Telangiectasia, Hereditary Hemorrhagic

Diagonal is advancing its lead program to treat the underlying cause of hereditary hemorrhagic telangiectasia (HHT)WATERTOWN, Mass., Oct. 08, 2024 (GLOBE NEWSWIRE) -- Diagonal Therapeutics, a biotechnology company pioneering a new approach to discovering and developing agonist antibodies, today announced they will participate in multiple presentations at Cure HHT’s upcoming 15th HHT International Scientific Conference, taking place in Mandelieu-la-Napoule, France, October 15-19th, 2024. HHT is a severely debilitating bleeding disorder caused by mutations in ALK1 or Endoglin genes. These mutations lead to severe nosebleeds and gastrointestinal bleeds that lead to transfusion-dependent anemia. People with HHT are also at risk for life-threatening arteriovenous malformation (AVM) ruptures in critical organs such as the liver, lungs, and brain. The disease affects roughly 150,000 people in the United States and European Union. “We’re grateful to Cure HHT for inviting us to speak at their 15th annual meeting, which focuses on advancements in HHT research and emerging therapeutic options for patients. The need for better treatment options is evident, and we are pleased to be able to provide an update on our lead program," said Alex Lugovskoy, Ph.D., Chief Executive Officer of Diagonal. “While still early, our ALK1 agonist antibody, designed specifically for people with HHT, has demonstrated the ability to prevent and reverse the formation of AVMs in two HHT-relevant in vivo models and restored normal signaling in patient-derived cells. We hope these data can translate to significant patient benefit in the clinic." Details on the presentations are as follows: Poster: Bispecific antibodies targeting the ENG-ALK1-BMPRII axis as a novel approach for the treatment of HHT Presenter: JC Hus, Ph.D., Senior Director, Informatics, Diagonal Therapeutics Invited Talk: Therapeutic Potential of ALK1 Activating Drugs in HHT Models Presenter: Philippe Marambaud, Ph.D., Professor, Institute of Molecular Medicine, Feinstein Institutes for Medical Research and Diagonal Therapeutics scientific collaborator Invited Talk: Advancing a New Approach to Tackle the Root Cause of HHT Presenter: Eric Duhaime, SVP, Finance and Corporate Development, Diagonal Therapeutics About Hereditary Hemorrhagic Telangiectasia (HHT) HHT is a rare disease that affects more than 150,000 people in the US and EU, and for which there are currently no approved therapies. In HHT, mutations in the TGF-β receptor superfamily complex create two types of abnormal blood vessels – telangiectasias and arteriovenous malformations (AVMs) – that are fragile and susceptible to rupture and bleeding. These bleeding events lead to chronic anemia, necessitating frequent iron infusions or red blood cell transfusions. AVMs, if left untreated, may result in lung and brain hemorrhage, stroke, heart failure, and death. Diagonal’s agonist antibody candidates reactivate dormant signaling, addressing the root cause of the disease. About Diagonal TherapeuticsDiagonal Therapeutics is a biotech company pioneering a new approach to discovering and developing agonist antibodies. The Company's DIAGONAL platform combines proprietary computational and experimental techniques to overcome historical challenges associated with agonist antibody drug discovery. Diagonal's emerging pipeline – discovered using the DIAGONAL platform – has the potential to deliver life-changing therapies to patients by tackling the underlying cause of disease. For more information, please visit www.diagonaltx.com.Media Contact:Cory Trombleemedia@diagonaltx.com

