With no known treatment and symptoms involving functional decline and the potential for death, Aberdeen University in Scotland recently signed on to a clinical trial addressing a novel investigational product known as Pridopidine delivered orally for Huntington’s disease. Called the PROOF-HD study, the company is sponsored by a biotech startup that’s raised nearly $70 million in venture capital funding called Prilenia. In Scotland, several thousand show symptoms of the disorder, with many more carrying the faulty gene that causes this rare disease. Caused usually by a genetic mutation, this rare disease afflicts between 4 to 15 per 100,000 among people usually of European dissent. The study at Aberdeen is led by Professor Zosia Miedzybrodzka, and the hope is that the experimental treatment known as pridopidine can help improve total functional capacity.
A rare genetic-based neurodegenerative disease primarily inherited, the earliest symptoms often involve subtle problems with mood or mental abilities followed by a general lack of coordination and ensuring unsteady gait. A basal ganglia disease triggering hyperkinetic movement disorder (Chorea), the disease advances with uncoordinated and involuntary body movements while physical ability gradually degrades. Horrifically, the disease ultimately impacts the individual’s ability to talk while mental abilities further decline and the patient transitions into a full dementia. Typically starting between the ages of 30 and 50, it can start at any age, and in the dominant inherited form, the condition can develop in each successive generation.
According to the Huntington Disease Association in the United Kingdom, with genetic testing, the actual diagnosis of the disease became more precise and hence the estimated incidence of the disease more accurate. For example, in the UK, it’s estimated that about 6,700 people in the UK are currently living with the disease or about 12.4 per 100,000 or 1 out of every 8,065 may be affected.
According to a comprehensive report from the Scottish Needs Assessment Programme titled Huntington’s Disease, Acquired Brain Injury and Early Onset Dementia, the incidence of the disease in Scotland is 10 to 12 per 100,000.
The Investigational Product
A small molecule investigational drug, pridopidine binds to the sigma 1 receptor (SIR) at low doses. S1R plays a role in neuroprotection—that is, it helps protect the structure and function of nerve cells by boosting the production of brain-derived neurotrophic factor (BDNF). Researchers believe that HD diminishes levels of BDNF, a mechanism leading to neurodegeneration. The hope here is that the experimental drug binds to S1R in the brain and thus activates the receptor to increase BDNF.
Clinical Trials Results
A few important clinical trials are relevant here. In the 227 HD patient, Phase 2b HART (NCT00724048) trial based in North America, the sponsor investigated the safety and effectiveness of three doses of the experimental drug (20,45 and 90 mg) daily for three months as compared to a placebo. The study led to the conclusion that the patients actually tolerated the drug well but unfortunately the treatment failed to successfully address the improvement of HD symptoms, reported Huntington’s Disease News.
In the Phase 3, 437 HD patient MermaiHD (NCT00665223) study in Europe, subjects were randomized and then received either 45 mg or 90 mg or a placebo once a day for 26 weeks. Like the HART study, the HD patients tolerated the drug well but the treatment failed to help patient’s movement related symptoms as compared to the placebo arm of the study, reported the study investigators out of the Department of Neurology, Hospital Ramón y Cajal, CIBERNED in Madrid, Spain.
The phase 2, PRIDE-HD study (NCT02006472) conducted between 2014 and 2016 and again sponsored by Prilenia in collaboration with the European Huntington’s Disease Network and the Huntington Study Group revealed the study drug failed to improve patient motor function at week 26 but potentially slowed disease progression based on a rating scale known as total functional capacity (TFC) that involves gaging the patient’s ability to perform basic functions, such as working or performing domestic tasks, for example. The study team reported no major adverse side effects during the duration of the study, reported Joana Cavaco Silva writing for Huntington Disease News.
To summarize, the product has been shown to maintain functional capacity in early HD patients as measured by TFC. Moreover, the product is also under investigation for ALS—in fact, according to the sponsor’s website, it was recently selected from an international competition of over 30 potential therapeutics for inclusion in the first ever ALS platform trial, led by the Healey Center for ALS at Massachusetts General Hospital. Now Pridopidine is in late Phase 3 clinical trials for both HD and the platform trial targeting ALS.
The clinical trial (NCT04556656) called Pridopidine’s Outcome On Function in Huntington Disease or “PROOF-HD” is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of the investigational product pridopidine 45 mg twice per day in patients with early stage Huntington’s disease (HD).
Launched in Q4 2020, this clinical trial runs until April 2023. A global effort, the study includes a couple dozen sites in both the United States as well as Europe and the United Kingdom, including Aberdeen University in Scotland.
Interestingly, perhaps due to the history of clinical trial results, the sponsor lists only one primary outcome measure that not surprisingly centers on the Unified Huntington’s Disease Rating–Scale Total functional capacity (UHDRS-TFC) from baseline to 65 weeks.
Recently launched in Scotland, Alistair Haw runs the Scottish Huntington’s Association and was quoted in Scottish press, “Whilst there are no current treatments that slow the advance of HD, families impacted by this appalling condition can be encouraged by the volume of trials currently underway to find the breakthrough we all long for.”
Founded by ex-Teva Pharmaceutical research and development (R&D) executive Michael Hayden, Prilenia is a clinical-stage biotech company focused on developing novel treatments for neurodegenerative and neurodevelopmental disorders. The company is led by Dr. Michael Hayden, MD, PhD, the founder of five biotech companies and previous President of Global R&D and Chief Scientific Officer at Teva. Michael has directed the development of multiple innovative drug products, leading to 35 approvals between 2012-2018. Their lead asset is Pridopidine, a first-in-class drug candidate with an established safety profile and potential in multiple movement disorders and neurodegenerative diseases affecting adults and children. Pridopidine is currently being evaluated for the treatment of Huntington’s disease in our global Phase 3 PROOF-HD trial, and for the treatment of ALS in the Phase 2/3 HEALEY platform trial. The Company is based in Naarden, the Netherlands, Herzliya, Israel and Boston, MA.
The company has raised $68.5 million in venture capital funding led by Forbion accompanied by Morningside Venture Investments, Sectoral Asset Management, Talisman Capital Partners and ALS Investment Fund. Founder Hayden is an MD and PhD who is the former President of Global R&D and Chief Scientific Officer at Teva Pharmaceuticals where he led the development of approximately 35 novel therapies toward approval in several therapeutic areas primarily in the central nervous system (CNS).
Aberdeen University Clinical Trials
Aberdeen has prestige: its founding in 1495 is noteworthy by itself, representing Scotland’s third oldest university (fifth oldest in all of the UK). Ranked in the top 20 of the UK, its in the top 180 universities worldwide.
In the university’s Health Services Research Unit, clinical trials are actually managed by what’s known as CHaRT, established in 2004 with full registration status from the UKCRC by November, 2007. Directed by Professor Graeme MacLennan, CHaRT includes over 35 staff. CHaRT supports the necessary collaboration for high quality randomized controlled trials providing access to the core competencies of experienced trialists, trial management, data processing and management, statistics, and more. Aberdeen’s Clinical Research and Quality Assurance division also is involved overseeing clinical trials.
Lead Research/Investigator for PROOF-HD in Scotland
Professor Zosia Miedzybrodzka, MB, ChB, PhD, FRCP, Edin, FRCOG
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