ADAR1 inhibitors (Accent Therapeutics)

Read about TFF Pharmaceuticals and Augmenta Bioworks' dry powder COVID-19 antibody formula, the world's first gene editing clinical trial for PKU, Bayer's COVID-19 vaccine and other key developments in life sciences research. TFF Pharmaceuticals, Augmenta Bioworks mAb therapy for SARS-CoV-2 infection show promise in preclinical study AUG-3387, the monoclonal antibody (mAb) therapy that TFF Pharmaceuticals and Augmenta Bioworks are developing, demonstrated a strong potential to treat SARS-CoV-2 infection in preclinical studies. The mAb is in dry powder formulation, created using TFF's proprietary Thin Film Freezing method to remove the need for intravenous infusion and, instead, allow the direct delivery of the drug to the lungs. Scientists isolated AUG-3387 using Augmenta Bioworks' SingleCyte platform, which uses artificial intelligence to instantly pro immunity to find antigen-specific antibodies. Around 24 hours after infection, the dry powder was given to hamsters infected with SARS-CoV-2, which later resulted in a dose-dependent decrease in viral load. Other mAbs that were granted emergency use authorization (EUA) by the U.S. Food and Drug Administration only showed efficacy when used as prophylaxis 24 hours post-infection. The study, thus, is the first report of success in viral load decrease through inhaled delivery of a powder formulation. AUG-3387 also appears to be effective against different SARS-CoV-2 variants, including Alpha, Beta, Delta, Gamma, Kappa, Lambda, and Mu. Details of the study are published online through bioRviv, titled "AUG-3387, a Human-Derived Monoclonal Antibody Neutralizes SARS-CoV-2 Variants and Reduces Viral Load From Therapeutic Treatment of Hamsters in Vivo." CureVac Withdraws COVID-19 Vaccine Application From the EMA CureVac has announced that it is withdrawing the application for its first-generation CVnCoV COVID-19 vaccine candidate from the European Medicines Agency to focus on the new vaccine it is developing with GlaxoSmithKline. CureVac called the move a "strategic decision" as it would likely not be until the second quarter of 2022 until the EMA grants approval. At that point, the company would have already been in late-stage clinical trials for the second-generation mRNA COVID-19 vaccine it is building with GSK. Shares in CureVac dropped by 15% Friday following the announcement. The German biotech had been developing the first-generation drug with Bayer and applied for EMA approval in February this year. However, clinical trials had delivered disappointing results with only 47% efficacy against the disease, compared to at least 90% for the other vaccines that are already in the market. "The decision is also aligned with the evolving dynamics of the pandemic response towards a greater need for differentiated vaccines to address the developing endemic SARS-CoV2 situation. As a direct consequence, the existing Advanced Purchase Agreement with the European Commission, which was predicated on employing CVnCoV to address the acute pandemic need, will cease," said CureVac in a statement. CureVac and GSK are expected to begin clinical development over the next months, with the goal to obtain regulatory approval for market readiness in 2022. Pre-clinical results have demonstrated strong potential in the second-generation vaccine, CV2CoV, compared to CVnCoV, exhibiting as much as 10x higher immunity in animal models. Regulus Therapeutics Shifts Focus to Prioritize Drug Candidate for ADPKD San Diego-based biopharmaceutical firm Regulus Therapeutics announced that it is shifting its efforts toward the next-generation autosomal dominant polycystic kidney disease (ADPKD) drug RGLS8429 and will be filing an Investigational New Drug (IND) application soon. In a statement, the company said that prioritizing RGLS8429 would be a better use of its resources due to dose limitations and shorter therapy duration. Regulus had been focused on the Phase Ib trial of its first-generation drug RGLS4326 in ADPKD. Under the new strategy, the data gathered and research efforts placed into the latter will be used to strengthen studies into RGLS8429. "The extensive work and investment we have made in RGLS4326 will directly inform the advancement of RGLS8429, and we believe will make this transition both expeditious and productive. This prioritization of RGLS8429 is supported both by robust data in preclinical models, where we have seen clear improvements in kidney function, size, and other measures of disease severity, as well as the compound's superior pharmacologic profile," said Jay Hagan, chief