in Prometheus’ Phase II trial. In the ARTEMIS-UC study, all trial participants were tested with the complementary diagnostic and stratified according to the result. Of the 135 enrolled patients, 32 were positive for a SNP-based signature that includes the TL1A risk alleles (16 were on placebo and 16 received the antibody), and a greater proportion who were positive for risk alleles or other biomarkers achieved remission with the antibody compared to those who were negative, Pangan shared. Merck has embarked on a global Phase III trial that will enroll over 1,000 patients. “If we can identify the population that is most likely to get into remission with this antibody, we can help patients and physicians everywhere,” she said. Biotech entrepreneur Andrew Pannu told BioSpace that the biomarker-driven approach being taken by both Merck and Roche reflects a belief that these biomarkers will credibly predict responders and that this will help with reimbursement efforts in a “fairly crowded market.” Beyond IBD TL1A inhibitors also hold potential in other autoimmune diseases. In a 2022 summary review article published in Frontiers, TL1A was found to be was abnormally expressed in IBD, as well as in rheumatoid arthritis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. And, as the molecule binds to activated fibroblasts, targeting TL1A might offer another novel benefit: the reversal of fibrosis and scarring. “In a lot of our work in animals, we found that, lo and behold, TL1A inhibitors could reverse scarring,” Targan said. That could have applications for strictures in Crohn’s disease—although anti-TL1A drugs can’t ‘fix’ already formed strictures, they might help keep them from forming or re-forming after surgical intervention, he said. TL1A inhibitors might also be helpful in other diseases where fibrosis and scarring are significant such as systemic sclerosis and primary sclerosing cholangitis, Targan noted. And Merck is currently conducting a Phase II study looking at fibrosis in systemic sclerosis associated with interstitial lung disease. Lee also noted the potential durability and success of the class. “Data could get even better over time given the anti-fibrotic potential of TL1A inhibitors,” he wrote in the April 2023 investor note. “Of course, I’m prejudiced,” Targan said, “but I’ve been around a long time. I’ve been working on inflammatory bowel disease for half a century now, and I do believe TL1A inhibitors will be transformational for many immune-mediated diseases.” Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.

Cambridge/Boston, MA, USA – 18th January 2024. Vivtex Corporation (“Vivtex”), a biotech company aiming to transform the development of oral biologic therapies for major diseases, and AI Proteins, Inc., a growing biotechnology company that utilizes computational de novo protein design to create novel therapeutic miniproteins, today announced they have entered a strategic R&D collaboration to develop novel, oral biologic therapies for inflammatory diseases. The partners will leverage Vivtex’s proprietary and extensively validated GI-ORIS™ (“Gut on a chip” and AI) screening and formulation platform technology to evaluate and enhance the oral bioavailability of AI Proteins’ miniproteins designed to target and inhibit the activity of the TNF receptor 1 (TNFR1). Under the agreement, the companies will jointly conduct and share the costs of the program and will co-own any resulting data. No further financial details are disclosed. Preventing inflammation by inhibiting TNF-alpha (tumor necrosis factor alpha) signaling is a highly validated approach and the mechanism of action of multiple approved biologic products that generate multi-billion-dollar revenues each year. There are multiple receptors for TNF-alpha and inhibition of TNFR1, which is responsible for mediating pro-inflammatory signaling activity, has the potential to be a safe and highly effective target for inhibiting this clinically important pathway. There are no FDA approved therapeutics that inhibit TNFR1, with several companies having tried and failed. AI Proteins’ de novo design process provides complete control over miniprotein properties and activity allowing them to achieve remarkable potency and novel receptor engagement to successfully drug TNFR1. With current TNF-alpha pathway inhibitors being injectables, there is a major opportunity to develop oral anti-inflammatory medicines with differentiated best-in-class safety and efficacy. Maureen Deehan, CEO of Vivtex, commented “A key element of our new and evolved strategy is to enter collaborations with innovative companies where we can bring together our respective and cutting-edge technologies to create and co-develop novel therapeutic candidates that have the potential to address significant delivery and bioavailability challenges – in this case, an oral TNFR1 inhibitor to treat inflammatory diseases. AI Proteins’ miniprotein technology combined with our own GI-ORIS™ technology presents an opportunity to develop and bring a completely new oral anti-inflammatory medicine to patients, making this highly effective modality available to a much larger patient population.” Noah D. Beerman, CEO of AI Proteins, added: “At AI Proteins, we are