Quell Therapeutics Ltd.

Dive Brief:AstraZeneca is bolstering its rare disease division with the purchase of Amolyt Pharma, an endocrine disease specialist backed by Novo Holdings.Under the deal announced Thursday, AstraZeneca will pay Amolyt shareholders $800 million in cash up front, with the potential for another $250 million for reaching a specific regulatory milestone. The companies expect the transaction to close in the third quarter.For AstraZeneca, the jewel of the acquisition is eneboparatide, a drug in Phase 3 testing to treat patients with hypoparathyroidism. The disease, which mostly affects women, is caused by a deficiency in parathyroid production that lowers calcium in the blood and can lead to debilitating symptoms including kidney disease. It affects about 115,000 people in the U.S.Dive Insight:The $39 billion acquisition of Alexion three years ago instantly transformedAstraZeneca into a major player in rare diseases. Since then, the U.K. drugmaker has been selectively picking up additional assets.In September 2021, the company exercised an option to buy the rest of rare disease drugmaker Caelum Biosciences for $150 million. A few months later, AstraZeneca struck two deals in transthyretin amyloidosis, paying $30 million to Switzerlands Neurimmunefor rights to an experimental therapy and inking a development pact with Ionis Pharmaceuticals for a drug that won approval in late 2023.AstraZeneca is also using its foothold in rare diseases to make forays into genetic medicine, acquiring gene-editing specialist LogicBio Therapeutics and scooping up Pfizers early gene therapy work for as much as $1 billion. And last year, the company announced plans to work with Quell Therapeutics to develop cell-based treatments for autoimmune diseases.Amolyt has moved from a startup with preclinical assets to a Phase 3 company in less than five years. Its largest investor is Novo Holdings, the controlling shareholder of both Novo Nordisk and Novozymes. Owned by the Novo Nordisk Foundation, Novo Holdings co-led the Series A financing for Amolyt in 2019 and added to its investment with Series B and Series C funding rounds.In addition to eneboparatide, Amolyt has an experimental drug called AZP-3813 designed as a potential treatment for acromegaly, which occurs when the body makes too much growth hormone. '

Inflammation is like a fire you just can’t put out—inflammatory disorders are chronic conditions after all. If your house is ablaze and you know a gas leak is the cause, dousing the entire home isn’t a targeted way to stop what’s feeding the flames, says John Puisis, co-founder and CEO of Cour Pharmaceuticals. He compares his startup’s drugs to stopping fire at the source. “We go into the basement, and we turn off the fuel valve completely,” Puisis said. Cour’s technology found early validation in the hands of a large pharmaceutical company that picked up one of the biotech’s programs and is currently testing it in mid-stage clinical trials. Now the Chicago-based startup wants to do the same with its internal pipeline and it has raised $105 million for its plans. In doing so, Cour aims to show how its approach to inflammation stands apart from the company’s immunology peers. One of the hottest areas of autoimmune disease research involves harnessing regulatory T cells, or Tregs. These cells in our bodies counteract excessive immune responses. A slew of Treg startups—Sonoma Biotherapeutics, Gentibio, Abata Therapeutics, Quell Therapeutics, and Tr1X—are engineering Tregs to treat a variety of inflammation-driven conditions. The jury is still out on these experimental cell therapies, which have limited, if any, clinical data so far. But Puisis, whose experience includes serving as CEO of autoimmune disorder drug developer Tolera Therapeutics, said one problem with Tregs is that immune suppression from these engineered cells can spread beyond their targets, leading to unwanted effects. “What’s interesting with us versus the others—I won’t name them—they’re doing generalized Tregs, you can actually get off-target spreading,” Puisis said. “We’re basically telling the body ‘don’t attack these cells anymore.’” Cour does not engineer cell therapies. The company works with nanoparticles that trick the body into thinking that they’re cells. Inside of these particles is an antigen for a particular autoimmune disease. The composition of all Cour drug candidates is the same, with the exception of the disease-causing antigen encapsulated within. Cour’s nanoparticles are about the same size as a cell, which is important as they circulate throughout the body. Too large, and they could cause clotting problems, Puisis said. Too small, and the immune system won’t recognize them. Recognition is key to how Cour’s therapies reprogram the immune system, Puisis said. Immune cells that provide surveillance for the immune system pick up the nanoparticles and take them to the spleen, which makes white blood cells, and the liver, which plays a role in the adaptive immune response. Released in these organs without any accompanying inflammatory signals, the immune system perceives the antigens as belonging to the body. The body then produces Tregs that migrate to the site of disease to tamp down immune responses to that antigen. Cour’s technology is based on decades of research by Stephen Miller, a professor of microbiology-immunology at Northwestern University. The startup’s initial focus was celiac disease, an immune response to gluten in certain foods. Preclinical research presented and published in 2015 described how nanoparticles can be generated from biocompatible compounds and used to deliver an antigen to restore immune tolerance. Soon after, Takeda Pharmaceutical began a partnership on the Cour celiac disease therapy. Takeda licensed this therapy in 2019 and is now responsible for its clinical development. Meanwhile, Ironwood Pharmaceuticals holds an option to license a different Cour therapy for primary biliary cholangitis, a rare autoimmune disease affecting the bile ducts of the liver. Puisis isn’t ruling out more pharma alliances, but for now, he said Cour is focusing on developing its own pipeline. Cour’s nanoparticles can encapsulate multiple antigens to address diseases driven by more than one antigen, such as type 1 diabetes. That disease and the rare muscle disorder myasthenia gravis are Cour’s lead indications. Cour selected these diseases because the few available therapies for them leave patients wanting for something better, Puisis said. Drug hunters have pursued antibody therapies for both diseases. The 2022 approval of Provention Bio’s antibody Tzield made that therapy the first FDA-approved treatment for delaying type 1 diabetes progression. Sanofi acquired Provention for $2.9 billion last year. In myasthenia gravis, Argenx markets two antibody fragments, Vyvgart and Hytrulo. Last year, UCB won FDA approval for two myasthenia gravis therapies, Rystiggo and Zilbrysq. While Rystiggo is an antibody that works similarly to Argenx’s drugs, Zilbrysq is a peptide that addresses a different target. The approved type 1 diabetes and myasthenia gravis therapies are chronic treatments, like regular applications of fire suppression that do not extinguish the fire for good. In addition to potentially better efficacy, Cour aims to offer patients long-lasting effects. Puisis said preclinical research suggests the effect of Cour’s therapies last for the lifetime of the animal. To be fair, developers of engineered Tregs also say their therapies may offer long-lasting effects. The durability of both types of treatments still must be shown in human testing. But one advantage that Cour could have over Tregs is manufacturability. Making a therapy from nanoparticles is less expensive and more easily scalable compared to engineering a patient’s cells or donor cells into cell therapies. Cour’s Series A financing was co-led by Lumira Ventures and Alpha Wave Ventures. Other investors include Roche Venture Fund; Pfizer, through its Pfizer Breakthrough Growth Initiative; Bristol Myers Squibb; Angelini Ventures; and the JDRF T1D Fund. Puisis said the financing will support the advancement of both of its programs through Phase 2a clinical development. As for Cour’s name, Puisis said it’s derivative of the word “courage” and is the brainchild of one of the startup’s scientists. “You need a lot of courage to be in biotech and to be in the discovery business,” Puisis explained. Photo by Flickr user Peter Hill via a Creative Commons license

