DR3

Merck’s search for its next blockbuster product continues to go beyond cancer. The pharmaceutical giant has agreed to pay $10.8 billion to acquire Prometheus Biosciences, a biotech with a Phase 3-ready drug candidate that could be the first in a new class of immunology therapies. While Merck frames the Prometheus drug, PRA-035, as a potential blockbuster in ulcerative colitis and Crohn’s disease, the company says the acquisition is about more than those two inflammatory bowel disorders (IBD). The antibody drug’s potential extends to other autoimmune indications as well. Going further, Merck executives point to the technology that fuels Prometheus’s drug research, a platform that links genetics and biology to guide a precision medicine approach. Merck sees that technology as a way to build on an approach it took in cancer immunotherapy. “The fact that they have this extraordinary biomarker database and having already identified a very important biomarker for ulcerative colitis really will serve to change the way in which immunologists think about their patients and think about these diseases,” Eliav Barr, head of global development and chief medical officer, said during a Monday conference call. “We’ve done that revolution in immuno-oncology and anticipate similar things in the immunology space.” According to terms of the acquisition agreement, Merck will pay $200 cash for each Prometheus share, a 75.4% premium to the stock’s closing price on Friday. When San Diego-based Prometheus went public in 2021, it priced its shares at $19 apiece. Merck’s Prometheus acquisition is expected to close in the third quarter of this year. Merck is looking to expand the breadth of its drug portfolio as it faces expected revenue declines in cancer. The cancer immunotherapy Keytruda continues to be the pharma giant’s top-selling product with $20.9 billion in 2022 revenue, a nearly 22% increase over drug’s sales in the prior year. But sales will decline as the drug’s patents expire in coming years. In 2021, Merck acquired Acceleron Pharma in an $11.5 billion deal that brought pulmonary arterial hypertension drug candidate sotatercept, a potential blockbuster product. Immunology represents a wide open area for Merck growth. The company’s immunology portfolio is currently represented by two anti-inflammatory products, Simponi and Remicade. Sales for both antibody drugs have been declining. Despite the availability of drugs for IBD, it’s a large indication with large unmet medical need. Standard treatments include anti-inflammatory drugs and immune system suppressing therapies, but these products don’t work for all patients. Newer options include small molecule and biologic drugs. Nevertheless, the available IBD therapies come with side effect risks, some of them potentially fatal. PRA023 was designed to block tumor necrosis factor-like ligand 1A (TL1A), a protein associated with both intestinal inflammation and fibrosis. Last December, Prometheus reported positive data from separate Phase 2 tests of PRA023 in ulcerative colitis and Crohn’s disease. In addition to hitting trial goals for efficacy, the drug was well-tolerated and no safety problems were identified. In February, Prometheus presented results from both studies at the annual meeting of the European Crohn’s and Colitis Organisation. Based on those data, the company planned to advance the drug to Phase 3 testing in both intestinal disorders. Merck says it expects to begin that study late this year or in early 2024. Prometheus has said that PRA023’s ability to address both inflammation and fibrosis offers the potential for expanding the drug to other indications. In its 2022 annual report, the company notes the drug’s ability to bind to TL1A and activate the DR3 receptor, a pathway that modulates many types of immune cells and pathways. Last year, Prometheus began a Phase 2 study enrolling patients whose systemic sclerosis, an autoimmune disorder also known as scleroderma, has led to interstitial lung disease. This lung condition is characterized by fibrosis, the formation of scar tissue that causes damage that diminishes the organ’s function. Preliminary data from the study are expected in the first half of 2024. Prometheus has said it expects to disclose a fourth potential indication for the drug later this year. In 2021, Merck revealed its immunology ambitions with the $1.8 billion acquisition of Pandion Therapeutics and a lead drug candidate that at the time had recently posted encouraging Phase 1 data in ulcerative colitis. The drug pairs a signaling molecule called IL-2 with a mutated protein (mutein). The Pandion candidate is intended to selectively activate regulatory T cells in the body to counteract inflammation. But some IL-2 efforts have hit setbacks. Last year, Bristol Myers Squibb ended its alliance with Nektar Therapeutics after that company’s drug