Sunday, December 25, 2022


This holiday season – with the Ukraine conflict having raised fears of a World War III and hundreds of millions of people still lacking cures for neurological disorders, cancer, and thousands of other maladies – it’s time for people and their leaders everywhere to embrace a new global ethic: #FightDiseaseNotWar.


With the U.S. sadly far in the lead, nations spend trillions annually on their armed forces.


A Huntington’s disease gene expansion carrier who lost his mother to this devastating disease, I continue to watch HD brothers and sisters face enormous hurdles in their care – and die.


“Once again, Congress has failed to take action to ensure that families affected by Huntington’s disease (HD), a devastating brain disorder that impacts more than 200,000 American families, have uninterrupted healthcare coverage,” Huntington’s Disease Society of America CEO Louise Vetter wrote in a December 20 community statement.


As Vetter pointed out, the Fiscal Year 2023 federal spending bill, just approved by the Senate and the House, “does not include provisions of the Huntington’s Disease Parity Act (S. 868, H.R. 2050) which would eliminate the two-year waiting period for Medicare coverage and Social Security Disability Insurance (SSDI) benefits for those who qualify for federal disability because of the serious progression of their Huntington’s disease.”


‘Relative pennies on the national budget’


Vetter asserted that, despite twelve years of advocating for the HD Parity Act, “families affected by HD will continue to have to brace themselves for two years without medical care in a system that puts their needs at the bottom of the congressional priority list. Two years is too long for someone disabled by their incurable neurological disease to suffer without medical coverage, and Congress could close this loophole for relative pennies on the national budget.”


In Fiscal Year 2021, national defense outlays comprised almost half – $742 billion – of the $1.6 trillion discretionary federal budget. Health spending accounted for $140 billion.


The National Institutes of Health (NIH) – a major source of disease research – had a budget of $47 billion in Fiscal Year 2021. Its budget has showed a steady relative decline since 2003.


It can take up to $1 billion for a biopharma company to research, test, and market a single successful drug.


A new vision


#FightDiseaseNotWar: let’s dramatically shift our budgetary – and societal – focus by shifting more funds to the NIH, our health-related research universities, and other institutions focused on well-being.


The coronavirus pandemic has laid bare the deep, continuing inequalities, inconsistencies, and confounding nature of the U.S. health system


#FightDiseaseNotWar: let’s overhaul that system by creating a public, community-based network available to all and – instead of being driven by bureaucracy and profit – responsive to patient needs first.

Friday, December 16, 2022

In ‘Journal of Huntington’s Disease,’ my article analyzes record of my ‘realistic and unapologetic’ blog


Today the Journal of Huntington’s Disease (JHD) published my article “Striving for a Realistic and Unapologetic View of Huntington’s Disease,” which describes how this blog has helped give voice to the HD community since 2005.


In addition to the 322 articles of this blog, I have written about HD in EHDN News, The Chronicle of Higher Education, Huffington Post, and collections of essays produced by HD advocates.


My JHD article is my first for a peer-reviewed scholarly journal – a key in my quest to inform the HD community and deepen my exploration of the history of the HD cause.


The JHD, a scientific journal started in 2012, focuses on research, with occasional articles by advocates. My article is a “Perspective” piece.


As I report in the JHD, a fellow HD gene expansion carrier viewed my blog as exposing families’ difficult struggles with HD in a “realistic and unapologetic way.”


My blog “has explored major challenges for the HD community, has become a key reference for HD families, and has chronicled the quest to defeat the disease,” the JHD abstract states.


In the article, I analyze the blog’s thematic impact, featuring a table noting the dozens of HD-related topics covered in 314 articles produced by April 2022, including advocacy and awareness-building, clinical trials, genetic testing, and coping strategies.


The publication of the article also “marks the extraordinary feat of an HD gene expansion carrier continuing to blog in his 60s.” In January, the blog will enter its 19th year.