proud of the bold and dynamic science supporting our de novo miniprotein technology platform, which has the potential to make a profound impact on the development of novel medicines across multiple therapeutic spaces. To date, we have focused on designing our miniproteins to achieve ideal therapeutic characteristics and have now validated hits for over 100 targets. This collaboration aims to combine promising features of our powerful miniprotein platform and Vivtex’s transformational oral biologics platform to develop anti-inflammatory therapeutics.” ### About Vivtex Corporation Vivtex was launched as a spin out from the labs of Robert Langer (MIT) and Giovanni Traverso (MIT, Harvard University). The company is focused on transforming the market for biologic therapies through the development of novel oral biologics including enhanced, oral versions of existing high-value biologic candidates that can only be administered by injection or infusion. To achieve its mission, Vivtex is leveraging its proprietary and extensively validated high-throughput GI-ORIS™ (“Gut on a chip” and AI) screening and formulation platform (Nat. Biomed. Eng. 4, 544–559: 2020) through strategic co-development partnerships and R&D collaborations with biotechnology and pharmaceutical companies. To find out more about Vivtex, please visit our website: www.vivtex.com and LinkedIn. About AI Proteins Boston-based AI Proteins is a biotech company on a mission to re-imagine protein therapeutics with a novel approach for designing entirely new proteins. Using AI-based design and a high-throughput drug discovery platform, AI Proteins creates de novo proteins optimized for specific therapeutic applications with a current focus on inflammation, metabolic diseases, and oncology. The AI Proteins platform enables the development of inexpensive, durable, highly specific proteins that have the potential for oral delivery. Additionally, the AI Proteins platform can dramatically accelerate the development of lead therapeutic candidates ready for IND-enabling studies. For more information, please go to aiproteins.bio Contacts: VivtexMaureen Deehan, CEOmdeehan@vivtex.com MEDiSTRAVA Consulting (for Vivtex)Mark Swallow, Sandi Greenwood, Leila AdlamVivtex@medistrava.com Stern Investor Relations, Inc. (for AI Proteins)Janhavi Mohite

Pictured: Sanofi's headquarters in France/iStock, HJBC During its R&D Day on Thursday, Sanofi spotlighted 12 investigational products which it contends could each surpass $1 billion in annual sales as it tries to win back the confidence of its investors. The French pharma said it has nine pipeline assets under innovative medicines and vaccines that could each reach peak sales of $2.15 billion to $5.4 billion. These include tolebrutinib for multiple sclerosis, lunsekimig and rilzabrutinib for asthma and itepekimab for chronic obstructive pulmonary disease (COPD), as well as its vaccine candidates for acne, respiratory syncytial virus (RSV) in older adults and extraintestinal pathogenic Escherichia coli. In addition, Sanofi anticipates that its three “pipeline-in-a-product” assets—amlitelimab, frexalimab and SAR441566, an orally available inhibitor of soluble TNFR1—each have peak sales potential of more than $5.4 billion. Sanofi also announced it will invest more of its energy and focus into R&D, aiming for a 50% increase in Phase III trials between 2023 and 2025 to generate strong pipeline momentum. The pharma is also eyeing 25 mid- to late-stage readouts in the next two years, as well as nearly 20 regulatory filings. Houman Ashrafian, head of R&D at Sanofi, in a statement called the size and blockbuster potential of the company’s pipeline “unprecedented” while highlighting the strategy to prioritize its first- and best-in-class assets to cement “our leadership in immunology and neuro-inflammation.” Besides its projected blockbusters, Sanofi during Thursday’s investor event also touted the growth of its existing assets. Products that had recently been launched, as well as future pharma assets, could bring in nearly $11 billion in sales through 2030, according to the company. Sanofi’s vaccines business is also expected to reach a similar revenue level through 2030, taking into account its recently launched RSV vaccine Beyfortus. The pharma also projects that Dupixent (dupilumab), one of its top-selling products, will continue its strong growth through 2023, particularly as it expands into other indications such as COPD. CEO Paul Hudson said that taken together, the promise of its pipeline and the strength of its existing products in the market, will set the company up for “sustainable growth through 2030 and beyond.” Sanofi’s optimistic note during its R&D event comes more than a month after the company spooked investors by abandoning its previous 2025 profit target. In a strategy brief released alongside its third-quarter earnings report in late October 2023, Sanofi said that it would no longer aim to reach a 32% operating profit margin for 2025. Sanofi’s stock dropped 15% in reaction to the announcement, losing approximately $21 billion in market value. Since then, the company’s shares have underperformed compared to industry counterparts. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.