failed a Phase 3 test in melanoma, followed by trial failures in kidney and bladder cancers. Last October, Sanofi took a €1.6 billion writedown after the IL-2 drug from its Synthorx acquisition posted lower than projected efficacy. The Pandion drug, since renamed MK-6194, is still in Merck’s pipeline but no longer in ulcerative colitis. Dean Li, president of Merck Research Laboratories, said the company tries to understand how other drugs succeed and fail, while also understanding the ways that these molecules are different from its own pipeline candidates. Barr said that as a mutein, MK-6194 is different than IL-2-targeting agents. Based on Phase 1b testing, he said Merck plans to advance this drug to mid-stage testing in vitiligo, alopecia areata, lupus, and atopic dermatitis. Neither Li nor Barr specified why Merck did not decide to test the drug in ulcerative colitis. If TL1A offers a better way to treat ulcerative colitis than an IL-2 drug, Merck faces competition for the target. A new Roivant Sciences subsidiary formed late last year with rights to a TL1A-targeting antibody from Pfizer. Results from a Phase 2b test of the drug are expected in the first half of this year. Merck faces additional IBD competition. Last year, the FDA approved AbbVie drug Rinvoq for treating moderate-to-severe ulcerative colitis. The drug, a small molecule that belongs to a class of drugs called JAK inhibitors, has also been submitted for FDA review in Crohn’s disease. However, JAK inhibitors are associated with serious side effect risks. Eli Lilly aims to treat ulcerative colitis with mirikizumab, an antibody that blocks a protein called IL-23. The FDA rejected the mirizumab last week citing manufacturing issues. But the regulator did not flag any safety or efficacy problems with the Lilly drug and manufacturing problems usually amount to a delay for a drug’s approval. Though PRA032 was designed specifically to address patients whose IBD was characterized by higher levels of TL1A, Barr said there’s potential for the drug to be used more broadly. The Phase 3 study will enroll all patients with ulcerative colitis and will be sufficiently powered to assess whether being positive for the TL1A biomarker affects the overall efficacy of the drug. While citing the usual caveats of making cross-trial comparisons, Barr said the Phase 2 results of PRA023 showed efficacy that was comparable to available ulcerative colitis drugs.

In people carrying the APOE4 risk variant, a key brain cell type mismanages cholesterol needed to insulate neurons properly --another sign that APOE4 contributes to disease by disrupting lipids in the brain. It's well known that carrying one copy of the APOE4 gene variant increases one's risk for Alzheimer's disease threefold and two copies about tenfold, but the fundamental reasons why and what can be done to help patients remain largely unknown. A study published by an MIT-based team Nov. 16 in Nature provides some new answers as part of a broader line of research that has demonstrated APOE4's consequences cell type by cell type in the brain. The new study combines evidence from postmortem human brains, lab-based human brain cell cultures, and Alzheimer's model mice to show that when people have one or two copies of APOE4, rather than the more common and risk-neutral APOE3 version, cells called oligodendrocytes mismanage cholesterol, failing to transport the fat molecule to wrap the long vine-like axon "wiring" that neurons project to make brain circuit connections. Deficiency of this fatty insulation, called myelin, may be a significant contributor to the pathology and symptoms of Alzheimer's disease because without proper myelination, communications among neurons are degraded. Recent studies by the research group, led by Picower Professor Li-Huei Tsai, director of The Picower Institute for Learning and Memory and the Aging Brain Initiative at MIT, have found distinct ways that APOE4 disrupts how fat molecules, or lipids, are handled by key brain cell types including neurons, astrocytes and microglia. In the new study as well as in those, the team has identified compounds that appear in the lab to correct these different problems, yielding potential pharmaceutical-based treatment strategies. The new study extends that work not only by discovering how APOE4 disrupts myelination, but also by providing the first systematic analysis across major brain cell types using single nucleus RNA sequencing (snRNAseq) to compare how gene expression differs in people with APOE4 compared to APOE3. "This paper shows very clearly from the snRNAseq of postmortem human brains in a genotype specific manner that APOE4 influences different brain cell types very distinctly," said Tsai, a member of MIT's Brain and Cognitive Sciences faculty. "We see convergence of lipid metabolism being disrupted, but when you really look into further