Please click here to view the open access article, including a downloadable PDF.

Thursday, November 10, 2022

Ten years out of the terrible and lonely Huntington’s disease closet, as new research and investments offer hope for treatments


Ten years ago this month, I exited the “terrible and lonely Huntington’s disease closet” by publishing an essay on my plight and advocacy as an HD gene carrier in The Chronicle of Higher Education.


Fortunately, asymptomatic as I near 63, I continue to teach, research the history of the HD cause, and enjoy family milestones such as my gene-negative daughter Bianca’s graduation from college and my wife Regina’s and my 30th anniversary celebration – events that I feared HD would prevent me from appreciating.


As we approach Thanksgiving, my favorite holiday, I feel a profound gratitude to my family, friends, and colleagues at work and in the HD cause.


So I want to reflect on my journey since exiting the closet. I also want to report on new paths of research that could offer hope for what we in the HD community (and beyond) desperately await: effective therapies (treatments).


Becoming a more effective – and convincing – advocate


I started this blog in January 2005 under the pseudonym Gene Veritas. Having told my family’s story using my real name (Kenneth P. Serbin) in a widely read publication has enabled me to become a more effective – and convincing – advocate. I could now speak with full transparency about HD, provide an example for others still hiding in the closet, and build new partners in the fight to raise awareness and funds.


Before exiting the closet, I was sheepish about fundraising and other aspects of my advocacy, restricting my efforts to relatives and close friends who knew about my family’s struggles. After my exit, I became more self-assured.


In 2013, the Serbin Family Team in the annual Hope Walk of the Huntington’s Disease Society of America (HDSA) became the top fundraiser nationwide, taking in more than $16,000 in donations from dozens of generous supporters.


Collaborating with work colleagues


I most feared the consequences of revealing my story at my workplace, the University of San Diego (USD), because of concerns about discrimination. I knew HD gene carriers had been fired by their employers. My USD colleagues were shocked by my revelation.


However, those colleagues ultimately showed great solidarity. By advocating about HD at work, I attracted new allies, boosted awareness, and served as a bridge to resources for those facing HD (click here to read more).


My advocacy reached a milestone in May 2017, when I traveled with my family to Rome to help represent the U.S. HD community at HDdennomore: Pope Francis’ Special Audience with the Huntington’s Disease Community in Solidarity with South America. My trip was sponsored by several USD units, including the Frances G. Harpst Center for Catholic Thought and Culture, directed by Jeffrey Burns, Ph.D. Later that year, the center hosted a talk by me exploring the social, scientific, and religious meaning of this extraordinary the papal event.


Francis became the first world leader to recognize HD, declaring that it should be “hidden no more.”



Business card of Kenneth P. Serbin (aka Gene Veritas) shared at scientific conferences and with anyone interested in learning about the HD cause (photo by Gene Veritas)


In early 2020, before the coronavirus pandemic exploded in the U.S., Dr. Burns and I collaborated in a screening at USD of the short documentary Dancing at the Vatican, which features HDdennomore. In late 2020 I helped promote the launch of the film online.


This year, I fulfilled one of the long-term goals outlined in my 2012 coming-out essay: shifting my academic focus from my beloved Brazil to the history of the quest for HD therapies.


With support from USD and The Griffin Foundation, I submitted the project for funding to the National Science Foundation. Although I was not granted funding initially, the foundation’s program officers encouraged me to reapply.


PTC’s helpful infusion of new capital


We all anxiously await effective therapies. Over the past ten years, I have increased my attention to the intensification of the efforts by labs and biopharma companies to achieve success.


The last several years of such efforts have felt like an emotional roller coaster for the HD community, though that’s not unusual for a difficult endeavor like drug development, which involves both positive and negative clinical trial results and cumulative learning.


Last month, I reported on the abrupt shutdown of the firm Triplet Therapeutics, Inc., which had explored a much-awaited proposed therapy. I also noted that the U.S. Food and Drug Administration (FDA) had requested that PTC Therapeutics, Inc., provide further information before allowing a clinical trial of its HD drug, PTC518.