MONDAY, Sept. 23, 2024 -- For patients with hereditary hemorrhagic telangiectasia (HHT), pomalidomide yields a significant reduction in epistaxis severity, according to a study published in the Sept. 19 issue of the New England Journal of Medicine . Hanny Al-Samkari, M.D., from Massachusetts General Hospital in Boston, and colleagues conducted a randomized, placebo-controlled trial to assess the safety and efficacy of pomalidomide for HHT. Patients were randomly assigned to receive 24 weeks of pomalidomide at a dose of 4 mg daily or matching placebo (95 and 49 patients, respectively). After a planned interim analysis met a prespecified threshold for efficacy, the trial was closed to enrollment in June 2023. The researchers found that the baseline mean Epistaxis Severity Score was 5.0 ± 1.5, consistent with moderate-to-severe epistaxis. The mean difference between the pomalidomide and placebo groups in the change from baseline in the Epistaxis Severity Score was −0.94 points at 24 weeks. The mean between-group difference in the change in the HHT-specific quality-of-life score was −1.4 points. The pomalidomide group more often had adverse events, including neutropenia, constipation, and rash. "The benefits of pomalidomide were most apparent over the course of the second 12 weeks of the trial, persisted during the four weeks after the end of the treatment period, and were not dependent on HHT genotype or baseline epistaxis severity," the authors write. Bristol Meyers Squibb donated the pomalidomide and matching placebo.

Hereditary hemorrhagic telangiectasia is the second most common inherited bleeding disorder in the world and has been linked to severe disease burden, reduced life expectancy and a reduced quality of life. Vaderis Therapeutics’ goal to develop the first drug aimed specifically at a certain rare blood vessel disorder came one step closer today with the news that the therapy is safe and reduced nosebleeds.The therapy in question, a once-daily allosteric AKT inhibitor dubbed VAD044, was trialed in 75 patients with hereditary hemorrhagic telangiectasia (HHT), a genetic disorder that leads to abnormal blood vessels forming in the skin, mucous membranes and certain organs.Almost all HHT patients suffer from unpredictable and often debilitating nosebleeds. After 12 weeks, patients who received the 40-mg dose of VAD044 experienced “clinically meaningful” reductions in the frequency of their nosebleeds, a secondary endpoint of the trial, Vaderis said in an Aug. 27 release.The release was light on any actual data, but the Swiss company did say that regression of HHT-associated vascular lesions was also observed.Patients in the phase 1 trial either received the 40-mg dose, a 30-mg dose or placebo. The primary endpoint of the study was safety, and the data showed that VAD044 was similar to placebo when it came to the frequency and severity of off-target adverse events (AEs). On-target AEs associated with inhibiting the AKT pathway—which helps cells survive and grow in response to extracellular signals—were mostly mild, transient and resolved, the company said.Some of the patients have since been enrolled in a 12-month open-label extension, where they are receiving a 40-mg daily dose of VAD044. Interim six-month data from 27 of these patients “continue to show favorable safety and tolerability profiles with further improvements” in nosebleeds, Vaderis said.CEO Nicholas Benedict said the company is already “interacting with major health authorities to plan the pivotal phase of development for VAD044 in HHT.”“The excitement surrounding the results of the initial 12-week double-blind part of this trial is amplified by the continued improvements experienced by patients through six months,” Benedict added. HHT is the second most common inherited bleeding disorder in the world and has been linked to severe disease burden, reduced life expectancy and a reduced quality of life. Despite this health impact, there are no approved treatments for the condition, according to Vaderis, which described VAD044 as “the first novel therapy intended specifically for the treatment of HHT.”The company is also lining up the therapy to test in breast and prostate cancers, according to Vaderis’ website.“We … already see that after six months of continuous treatment with VAD044 patients experience further improvements in all [nose bleeding] endpoints compared to those seen at 12 weeks,” Hans-Jurgen Mager, M.D., Ph.D., head of the Netherlands Reference Centre for HHT and the study’s co-primary investigator, said in a statement.“It seems that VAD044 has not yet reached its peak effect on HHT disease activity at 12 weeks, and patients continue to improve over time without paying an unexpected price in terms of safety or tolerability,” Mager added.Academic centers in the U.S. are currently enrolling patients to test whether Novartis’ sarcoma drug Votrient can reduce the severity of nosebleeds in HHT. Votrient is a tyrosine kinase inhibitor that has been shown to inhibit the PI3K/Akt signaling pathway.Novartis has a more direct link to Vaderis, with the biotech having been set up in 2019 by two veterans of the Swiss Big Pharma, including Benedict himself.