detail at the kind of lipid pathways being disturbed in different brain cell types, they are all different. "I feel that lipid dysregulation could be this very fundamental biology underlying a lot of the pathology we observe," she said. The paper's lead authors are Joel Blanchard, an assistant professor at Mt. Sinai's Icahn School of Medicine who began the work as a postdoc in Tsai's MIT lab, Djuna Von Maydell and Leyla Akay, who are graduate students in Tsai's lab, and Jose Davila Velderrain, a research group leader at Human Technopole and former postdoc in the lab of co-corresponding author Manolis Kellis, Computer Science Professor at MIT. Many methods to examine myelination Postmortem human brain samples came from the Religious Orders Study and the Rush Memory and Aging Project. The team's snRNAseq results, a dataset that von Maydell has made freely available, encompasses more than 160,000 individual cells of 11 different types from the prefrontal cortex of 32 people -- 12 with two APOE3 copies, 12 with one copy of each APOE3 and APOE4, and eight with two APOE4 copies. The APOE3/3 and APOE3/4 samples were balanced by Alzheimer's diagnosis, gender, and age. All APOE4/4 carriers had Alzheimer's and 5 of 8 were female. Some results reflected known Alzheimer's pathology, but other patterns were novel. One in particular showed that APOE4-carrying oligodendrocytes exhibited greater expression of cholesterol synthesis genes and disruptions to cholesterol transport. The more APOE4 copies people had, the greater the effect. This was especially interesting given results from a prior analysis by Tsai's and Kellis's labs in 2019 that linked Alzheimer's disease to reduced expression of myelination genes among oligodendrocytes. Using a variety of techniques to look directly at the tissue, the team saw that in APOE4 brains, aberrant amounts of cholesterol accumulated within cell bodies, especially of oligodendrocytes, but was relatively lacking around neural axons. To understand why, the team used patient-derived induced pluripotent stem cells to create lab cell cultures of oligodendrocytes engineered to differ only by whether they had APOE4 or APOE3. Again APOE4 cells showed major lipid disruptions. In particular, the afflicted oligodendrocytes hoarded extra cholesterol within their bodies, showed signs that the extra internal fats were stressing organelles called the endoplasmic reticulum that have a role in cholesterol transport, and indeed transported less cholesterol out to their membranes. Later when they were co-cultured with neurons, the APOE4 oligodendrocytes failed to myelinate the neurons as well as APO3 cells did, regardless of whether the neurons carried APOE4 or APOE3. The team also observed that in post-mortem brains there was less myelination in APOE4 carriers than APOE3 carriers. For instance, the sheaths around axons running through the corpus callosum (the structure that connects brain hemispheres) were notably thinner in APOE4 brains. The same was true in mice engineered to harbor human APOE4 vs. those engineered to have APOE3. A productive intervention Eager to find a potential intervention, the team focused on drugs that affect cholesterol including statins (which suppress synthesis) and cyclodextrin, which aids cholesterol transport. The statins didn't help, but applying cyclodextrin to APOE4 oligodendrocyte cultured in a dish reduced accumulation of cholesterol within the cells and improved myelination in co-cultures with neurons. Moreover, it also had these effects in APOE4 mice. Finally, the team treated some APOE4 mice with cyclodextrin, left others untreated, and subjected them all to two different memory tests. The cyclodextrin-treated mice performed both tests significantly better, suggesting an association between improved myelination and improved cognition. Tsai said a clear picture is emerging in which intervening to correct specific lipid dysregulations by cell type could potentially help counteract APOE4's contributions to Alzheimer's pathology. "It's encouraging that we've seen a way to rescue oligodendrocyte function and myelination in lab and mouse models," Tsai said. "But in addition to oligodendrocytes, we may also need to find clinically effective ways to take care of microglia, astrocytes, and vasculature to really combat the disease." In addition to the lead authors, Tsai and Kellis, the paper's other authors are Hansruedi Mathys, Shawn Davidson, Audrey EffenbergerChi0yu Chen, Kristan Maner-Smith, Ihab Jahhar, Eric Orlund, Michael Bula, Emre Agbas, Ayesha Ng., Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta lin, Tak Ko, Lea R'Bibo, William Ralvenius, David Bennet and Hugh Cam. The Robert A. and Renee E. Belfer Foundation, the JPB Foundation, the Carol and Gene Ludwig Family Foundation the Cure Alzheimer's Fund and the National Insitutes of Health funded the study.