But there was also potential good news.


Despite the FDA-imposed delay in a U.S. trial, PTC has reached a financing deal with the investment firm Blackstone, based on PTC’s plans to expand its drug pipelines to other diseases. The deal, which in the best-case scenario could infuse $1 billion of investment, puts “PTC in a strong position to continue to execute our mission,” Emily Hill, PTC’s chief financial officer, stated in an October 27 press release.


PTC518, a so-called splicing molecule, is also classified as a small molecule drug. It is thus taken as a pill – in contrast with riskier, less convenient delivery methods used by other HD programs, which include brain surgery and spinal injections. Early next year, PTC will furnish an update on the PTC518 trial. The trial continues in several European countries and Australia.


Roche diversifies its approach


In March 2021, Roche reported disappointing news: its gene silencing drug tominersen (an antisense oligonucleotide, or ASO) failed to improve symptoms in volunteers in the firm’s GENERATION HD1 Phase 3 (large-scale testing of effectiveness and safety) trial. This September, Roche announced GENERATION HD2, a less ambitious, Phase 2 (effectiveness, dosage, and safety) retesting of tominersen to start in early 2023.


In its presentation of GENERATION HD2 at the annual Huntington Study Group annual meeting in Tampa, FL, on November 3, Roche revealed that it has expanded its pursuit of HD therapies by embarking on two preclinical (nonhuman) projects.


Whereas tominersen targeted both the normal and abnormal (expanded) huntingtin gene, Roche will now seek to develop a drug that aims at just the abnormal gene. (Wave Life Sciences already reported in September that it had successfully targeted the abnormal gene in an early stage clinical trial, although yet without evidence of impacting symptoms.)


Like PTC’s program, Roche’s second preclinical program will aim at developing a splice modifier that would be taken orally.


“The medical need in the HD community is clear and we recognize that a range of different therapeutic approaches are likely to be required,” Mai-Lise Nguyen, of Roche’s Global Patient Partnership, Rare Diseases, wrote me in a November 3 e-mail.



A slide from the Roche presentation at the 2022 Huntington Study Group meeting illustrating the firm's three approaches to attacking Huntington's disease (slide courtesy of Roche)


Another ten years?


After the major disappointment in the shutdown of Triplet, I was heartened to learn of Blackstone’s massive investment in PTC, which indicates that both firms see PTC’s potential treatments as viable and profitable.


I was also encouraged to see how Roche, in the words of its Huntington Study Group presentation (see photo below), has augmented its HD research portfolio, reflecting a “commitment to advance scientific understanding and drug development in HD through continued collaborations” with HD organizations.


With the ingenuity of HD scientists and the dedication of HD family members to participation in research, the march towards potential therapies continues. I hope to chronicle continuing progress over the coming years not only free of the “HD closet,” but, thanks to new therapies, free of significant HD impacts, as well.


A slide from the Roche presentation demonstrating the commitment and collaborations involved in the quest for HD therapies (slide courtesy of Roche)

Friday, October 21, 2022

After abrupt shutdown of Triplet Therapeutics, Huntington’s disease community regroups in the fight for therapies


Triplet Therapeutics, Inc., a Cambridge, MA-based start-up that aimed to transform the treatment of Huntington’s disease and related disorders, has shut down, citing a lack of new investment partners and the discovery that its proposed HD drug caused adverse effects in animal tests.


On October 11, Triplet CEO Nessan Bermingham announced the company’s closure on his LinkedIn page. The abrupt closure was another piece of tough news regarding potential therapies for HD.


In March 2021, Roche and Wave reported negative trial results for drugs aimed at reducing the toxic mutant huntingtin protein in patients’ brains. These drugs are antisense oligonucleotides (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.