executive officer for Regulus. A Phase I study has been planned for the new drug candidate for the second quarter of 2022. Homology Medicines Preps For World’s First Gene Editing Clinical Trial on Phenylketonuria Drug Candidate Genetic medicines company Homology Medicines has launched the Phase I pheEDIT clinical trial for its one-time, in-vivo treatment candidate for phenylketonuria (PKU). The announcement comes shortly after the FDA approved its Investigational New Drug Application (IND). HMI-103, the gene editing-based treatment that's part of Homology's dual gene therapy and gene editing technology platform, will be the first of its kind for PKU to enter clinical trials. The HMI-103 pheEDIT trial aims to enroll up to nine patients aged 18 to 55 years old and diagnosed with PKU due to PAH deficiency. The Phase I study will evaluate three doses of HMI-103. Once efficacy and safety are established, the company plans to include younger patients in the trial. The trial will also measure changes in serum phenylalanine (Phe). In addition, Homology shared an update from its ongoing Phase II pheNIX clinical trial, which looks into the effectiveness and safety of HMI-102 gene therapy with adults diagnosed with PKU. Results as of September 30 showed significant reductions in Phe levels, increases in Tyr levels, and reductions in the Phe-to-Tyr ratio. A more detailed update will be shared in mid-2022. Exelixis, STORM Therapeutics Sign Exclusive Partnership To Advance Cancer Research Exelixis has entered into an exclusive partnership with STORM Therapeutics to tap into each other's resources in the development of cancer treatments. The collaboration will start with ADAR1, STORM's therapy under development which makes use of its RNA epigenetic platform to edit double-stranded RNA (dsRNA) molecules and lower their capacity to activate innate immunity. Inhibiting or depleting ADAR1 can, thus, trigger the death of tumor cells. This is significant because around 30% of the tumor cells listed in the The Cancer Genome Atlas are likely to be ADAR1 dependent. "ADAR1 holds tremendous promise as a novel target for cancer. However, discovery efforts to identify ADAR1 inhibitors have remained a challenge, notably the development of rigorous, relevant assays to support small molecule drug discovery... We believe this collaboration has the potential to expand our portfolio of differentiated small molecule therapies in the field of oncology and deliver a first-in-class ADAR1 inhibitor," said Peter Lamb, Ph.D., executive vice president for scientific strategy and chief scientific officer at Exelixis, in a statement. Under the terms of the deal, Exelixis will pay STORM $17 million upfront in exchange for two of the latter's discovery programs that involve RNA modifying enzymes. It will also fund any discovery research activities that STORM is conducting. Exelixis will be responsible for global development, production and commercialization, while STORM will take care of development, regulatory and commercialization milestones and royalties.

University of Cambridge researchers published the first preclinical validation for a novel therapeutic strategy targeting epitranscriptomic modifiers of RNA, opening the door for spinout STORM Therapeutics’ acute myeloid leukemia therapy (AML)–and potentially much more. Tony Kouzarides, cofounder and director of Milner Therapeutics Institute at Cambridge and a Storm co-founder, led the team that published the paper in Nature in April, which was the first published data showing the efficacy of a catalytic METTL3 inhibitor in mouse models of AML. Consistent with earlier findings on METTL3’s role in regulating disease, Storm’s STM2457 decreased AML engraftment and increased survival. Last year the company nominated a related compound as its lead clinical candidate, and Kouzarides said Storm expects it will reach clinical testing early next year. This is the first published in vivo data for a small molecule inhibiting an epitranscriptomic disease target, but the approach has been brewing for years. Just as epigenetic modifications to DNA can directly control gene expression, epitranscriptomic modifications control RNA gene expression indirectly via RNA translation, making them potential therapeutic targets. While the first epigenetic therapy was approved in 2004, the connection between epitranscriptomic modifiers and disease pathways have only begun to be characterized. METTL3 is an epigenetic writer of N6-methyladenosine (m6A) modifications, the most prevalent reversable epitranscriptomic modification in human cells. METTL3 and other