When immune cells go awry and spark inflammation, a different type of immune cell stands ready to counteract that effect and return the immune system to a state of balance. Therapies based on such cells are part of an emerging area of research for the treatment of a wide range of autoimmune diseases. The work of Tr1X focuses on a particular type of these cells and the startup has emerged from stealth with $75 million and a lead program on track for the clinic later this year. The cells that tamp down excessive immune responses are called regulatory T cells, or Tregs. Some industry research efforts underway involve harvesting a patient’s Tregs and engineering them to go after a target, an approach that emulates the CAR T-therapies that blazed the trail for cell therapies developed to treat cancer. The field is also pursuing allogeneic cell therapies, which are made by engineering immune cells from healthy donors. This is the approach that Tr1X is taking. San Diego-based Tr1X focuses on type 1 regulatory (Tr1) cells, which are which are a subset of Tregs whose functions include dampening local inflammation and downregulating the inflammasome, a protein complex that mediates inflammatory responses. While Tr1X’s therapies are allogeneic, rather than trying to harvest Tr1 cells—which are not plentiful in the blood—the company works with more abundant CD4+ T cells sourced from healthy donors. The company says its proprietary technology converts these cells into Treg-like cells that function similarly to naturally occurring Tr1 cells. Furthermore, the company says additional engineering can get these cells to target specific tissues or enable local, targeted immunomodulation. The science of Tr1X is based on the research of scientific founder Maria Grazia Roncarolo, a professor of stem cell and regenerative medicine at Stanford who discovered type 1 regulatory (Tr1) cells. Tr1X describes its approach as a reset or a reboot of a patient’s immune system. Roncarolo, who is also Tr1X’s president and head of R&D, said in a prepared statement that the startup’s technology enables dual targeting of pathogenic T cells and B cells. She added that the company can engineer cells with the potential to induce tolerance of immune cells, which offer the potential to cure an autoimmune disease in contrast to current therapies that must be taken chronically. “The ability to develop a pipeline of medicines based on our work on regulatory T cells represents the culmination of decades of discovery and research into the underpinnings of immunological tolerance and autoimmunity,” Roncarolo said. “Tr1 cells have unique properties and represent the ideal therapeutic platform from which to develop ‘immune reset’ products.” Lead program TRX103 is in development for the prevention of graft-versus-host disease in transplant patients. This complication develops when donated immune cells see the host’s cells as foreign, leading them to attack the host cells. Tr1X is readying its therapeutic candidate for Phase 1 testing in patients undergoing hematopoietic stem cell transplants with cells from a mismatched donor. Other programs in the startup’s pipeline are in development for inflammatory bowel disease, type 1 diabetes, and various B-cell mediated autoimmune diseases. Tr1X isn’t the only company turning CD4+ cells into potential Treg therapies. Gentibio works with these immune cells, engineering them into Tregs that selectively go after particular disease targets. The startup, which splits its operations between Cambridge, Massachusetts, and Seattle, is in preclinical development with a lead program for type 1 diabetes. Some Treg startups have landed partnerships with big pharmaceutical companies. The deal that Regeneron Pharmaceuticals inked with Sonoma Biotherapeutics last year focuses initially on ulcerative colitis and Crohn’s disease. Sonoma’s most advanced internal program is in preclinical development for rheumatoid arthritis. AstraZeneca entered the Treg space through a partnership with Quell Therapeutics. This alliance focuses on type 1 diabetes and inflammatory bowel disease. Quell’s most advanced internal program is in preclinical development for preventing organ rejection in liver transplant patients. The lead program of Abata Therapeutics is a potential Treg therapy for multiple sclerosis. The startup has said it expects to bring this therapy into human testing in 2024. Now that it’s out of stealth, Tr1X is in position to keep pace with other Treg startups and perhaps beat them to the clinic. The company said it expects to be in Phase 1 testing in multiple indications in 2024. Tr1X’s Series A financing announced Wednesday was led by The Column Group. Other participants in the round are NEVA SGR and Alexandria Ventures. Public domain image by Flickr user NIH Image Gallery