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Dr Michael Hayden’s early encounters and experience with patients and families suffering from Huntington’s Disease has had a significant personal impact that shaped his career. As CEO of Prilenia Therapeutics, he tells Lu Rahman why he has dedicated his career to advancing research into this and other neurodegenerative diseases.
Dr Michael Hayden’s experience with Huntington’s Disease (HD) began in the late 1970s, when he first worked with HD families in South Africa, after qualifying as a physician. He visited families in their homes, hospitals and mental institutions as part of a project aimed to determine the prevalence of HD in the country.
“I was moved by these families’ courage, resilience and generosity, and I became imprinted in the early part of my career to do everything I could to alleviate some of the suffering I have seen. I have remained close with some of those families for over 40 years,” he reveals.
He was involved in the creation of the first multi-racial clinic, as well as the first national patient organisation for HD families in South Africa. “As part of this work, I was invited to talk at the first and second international HD meetings in San Diego in 1977. There I met Marjorie Guthrie, founder of Huntington’s Disease Foundation of America (HDSA), who encouraged my move to the Children’s Hospital, Harvard Medical School in Boston in 1980.”
Since then, Hayden has dedicated his career to advance research in HD and other neurodegenerative diseases. As part of his role as the President of Global R&D and Chief Scientific Officer at Teva Pharmaceuticals, he led the approval of Austedo (deutetrabenazine), the second drug ever to be approved for HD. He adds: “At Teva I saw pridopidine’s potential and brought it into the R&D pipeline so we could better understand its mechanism and potential. Later in 2018, I founded Prilenia to further drive pridopidine’s clinical development.”
Pridopidine is currently in late-stage clinical development for HD and ALS. Both trials, the global Phase III clinical trial in HD (PROOF-HD) and the platform trial in ALS are currently active and advancing well despite Covid-19.
Challenges in developing treatments for HD
“HD research presents several challenges,” says Hayden. “Firstly, as it is a slowly progressive neurodegenerative condition, it takes time to study its impact, and therefore clinical trials require longer duration (they can take one to two years).”
“Moreover, regulators have only recently accepted and validated Total Functional Capacity (TFC) as a primary endpoint for potential drug approval. In fact, pridopidine (currently being evaluated in PROOF-HD) has previously shown beneficial effect on TFC, a clinically meaningful endpoint. To patients and their families, functional capacity translates to a patient’s ability to maintain a level of independence and continue to manage their daily lives for longer.”
Unfortunately, the currently approved drugs (Xenazine and Austedo) only address chorea (a symptom of HD characterised by involuntary and unpredictable muscle movements) and no medicines have been approved to either delay onset or slow disease progression.
He adds: “I think there needs to be greater awareness and recognition of mechanisms and treatments that could possibly slow the progression of these diseases. Focus on such mechanisms could have a broader impact and may even be relevant for other neurodegenerative diseases, such as ALS, Parkinson’s or Alzheimer’s diseases. Pridopidine’s mechanism of action through the Sigma-1 Receptor is one of these mechanisms that could have impact on disease progression.”
The Wave and Roche trials
According to Hayden, the termination of these trials, which were focused on silencing the mutant Htt gene – known to drive the development of HD – has been devastating for the HD community.
“In the case of Roche’s trial, one treatment group did worse than placebo, which prompted the trial to be stopped. We do not precisely know yet why it failed, but we do know that many challenges have to be overcome. Potentially tominersen could have failed due to the inability to reach the deep part of the brain that would be necessary, or that the drug knocked down, together with the mutant huntingtin gene, also wild-type huntingtin (normal), which we know has neuroprotective properties. Also, an inflammatory response was seen, and the particular approach did not knock down the alternate spice form of the gene causing HD that includes exon 1.
“It is important to note that an insight into some of the adverse effects could be seen in an earlier open-label study that showed an increase in neurofilament light chain (a biomarker for several neurodegenerative diseases) early in treatment. The correlation of the negative clinical data together with the increase of this biomarker suggests that the biomarker could potentially be a good predictor of clinical effect.”
In the Wave study, there was no evidence of knockdown of huntingtin at all, and with higher dosage, some patients experienced serious temporary adverse events, such as delusions or amnesia among other serious side effects.
“This sadly leaves, pridopidine as the only drug in late-stage development that is assessing clinical outcome of HD as measured by TFC,” says Hayden.
Potential gene therapy approaches
There are currently a number of companies looking at gene therapy approaches. For instance, uniQure is focusing on decreasing huntingtin in the basal ganglia, with targeted delivery, which means intracranial surgery. However, this could also knock down wild-type huntingtin and a more selective approach may be advantageous.
“There are other companies focusing on knock-down, mostly oral therapies, such as Novartis or PTC Therapeutics. The advantages of oral drugs are that they could reach different sections of the brain and are easier to administer (as opposed to intracranial surgery),” Hayden explains.
“Unfortunately, most of these studies are still early in their development (Phase I) and it will take time to see if there are possible therapeutic benefits. Similar to other serious diseases, there is also the potential of combination therapies. That is why we need to support multiple approaches for treating both symptoms, clinical progression as well as treating, hopefully, the cause of the illness.”