Triplet’s strategy


Triplet had designed its own ASO, but with a different strategy: to stop the deleterious expansion of the mutant huntingtin gene (click here to read more). Known as somatic expansion, this process drives the disease and can hasten the onset of symptoms. By slowing this expansion, Triplet had hoped that its drug would head off the disease early.


Triplet scientists and others have viewed this approach as a more effective alternative to the “huntingtin lowering” strategy devised by Wave, Roche, and others.


Capitalizing on recent groundbreaking HD genetics research, Triplet, founded in late 2018, developed the only clinical trial program to slow or stop somatic expansion in HD. Triplet also had hoped to develop treatments for others among the 50 rare conditions with somatic expansion, which, like HD, are called repeat expansion disorders.



Brian Bettencourt, Ph.D., Triplet's former senior vice president for research, explains a slide illustrating the firm's pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference, 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).


“It is with great sadness we announce the closure of Triplet Therapeutics,” Bermingham wrote on LinkedIn.


The “underlying science of targeting repeat expansion disorders” remains “a viable approach from our vantage point,” Bermingham wrote. However, crucially, in animal studies, the data from Triplet’s HD drug “reflected prior experiences” with ASO toxicity in the central nervous system – a reference to the Roche and Wave results.


Specifically, the ASO showed signs of harming neurons (brain cells). “As a therapeutic modality, given Roche’s data, our data, lack of efficacy from Wave products, our belief is that neurons may be particularly sensitive to antisense oligonucleotides,” Bermingham told STAT.


Triplet secured $59 million in initial financing and investment. After the bad news in 2021 from Roche and Wave, Triplet struggled to raise the money needed for its planned next step: an early phase clinical trial of its ASO. “The clinical data really put a chill on the overall interest or risk perceived within Huntington’s disease,” Bermingham noted.


SHIELD HD continues to provide key data


To provide data about the disease for the clinical trial it was planning, Triplet has run a separate, two-year study, without a drug, of approximately 70 presymptomatic and early-disease-stage carriers of the HD mutation. Called SHIELD HD, the study involves cognitive testing, brain MRI scans, blood tests, and examination of cerebrospinal fluid drawn from spinal taps (click here to read more). The sites are Canada, France, Germany, the United Kingdom, and the U.S.


In March, Triplet scientists presented a preliminary analysis of this data at the 17th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the virtual nonprofit biotech focused exclusively on developing HD therapies. CHDI is the largest private funder of HD research.


SHIELD HD may end in the next few months. In Bermingham’s announcement about the closure of Triplet, he said that CHDI, “a great partner and patient advocate,” stepped in to help SHIELD HD sites complete their work.


Triplet’s representatives are now seeking potential partners to continue the company’s research, including a new plan for a clinical trial.


Assessing risk


In an online interview with me on October 21, Irina Antonijevic, M.D., Ph.D., the former chief medical officer of Triplet, explained that discovering toxicity of the ASO in the animal studies surprised the firm’s researchers. However, she emphasized that the toxicity was “minimal” at therapeutic dose levels, with the animals not suffering any functional loss.


As noted publicly, Triplet had also developed several, more potent backup ASOs, Dr. Antonijevic said. The more potent the drug, the smaller the dose needed, therefore reducing the chance of toxicity or an adverse effect, she added.


Nevertheless, in a more risk-averse investment climate, Triplet could not find the necessary partners to carry on its clinical trial program with the added concern about the toxicity, Dr. Antonijevic observed.


“I think that they are just sort of very different risks,” she said. “Somebody takes maybe a risk to say, ‘Maybe this drug has a risk, but I have a disease, and I know what this disease will do to me.’”


For a drug company, the risk involves “investing millions” and waiting years to see if there is a return on investment, she said.


Tweaking drug safety, efficacy, and delivery


Triplet’s experience revealed how the field of HD drug development needs to tweak the safety, efficacy, and delivery of ASOs into the brain. Despite the challenges, a number of other firms and many researchers believe ASOs merit more study and clinical trials.