DURHAM, N.C., May 19, 2021 (GLOBE NEWSWIRE) -- Heat Biologics, Inc. (Nasdaq: HTBX), a clinical-stage biopharmaceutical company focused on developing first-in-class therapies to modulate the immune system, today announced that PTX-35 will be featured in several presentations and panel discussions at the 3rd Annual Treg Directed Therapies Summit on May 19-20. PTX-35 is a novel, potential first-in-class antibody modulating TNFRSF25 (death receptor 3 or DR3), a receptor that is preferentially expressed by antigen-experienced T-cells. The 3rd Annual Treg Directed Therapies Summit is focused on targeting and translating Treg modifying therapies and brings together executives and leading researchers from large pharma, biotech and academia to discuss developments in Treg therapies. About PTX-35PTX-35 is a novel, potential first-in-class antibody modulating TNFRSF25 (death receptor 3 or DR3), a receptor that is preferentially expressed by antigen-experienced T-cells. PTX-35 is currently enrolling in a Phase 1 clinical trial for the treatment of patients with solid tumors. About Heat Biologics, Inc.Heat Biologics is a biopharmaceutical company focused on developing first-in-class therapies to modulate the immune system. Heat’s gp96 platform is designed to activate immune responses against cancer or infectious diseases. The Company has multiple product candidates in development leveraging the gp96 platform, including HS-110, which has completed enrollment in its Phase 2 trial, and a COVID-19 vaccine program in preclinical development. In addition, Heat Biologics is also developing a pipeline of proprietary immunomodulatory antibodies and cell-based therapies, including PTX-35 and HS-130 in Phase 1 clinical trials. Forward Looking StatementThis press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 on our current expectations and projections about future events. In some cases, forward-looking statements can be identified by terminology such as "may," "should," "potential," "continue," "expects," "anticipates," "intends," "plans," "believes," "estimates," and similar expressions. These statements are based upon current beliefs, expectation, and assumptions and include statements such as the planned presentations. These statements are subject to a number of risks and uncertainties, many of which are difficult to predict, including the contributions of, the ability of Heat's therapies to perform as designed, to demonstrate safety and efficacy, as well as results that are consistent with prior results, Heat's vaccine platform to provide protection against COVID-19, the ability to enroll patients and complete the clinical trials on time and achieve desired results and benefits, especially in light of COVID-19, Heat's ability to obtain regulatory approvals for commercialization of product candidates or to comply with ongoing regulatory requirements, regulatory limitations relating to Heat's ability to promote or commercialize its product candidates for specific indications, acceptance of its product candidates in the marketplace and the successful development, marketing or sale of products, Heat's ability to maintain its license agreements, the continued maintenance and growth of its patent estate, its ability to establish and maintain collaborations, its ability to obtain or maintain the capital or grants necessary to fund its research and development activities, its ability to continue to maintain its listing on the Nasdaq Capital Market and its ability to retain its key scientists or management personnel, and the other factors described in Heat's most recent annual report on Form 10-K filed with the SEC, and other subsequent filings with the SEC. The information in this release is provided only as of the date of this release, and Heat undertakes no obligation to update any forward-looking statements contained in this release based on new information, future events, or otherwise, except as required by law. Media and Investor Relations ContactDavid Waldman+1 919 289 4017investorrelations@heatbio.com