Healx Drug Repurposing Programme for Fragile X Syndrome

Healx has a range of methods, and two of these proved particularly successful in identifying drugs that could be repurposed for use in Fragile X. Single drugs were selected initially, then combinations were explored. Some combinations of two drugs exhibited remarkable synergy of action, boosting their effectiveness in the mouse model of Fragile X. These methods will be described in the presentation.

Dr David Brown is Co-founder and Chair of the Board of Healx Ltd, a Cambridge University spinout company which uses Machine Learning to find treatments for children with rare diseases. He was also co-founder of the antibody company Crescendo Biologics. He was listed in the Maserati 100 UK Innovators/ Entrepreneurs list for 2019. Earlier in his career he pursued medical research in the pharmaceutical industry. Whilst at Pfizer he was named co-inventor on the patent for Viagra, and for 8 years he led the team developed Viagra through to proof of clinical efficacy in male impotence. Relpax (migraine) and Revatio (Pulmonary Arterial Hypertension) also came from his team and together these drugs have sales of over $40bn. While at Roche in Switzerland, he was a Director of the company and, as Global Head of Drug Discovery, he had responsibility for productivity of over 2000 scientists at Roche’s five research sites in the USA, Europe and Asia.

Fragile X syndrome (FXS) is a common inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. FXS is caused by the silencing of the FMR1 gene. The Fmr1 knockout (KO) mouse model presents several behavioral characteristics that recapitulate the human condition. Healx’ drug repurposing approach uses computational biology methods to rank drug predictions, pharmacology analysis to propose a rationale to support the in silico predictions, and preclinical validation to demonstrate efficacy. This methodology has been successful in identifying several drug candidates that benefit multiple behavioral phenotypes of the Fmr1 knockout (KO) mouse. Additionally, when these drugs are used in combination at ineffective low doses they also rescued several behaviors that suggest a synergistic or additive effect of the two drugs toward the impaired behaviors. This data will be presented along with complementary biochemical readouts as part of the preclinical package to support Healx clinical studies.

Dr. Ivan Angulo-Herrera received his Ph.D. in Molecular Biology at the Autonoma University, Madrid, focusing on infectious diseases and structural biology. Then, he conducted postdoctoral studies at Scripps Research, Florida, working on the Hepatitis C virus replication and later at the University of Cambridge where he participated in the discovery and characterization of novel primary immunodeficiencies. He has over 8 years of industry experience across different therapeutic areas gained in biotech and contract research organizations. Currently, he is Associate Director of Pharmacology at Healx, where he leads a team of pharmacologists analyzing drug repurposing candidates from Healnet, Healx AI drug discovery platform, making recommendations based on the drug properties and disease biology, and progressing them to preclinical testing for validation.

There have been many clinical trials in Fragile X, yet there are no authorised treatments available for patients. There are many possible reasons for the lack of success in Fragile X clinical programmes; it may be that the drugs under study were ineffective, or that the studies as designed were unable to detect the effects, even though they existed. This talk will discuss some of the considerations we had at Healx when designing our proof of concept clinical trial, in order to maximise the chances of seeing an effect if one exists.

Dr Anthony Hall (Tony) graduated from King’s College London with first class honours in physiology and pharmacology before going on to qualify as a doctor in 1991 from the Royal Free Hospital London. He joined the pharmaceutical industry in 1994 and has spent many years working on the development of drugs for rare diseases. During the past 5 years Tony has worked at Prosensa/Biomarin on the development of antisense oligonucleotides for the treatment of Duchenne muscular dystrophy and at Mereo BioPharma where, as Therapeutic Area Head Orphan Diseases, he worked on the development of a monoclonal antibody for the treatment of osteogenesis imperfecta. In January 2020 Tony joined Healx as Chief Medical Officer, with overall responsibility for the company’s clinical programmes.

Tony was one of the key people who conceived the development programme and clinical trials for the repurposing of nitisinone for the ultra-rare disease alkaptonuria (AKU). The DevelopAKUre Consortium, in which his company participated, was awarded EUR 6 million under the EU’s 7 th Framework Programme and for which a Marketing Authorisation is anticipated. Tony is Co-founder and Trustee of the rare diseases charity Findacure and sits on the Scientific Advisory Board of the patient groups H-ABC Foundation and Duchenne UK. Together with Findacure’s Co-founder, he published a book entitled “The Patient Group Handbook: A Practical Guide for Research and Drug Development”.