Roche has developed a revised clinical trial plan, including lower and thus potentially less toxic doses of its ASO. It will start a second trial of that ASO in early 2023.


Wave, building on its failed 2021 early stage trials of two ASOs, put a third drug into another small, early phase trial. Unlike the previous drugs, this Wave ASO successfully reduced the mutant huntingtin protein. Also, for the first time, it did this without lowering the level of the healthy protein – something that occurs with the Roche drug.


“This is, as far as we know, the first time anyone has ever selectively lowered only one copy [of a total of two] of a protein inside of a human body,” the HD science site HDBuzz commented on Sept. 30.


The method of delivery is important for all drugs, especially for ones introduced into the brain. The Roche and Wave trials use spinal taps (intrathecal injections). Triplet had projected using an

injection via a small reservoir implanted on the top of the brain. The firm uniQure is injecting its drug using brain operations.


Developing a pill


Drug developers point out that the most convenient HD drug would be a pill – taken orally, at home, and without medical assistance. These drugs are known as small molecules.


Several firms have embarked on small molecule clinical trial programs for HD.


An important trial of one of these small molecule drugs, a huntingtin-lowering pill developed by Novartis, was halted in August for safety reasons. Some of the trial volunteers on the drug developed problems with their nerves, known as peripheral neuropathy.


FDA requests more data from PTC


On October 18, another firm enrolling people in a clinical trial for a small molecule, PTC Therapeutics, Inc., was asked by the U.S. Food and Drug Administration (FDA), to provide further information before allowing a clinical trial of its HD drug, PTC518. PTC announced that enrollment is ongoing for the planned 12-month Phase 2 trial in several European countries and Australia.


Both branaplam and PTC518 are so-called splicing molecules.


“PTC pioneered the development of splicing molecules and we have learned about the essential elements to successfully develop these molecules,” Jeanine Clemente, the senior director of corporate communications at PTC, wrote me in an October 20 e-mail in response to my questions about the FDA decision. “We cannot comment on the FDA’s thoughts regarding branaplam or splicing molecules, in general.”


However, Clemente pointed out that PTC518 is highly specific and selective for the huntington gene.” She added that, in many important ways, “PTC518 is different than branaplam.”


HDBuzz also noted that PTC518 “may have more ideal drug properties, compared to branaplam.”


The FDA has asked PTC for additional data to support the dose levels and duration proposed in the trial, Clemente wrote.


Clemente added that PTC enrolled its trial entirely with patients outside of the U.S., including approvals to conduct the study at all proposed dose levels. “There have been no treatment-associated adverse events reported to date,” she stated. “We will continue to work with the FDA to potentially enable enrollment of U.S. patients in the trial.”


Keeping perspective in a difficult fight


Triplet will host a podcast later this year to discuss the “birth, life and death” of the firm, CEO Bermingham stated in his announcement of the closure.


The HD community must keep the Triplet shutdown – and all news regarding the ups and downs of the search for HD therapies – in perspective, noted Martha Nance, M.D., the director of the Huntington’s Disease Society of America Center of Excellence at Hennepin County Medical Center in Minneapolis.


“We would not do research if we already knew all the answers,” Dr. Nance wrote me in an October 18 e-mail. “HD patients and families have bravely faced their difficult disease for generations, and the doctors and scientists are doing their best, along with patients and families, to find a brighter path.”


As an asymptomatic HD gene expansion carrier who has not yet participated in a clinical trial, I had high hopes for the Triplet program, with its focus on attacking the disease in the early stages. I was deeply saddened to hear that the firm closed. I also felt in the gut once again the hard reality of marshalling resources – including financial support – for combating rare diseases.


Companies like Triplet are venture capital-funded businesses pursuing high-risk, high-reward endeavors, and many such endeavors fail. So we are fortunate to have a nonprofit like CHDI as a backstop.