The future of pridopidine
Hayden is hopeful that the Phase III trial will confirm pridopidine’s therapeutic potential: “Pridopidine has an established safety and tolerability profile and potentially neuroprotective properties.” The drug candidate recently received Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of HD. Fast Track designation means that investigational drug therapies may be eligible for more frequent communications with the FDA to review the drug’s development and may also qualify for accelerated approval and priority review of new drug applications.
“In addition, we now understand pridopidine’s mechanism of action as a highly selective Sigma-1 receptor (S1R) agonist. The S1R is highly expressed in the brain where it regulates several cellular mechanisms common to neurodegenerative diseases such as HD and ALS. Activation of the S1R by pridopidine enhances the clearance of toxic proteins, enhances energy production and reduces cellular stress and inflammation. These mechanisms are crucial for a neuron’s function and survival. We also know that pridopidine fully occupies the S1R at the dose we are currently studying in our clinical trials (45mg twice per day),” he adds.
Pridopidine is an oral drug candidate, and therefore easy to administer. This means it could be much more accessible to patients than some of the other modalities of therapy.
“We have designed our Phase III study, PROOF-HD, to replicate the previous findings. We have the correct dose, the right duration, the mechanism of action as well as regulatory accepted endpoints, which together make us hopeful that pridopidine will be successful.”
The Phase III trial (PROOF-HD)
The PROOF-HD clinical trial recently completed patient enrolment ahead of schedule and with numbers over the enrolment target despite the Covid-19 pandemic. Prilenia has a total of 499 participants across 59 sites in North America and Europe.
“With the appearance of Covid-19, we had included mitigation measures into the trial design, such as virtual visits, but I am pleased to say that we did not need to implement any of these to date,” Hayden notes.
The study is being conducted in collaboration with the Huntington Study Group (HSG), the Clinical Trials Coordination Center (CTCC) and TFS International and is on track to generate results in early 2023. “It is a real pleasure to be working on this trial with true experts and leaders in HD, including the HSG, CTCC and TFS teams and our principal investigators Andrew Feigin, Ralf Reilmann, Anne Rosser and Sandra Kostyk,” he says.
The ALS platform trial
Hayden explains that the S1R is an attractive target for therapy in ALS because we know that mutations in the S1R are causative for certain forms of ALS. Furthermore, there is a gene-dose relationship with S1R, where complete absence of the S1R leads to childhood onset, whereas if the mutation results in some residual function, there is onset of ALS in adulthood. In addition, pre-clinical studies have shown that overexpression of Sigma-1 receptor can improve outcomes in animal models, including an overall increase in muscle strength. There is also prior clinical evidence that S1R agonists may improve certain features of ALS such as swallowing, saliva and speech. “This validation, together with pridopidine’s safety and tolerability data led to the selection of pridopidine (out of 30 potential therapeutics) to participate in the HEALEY ALS platform trial led by the Healey Center at Massachusetts General Hospital. This is the first platform trial in ALS, and we are honoured to be a part of it,” he says.
“The platform trial is designed to accelerate development of promising new treatments by enabling investigators to simultaneously assess multiple therapeutic candidates through pooling of placebo data across regimens. This minimises the number of patients on placebo and the reduces the total number of patients that otherwise would have had to be recruited to complete multiple separate trials. The Phase II/III clinical trial enrolled its first participant in the pridopidine regimen in January 2021 and we are on track to generate results in early 2023. The PI of this trial is Dr Merit Cudkowicz Chair of Neurology at Mass General Hospital at MGH.”
Pridopidine: promising indications?
“Pridopidine acts on the Sigma-1 receptor, which influences numerous pathways in the cell, including improving mitochondrial function, increasing secretion of protective factors like BDNF, decreasing neuro-inflammation and enhancing autophagy. All these pathways could be useful for various neurodegenerative diseases. We already have promising pre-clinical data for Parkinson’s and Alzheimer’s diseases and in addition, are looking at Fragile X or Rett syndrome with interesting results in animal models.”
Another possible indication is prodromal HD patients who are not yet ill but are destined to develop HD in their lifetime. As with any attempt at neuroprotection, the earlier treatment begins, the more likely we can protect neurons from injury. Early treatment of patients with less neural loss could maintain function at a higher level and potentially lead to a longer lifespan and quality of life.
“My vision for pridopidine is that it could become a standard of care for neuroprotection. For diseases where we can define patients who are close to onset of a neurodegenerative condition, an oral therapy with a benign safety profile – which is what we are trying to establish in our current and planned clinical trials – could become a preventative treatment option,” he states.
Volume 23, Issue 1 – Winter 2021/22
About the author
Dr Michael Hayden is the founder and CEO of Prilenia Therapeutics, a clinical-stage biotech company focussed on developing novel treatments for neurodegenerative and neurodevelopmental disorders. He has authored approximately 900 peer-reviewed publications and is the most cited author for Huntington’s disease. He has been named among 20th Century Canadians “who changed the world” and was inducted into the Canadian Medical Hall of Fame. Dr Hayden is also a Killam Professor at the University of British Columbia and Senior Scientist at the Center for Molecular Medicine and Therapeutics.