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).

Bridging the Huntington’s and early onset Alzheimer’s disease communities: a report from a family conference

 

In the quest to conquer chronic illnesses, members of disease communities need to build solidarity and learn from one another. I explored this theme in a 2018 article about the fellowship

that a sufferer of type 1 diabetes and I, a gene carrier for Huntington’s disease, had built in our student-teacher relationship at the University of San Diego.

 

On July 30, the common challenge of the daunting search for therapies for neurodegenerative diseases hit home again as I participated in the eighth international DIAD Family Conference, held at the Hilton San Diego Bayfront hotel in downtown San Diego. DIAD stands for “dominantly inherited Alzheimer’s disease,” also known by other names, including early onset familial Alzheimer’s disease.

 

Late onset Alzheimer’s affects more than 5.8 million mainly elderly Americans but has no clear cause. In contrast, early onset Alzheimer’s ­– like Huntington’s – is a rare disease with a known genetic cause. Like HD, it strikes in the prime of life, when people as young as their twenties are affected.

 

Both HD and early onset Alzheimer’s are autosomal dominant conditions: carriers of a mutant gene will definitely develop the disease, and their children have a 50-50 chance of inheriting the disorder. In HD, the mutant huntingtin gene is the culprit. In early onset Alzheimer’s, one of three different mutations causes disease.

 

Early onset Alzheimer’s is rarer than HD. Approximately 41,000 individuals live with HD in the U.S. Globally, an estimated 45,000 people have early onset Alzheimer’s.

 

Sadly, as with HD, there is no treatment yet to arrest the progression of the disease.

 

As I learned at the conference, early onset Alzheimer’s, like HD, produces devastating, ultimately deadly symptoms mainly affecting a person’s memory and behavior. Common symptoms include: abnormal social behavior, agitation, confusion/disorientation, hallucinations, hypertonia (arms/legs are difficult to move/reduced flexibility), language impairment, dementia, Parkinsonism (movement abnormality: tremor, slow movement, muscle stiffness), seizures, and disinhibition.

 

 

Gene Veritas (aka Kenneth P. Serbin) at the 2022 DIAD Family Conference (photo by Gene Veritas)

 

Sharing insights with an Alzheimer’s researcher

 

I was invited to the DIAD Family Conference by Lindsay Hohsfield, Ph.D., co-founder of Youngtimers, a 501c3 nonprofit established in 2021 to promote education, support, and research for the early onset familial Alzheimer's community.

 

The group’s motto is: “we are too young to forget, too many to be forgotten.”

 

An Alzheimer’s researcher focusing on ways brain cells control inflammation, Dr. Hohsfield was inspired to enter the field after her father’s diagnosis with early onset Alzheimer’s. He died in his early 50s.

 

“When my father was sick, my family and I felt isolated and lost,” Dr. Hohsfield wrote in a letter on the organization’s website. “My hope is that with Youngtimers, no early onset familial Alzheimer’s patient and family will ever have to feel alone.”

 

Dr. Hohsfield has also explored the dilemma of “childbearing versus clinical trial participation” for Huntington’s and early onset Alzheimer’s families. Currently, pregnant women are excluded from clinical trials for those disorders. She calls for the establishment of a standard to address patient well-being and needs concerning this dilemma.

 

In May Dr. Hohsfield, a reader of this blog, interviewed me on Zoom about my article reflecting on the significant benefits of psychotherapy in my fight against Huntington’s. That article sparked a discussion in the early Alzheimer’s community about finding a life coach/mind coach to help cope with testing positive for that disorder and living life to the fullest. The interview with Dr. Hohsfield will be posted on the Youngtimers’ website.

 

Facilitating support sessions

 

Dr. Hohsfield and the conference organizers invited me to facilitate two one-hour drop-in support sessions for members of early onset Alzheimer’s families. Leveraging my long experience as an HD gene carrier and advocate, I was assigned to a table discussing “post genetic testing: coping with risk and how it changes over time.”

 

Other tables covered grief, communication, living with symptoms, and “catching your breath.”

 

In all, about a dozen people came to my table over the two hours. Usually, rather than having me facilitate, we exchanged ideas about genetic testing, prenatal testing, workplace confidentiality about our genetic status, securing insurance coverage, and more. 

 

The "post genetic testing" support sign at the 2022 DIAD Family Conference (photo by Gene Veritas)

 

The most poignant moment came when three members of an affected family asked how to navigate tensions in the extended family over the onset of symptoms one of them had suffered. That individual, having stopped being a breadwinner, needed medical care and caregiving.

 

This went beyond the scope of genetic testing, so I relied on memories of similar predicaments at my local HD support group. The other members of the group and I provided a sounding board for this family, encouraging them to use the resources offered by Youngtimers and seek out local support.

 

At these sessions all of us quickly bonded. We found comfort in our shared plight: facing a devastating neurological disorder.

 

Framing HD in a broader light

 

The DIAD Family Conference was sponsored by the Dominantly Inherited Alzheimer Network Trials Unit, the Alzheimer’s Association, and the National Institute on Aging. It was held in conjunction with the Alzheimer’s Association International Congress, July 31-August 4, in San Diego.

 

In between several moving family presentations to the nearly 200 attendees, the audience heard updates from Alzheimer’s physicians and researchers on the progress of research, including ongoing global clinical trials to prevent the disorder.

 

As I have witnessed at Huntington’s conferences, the Alzheimer’s scientists pointed out that research advances have brought the field to an unprecedented moment in the search for treatments. Leading Alzheimer’s researcher Randall Bateman, M.D., stated that it is a question of not “if” but “when” effective therapies become available.

 

After the conference, I met with Jason Karlawish, M.D., a University of Pennsylvania specialist on late onset Alzheimer’s and the author of the key 2021 book The Problem of Alzheimer’s: How Science, Culture, and Politics Turned a Rare Disease into a Crisis and What We Can Do About It.

 

This book has helped me frame my efforts to understand the history of the HD cause in a broader, comparative light.

 

A deeply personal and fulfilling introduction

 

My participation in the DIAD Family Conference will help me to understand the strengths and weaknesses of the Huntington’s movement in comparison with others facing similar challenges. I hope that, however modestly, it helps point the way towards increased collaboration in the quest for therapies.

 

I look forward to learning more about early onset familial Alzheimer’s disease, its causes, and symptoms.

 

I was moved by the many stories of struggle, but also humor and optimism, from affected individuals and their families.

 

After this deeply personal and fulfilling introduction to the early onset Alzheimer’s community, I felt energized.

 

I look forward to when both communities can celebrate the discovery of therapies.