Dr. Nance’s wisdom reminded me of the need to join with my fellow HD and rare disease advocates to regroup in the fight for therapies.


“Finding a solution to brain cell death in HD is not easy,” she observed. “And as we edge closer to an answer, each failure seems more dramatic. It would be nice if the answer would just reveal itself, if the answer to HD was simple and easy, but we will not let the setbacks of the last two years prevent us from moving forward.”

Tuesday, September 20, 2022

Roche confirms second, more focused, trial of Huntington’s disease drug will start early next year


As anticipated, the pharmaceutical firm Roche will retest its Huntington’s disease gene silencing drug, tominersen, by enrolling a more limited group of volunteers for a new clinical trial, which should start in early 2023.


Roche announced the new trial, GENERATION HD2, on September 18 at a meeting of the European Huntington’s Disease Network (EHDN) in Bologna, Italy. Roche also issued a letter to the HD community.


Roche halted the GENERATION HD1 trial of tominersen in March 2021 because of lack of efficacy against HD symptoms.


However, after months analyzing the GENERATION HD1 data, Roche reported in January that tominersen might benefit younger patients with less advanced symptoms. The new 16-month study, GENERATION HD2, will verify efficacy in that group.


GENERATION HD1 enrolled clinical trial volunteers ranging in age from 25-65 and included people with more advanced disease.


GENERATION HD2 will limit participation to people aged 25-50 who have “prodromal (very early subtle signs of HD) or early manifest HD,” the Roche letter stated.


“I am very excited about this new trial,” Jody Corey-Bloom, M.D., Ph.D., wrote me in a September 19 e-mail.


Dr. Corey-Bloom directs the Huntington’s Disease Society of America (HDSA) Center of Excellence  at the University of California San Diego, a site for GENERATION HD1 and again for GENERATION HD2.


“A lot of thought has gone into the new trial,” Dr Corey-Bloom observed. “I think this is a very well-planned trial!”


Roche world headquarters in Basel, Switzerland (photo by Norman Oder)


Key adjustments in dosing


According to the Roche statement, GENERATION HD2 aims to sign up approximately 360 participants in approximately fifteen countries (Argentina, Austria, Australia, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, the United Kingdom, and the United States). Additional locations might be added.


The study will have three cohorts. One third will receive placebo, one third 60 mg of tominersen, and one third 100 mg. To ensure the objectivity of the trial, neither the participant nor study team will know what the participant receives.


In contrast with GENERATION HD1, the new trial also will administer lower doses of tominersen. In GENERATION HD1, all volunteers receiving the drug took 120 mg. In GENERATION HD2, participants taking the drug will get either 60 mg or 100 mg.


Another key difference involves the frequency of dosing. GENERATION HD1 administered the drug every two or four months, whereas the new study will dose at only four months.


These adjustments are a major goal of the study: to determine whether lower or less frequent dosing can be beneficial. Such lower dosing or less frequent dosing potentially avoids some of the problems seen in GENERATION HD1. In that trial, the higher dose did not benefit volunteers (click here and here to read more).


As in the first trial, in GENERATION HD2 tominersen will be administered via lumbar puncture (spinal tap).


Renewed but cautious hope for preventing HD


The Roche letter reported that GENERATION HD1 and all other related tominersen studies have closed.


“These studies comprised the first-ever Phase III [efficacy] clinical program to test the huntingtin-lowering hypothesis,” the letter noted, referring to tominersen’s mechanism of lowering the amount the huntingtin protein involved in HD. “Additionally, it was because of the HD community’s commitment to research that the trials recruited faster than anticipated, and thus generated data faster than anticipated.”


That commitment, the letter observed, “inspires all researchers to continue pursuing potential options for people impacted by the disease.”


Roche will announce additional information about GENERATION HD2 in the coming months.


After the devastating news about tominersen 18 months ago, its potential seemed dead. Now, though enthusiasm about tominersen has perhaps diminished, a new, albeit less ambitious, path perhaps has emerged for the drug.