writers form m6A modifications via methylation of certain RNA sequences, which is key for numerous processes in normal cells. This would seem to make it an unlikely therapeutic target. But in 2017, two key publications began to elucidate the role of m6A in AML and demonstrate the possibility of targeting the pathway without toxicity in healthy cells. Kouzarides and colleagues published findings showing the role of METTL3 in both establishing disease and in leukemia cell differentiation. Separately, a team from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center showed in a Nature Medicine paper that leukemia cells were more dependent on METTL3 than normal hematopoietic cells. Samie Jaffrey, an author on the paper and a professor of pharmacology at Weill Cornell, said that the abnormal differentiation seen in leukemia cells was abrogated by only mild inhibition of METTL3–important because a complete METTL3 inhibitor delivered systemically would be highly toxic. The new paper from the Cambridge researchers was therefore a proof-of-concept for Jaffrey’s approach as well. “I think a lot of other people were cautious because they felt it was a fool’s errand to go after METTL3,” he said. “I think this makes the METTL3 target seem much more validated.” Researchers from both groups founded companies to exploit the therapeutic pathway in leukemia. Kouzarides and fellow Cambridge professor Eric Miska co-founded Storm Therapeutics in 2015 to develop first-in-class therapies against RNA epigenetic targets. Jaffrey co-founded Gotham Therapeutics in 2017. Storm has raised £42 million ($59.4 million) seed and Series A rounds, while Gotham raised $54 million in a Series A. At least one other company appears to be chasing METTL3: Accent Therapeutics, which last year raised a $63 million B round and announced a co-development deal with AstraZeneca utilizing its RNA-modifying protein platform, has presented in vitro data in AML for its inhibitors of METTL3 and METTL14, another m6A writer. Additional publications have shown more therapeutic possibilities for targeting the m6A pathway, suggesting it may be possible to increase sensitivity to existing therapies in pancreatic and ovarian cancer, for example. m6A methylation has also been linked to a suppressed immune response in infectious diseases like Zika and HIV, and in April a team led by University of California San Diego School of Medicine professor Tariq Rana published in vitro data showing METTL3 inhibition could suppress SARS-CoV-2 replication. Rana’s team has previously shown that the inhibition of ALKBH5, an m6A eraser, can improve the efficacy of cancer immunotherapies in mice, and Rana has spun out ViRx Pharmaceuticals with plans to license intellectual property from the university around RNA therapeutics for broad-spectrum antivirals. But Storm, Accent and Gotham are starting in AML for a reason. Optimizing compounds for AML is an easier task because unlike other cancers, “when you inhibit the METTL3 pathway, you can see the cells differentiating with your eyes,” Jaffrey said. “In most cancers, you can inhibit METTL3 and they will die but you’re inhibiting it to such a degree that probably normal cells will die too. it all comes down to one thing: therapeutic index.” Gotham has identified several solid tumor types with comparable “m6A addictions” it is looking at closely, he added. Several other companies are likely targeting different epitranscriptomic targets. Academic work by an Accent scientific cofounder, Chuan He, has focused on YTHDF1, an RNA reader that could function as an immune system control switch for modulating the response to cancer immunotherapy. He is also a chemistry professor at the University of Chicago. Accent is also pursuing ADAR1 inhibitors for cancer. Silicon Therapeutics, which uses a physics-based approach to drug design for intractable protein targets, is developing an ADAR1 antagonist for cancer. The company said inhibiting ADAR1 can both activate innate antitumor immune cells and directly kill tumors. Gotham is also looking into additional epitranscriptomic regulators that are much less prevalent than m6A, Jaffrey says, using its screening platform to identify and analyze RNA modifiers. Kouzarides envisions a lot more opportunities ahead for the burgeoning space. “These enzymes can potentially regulate many different processes in many different diseases,” he said. He declined to specify which other epitranscriptomic targets Storm is chasing, but the company is currently raising a Series B round to support its anticipated clinical testing for a METTL3 inhibitor in 2022.