"Overall, the announcement of the new GENERATION HD2 trial at the EHDN meeting was well received by the audience in Bologna, which was a mix of clinicians, scientists, and families," HDSA CEO Louise Vetter, who attended the meeting, wrote me in an e-mail. "The fact that this trial is clearly a dose-finding study was notable, and it seem representative of the more conservative mood in the HD clinical science right now."


“While the results of GENERATION HD1 were certainly disappointing for everyone, they don’t mean that huntingtin-lowering isn’t a viable therapeutic approach,” Sarah Hernandez, Ph.D., the Director of Research Programs for the HD-focused Hereditary Disease Foundation, wrote me in an e-mail. “Targeting huntingtin directly targets the cause of HD and remains one of the strongest therapeutic hypotheses.”


GENERATION HD1’s results “also don’t mean that HTT lowering won’t eventually work for a broad population of people with HD,” Dr. Hernandez added. “They just mean that tominersen seems to require a more narrow patient group for efficacy. The new GENERATION HD2 trial seeks to define exactly what that patient group is, which could be very significant in moving the field forward.”


My hope is that GENERATION HD2’s aim to treat individuals earlier in the disease could generate valuable insights for a major goal in the science of HD and other neurodegenerative diseases: a therapy to prevent symptoms from appearing in disease gene carriers like me.

Tuesday, August 30, 2022

After other firms’ setbacks, Prilenia readies for readout on Huntington’s drug that improves daily function


August brought more difficult news for the Huntington’s disease community with the halting of yet two more clinical trials. However, Prilenia Therapeutics announced at a major research conference last week that it expects to obtain definitive results from a study of a drug proposed to improve function in the early stages of the disease.


Prilenia CEO and founder Michael Hayden, M.D., Ph.D., a leading HD scientist, reported that the Phase 3 clinical trial of pridopidine is on schedule, with administrators expected to release results early in the second quarter of 2023. (Click here for background on pridopidine, Dr. Hayden, and Prilenia.)


On August 25 Dr. Hayden provided a brief update on the trial, called PROOF-HD (PRidopidine Outcome On Function In Huntington Disease), at HD2022: Milton Wexler Biennial Symposium, sponsored by the HD-focused Hereditary Disease Foundation. It was held August 24-27 at the Royal Sonesta Hotel in Cambridge, MA.


If successful, the PROOF-HD trial will result in a landmark not just for HD, but neurodegenerative diseases in general. Its potential significance has increased because of the disappointing results from two important HD gene silencing clinical trials in March 2021 and the news this month that key trials by Novartis and uniQure had to stop dosing because of safety concerns.


In an August 27 interview with me, Dr. Hayden explained pridopidine’s benefits.


“It's the only drug that has showed some impact on stabilizing TFC [total functional capacity], keeping patients functional, keeping them managing their finances, keeping them at work, keeping them going for walks with their children and grandchildren, keeping them doing activities of daily living for longer,” Dr. Hayden said.


Analysis of pridopidine has demonstrated that patients taking the drug showed a slower decline in TFC. In early patients, pridopidine can maintain TFC and slow deterioration


Dr. Michael Hayden (left) confers with Peter McColgan, M.D., the clinical director for the HD program at Roche, during a break in the Milton Wexler Symposium (photo by Gene Veritas, aka Kenneth P. Serbin)


Neuroprotective effects


The earlier, revised analysis of pridopidine led to a “surprising but very welcome result,” Dr. Hayden continued. Pridopidine works as a “highly potent and highly selective sigma-1 receptor agonist.” An agonist is a drug that mimics a natural substance, while sigma-1 is “a molecular chaperone,” a chemical that helps proteins perform the important function of folding. He called pridopidine “the most potent and selective” sigma-1 agonist ever described.


In everybody’s cells, decreased sigma-1 has a negative impact on monitoring stress, including for the endoplasmic reticulum, a key organelle (subunit) that manages stress. In HD, this subunit experiences disturbances that cause an imbalance in the cell, Dr. Hayden said.


Overall, a reduction in sigma-1 makes neurodegeneration (slow and progressive loss of brain cells) get worse, Dr. Hayden explained.


However, pridopidine enhances sigma-1. The drug has “all in all neuroprotective effects,” by reducing cellular stress and even increasing the critical “connectivity” of the brain and the removal of “toxic products.”


Critically, pridopidine is “the only [HD] drug that has shown stabilization of neurofilament,” an important marker of disease progression, Dr. Hayden observed. An increase in levels of neurofilament, which makes up a brain cell's scaffolding, indicates dysfunction.


A Prilenia poster demonstrating the positive effect of pridopidine on total functional capacity and stabilization of neurofilament (photo by Gene Veritas)


A safe and tolerable drug


PROOF-HD seeks to confirm pridopidine’s efficacy so that it might be approved as a drug by the U.S. Food and Drug Administration (FDA).


“We submitted this to the FDA, and the FDA was hugely supportive,” Dr. Hayden said. Last November the FDA granted pridopidine a “fast track” designation to potentially speed drug approval, because HD is a “significant unmet need,” Dr. Hayden noted.


The designation “allows us to have a closer relationship with the regulators as we go through this process,” he said.


Despite the coronavirus pandemic, PROOF-HD began ahead of schedule in October 2020 and is on schedule to report results in about eight months. It recruited 499 clinical trial volunteers, more than the goal of 480, at several dozen sites in the U.S., Canada, and Europe.


So far, the standard safety monitoring board has found no reason halt the trial.


“So that's also encouraging that this is a very safe and tolerable drug,” said Dr. Hayden. 


A Prilenia slide with an overview of PROOF-HD, including the main goals (endpoints) (photo by Gene Veritas)


Seeking to prevent disease


In contrast with other top HD drug programs using brain or spinal injections, pridopidine is taken orally twice daily, “without any need for nursing care,” Dr. Hayden pointed out.


If PROOF-HD is highly successful, inviting a priority review by the FDA, Dr. Hayden said that pridopidine could become available for patients in mid-2024.


“My vision for pridopidine is that it could become a standard of care for neuroprotection,” Dr. Hayden stated in a January interview. “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.”


In a January 2021 Huntington’s Disease Society of America (HDSA) webinar, Sandra Kostyk, M.D., Ph.D, the co-principal investigator for PROOF-HD in the U.S., referred to pridopidine as a possible “disease-modifying intervention – something that slows the course of the disease.” The data indicate that early-stage HD patients could obtain “long-term beneficial effects” from an approved pridopidine drug for five years or more, she said.


A Prilenia slide about the advantages of small molecule drugs, the preferred method of treatment in HD. Pridopidine is in that category (photo by Gene Veritas)

An upcoming update, a caution, and hope


On September 7, HDSA will host a webinar further updating PROOF-HD and featuring Dr. Hayden, Dr. Kostyk, and Andrew Feigin, M.D., the trial’s principal investigator in the U.S. Click here to register.


“Of course, there's no certainty that this drug will be successful,” Dr. Hayden told me. “Forty percent of Phase 3 trials fail. So, we have a 60 percent chance. In a Phase 3 trial, things fail for all kinds of unexpected reasons, as sadly we've seen in the Huntington's field.”


Pursuing successful trials for pridopidine “has been a long struggle for everybody,” Dr. Hayden concluded. “This is hopeful, but we're not there yet. But hold on as we go on this journey as co-travelers in the attempt to find some way to moderate the course of this dreadful illness.”


(Future articles will cover other aspects of the Milton Wexler Symposium. Also see @HDBuzzFeed on Twitter and this article.)


Dr. Hayden (right) and Nicholas Caron, Ph.D., exchange ideas at the poster session of the Milton Wexler Symposium (photo by Gene Veritas).