Exploring the unique qualities of INGREZZA, the newest FDA-approved drug for Huntington’s disease chorea

 

After the news last year that the U.S. Food and Drug Administration (FDA) had approved INGREZZA to treat chorea associated with Huntington’s disease, a debilitating movement disorder, I wanted to better understand the development of this drug and the unique qualities claimed by its creator.

 

On November 17 I interviewed company officials at Neurocrine Biosciences, Inc., which fashioned valbenazine – the chemical name for INGREZZA – in the early 2000s. In 2017, INGREZZA was approved by the FDA for the treatment of tardive dyskinesia, an irreversible involuntary movement disorder unrelated to HD. Neurocrine is in San Diego, one of the world’s leading biotech hubs and where I reside.

 

In an initial report on INGREZZA, including a Zoom interview with three Neurocrine officials, I noted the drug’s advantages over the two other FDA-approved chorea remedies, Xenazine (tetrabenazine) and Austedo (deutetrabenazine).

 

INGREZZA is easier to take, requiring just one daily dose in capsule form. Xenaxine and Austedo have long required multiple daily doses, although in May the FDA approved once-daily extended-release tablets for Austedo. Unlike the other drugs, INGREZZA also does not require titration, that is, slowly increasing the dosage over weeks. INGREZZA is always just one pill.

 

 

In contrast with the other drugs aimed at chorea, INGREZZA is a capsule – not a tablet – and is taken once daily even without an extended-release formulation. These characteristics potentially provide physicians and patients greater flexibility in dosing, because INGREZZA can be crushed and is available in three effective doses. As a result, Neurocrine’s drug, while indicated for oral administration, can also be crushed and mixed with food or provided through a feeding tube – often necessities for late-stage HD patients.

 

In April the FDA approved INGREZZA SPRINKLE capsules, a new formulation of the drug, in oral granules. Neurocrine developed this version of the drug for those with HD or tardive dyskinesia who experience difficulties in swallowing. It can be sprinkled on soft food. INGREZZA SPRINKLE offers the same three simple and effective dosing options (40 mg, 60 mg and 80 mg) as INGREZZA.

 

In last year’s interview, recognizing that INGREZZA only treats chorea, the Neurocrine officials stated that they plan to seek potential disease-modifying remedies that could potentially slow, halt, or reverse the progression of debilitating neurological conditions, which might include HD.

 

A substantial reduction in chorea

 

According to a Neurocrine press release (and also a June 2023 scholarly article in Lancet Neurology), INGREZZA decreased chorea severity three times better than a placebo.

 

So far researchers have not done a head-to-head study of Xenazine, Austedo, and INGREZZA. All three are VMAT2 inhibitors, designed to reduce involuntary movements of chorea. VMAT2 inhibitors help regulate dopamine, a chemical messenger in the brain that affects movements.

 

As my above-mentioned article stated, Dietrich Haubenberger, M.D., the executive medical director at Neurocrine and clinical lead for the firm on the successful Phase 3 KINECT-HD clinical trial leading to INGREZZA’s approval, called valbenazine a “unique molecule.”

 

Comparing INGREZZA with competitors

 

In 2015 I reported on the key differences between tetrabenazine (Xenazine) and its derivative deutetrabenazine (Austedo), which was also developed in San Diego.

 

During my November 2023 interview with Dr. Haubenberger and other Neurocrine scientists, I sought to better understand INGREZZA’s uniqueness and its benefits for HD-affected individuals. How does valbenazine contrast with tetrabenazine and its derivative deutetrabenazine?

 

The basics were described by Dimitri Grigoriadis, Ph.D., a pioneer of valbenazine and today a semi-retired distinguished scholar at Neurocrine. A neuropharmacologist by training, Dr. Grigoriadis started with the firm at its inception in 1993 and previously served as chief research officer.

 

Understanding the chemistry

 

Dr. Grigoriadis explained how INGREZZA works in the brain.

 

The “unique part of INGREZZA,” he said, is that it gets broken down by the body, then produces a single “isomer” that is a key metabolite of tetrabenazine. A metabolite results from the breaking down of a chemical.

 

“That is the chemical that binds to VMAT2, the protein, and blocks the entrance of dopamine” into relevant parts of brain cells, Dr. Grigoriadis added.

 

The drug discovery that Neurocrine did for valbenazine involved a drug profile that was highly selective for the VMAT2 protein, Dr. Grigoriadis recalled. “And through our research, we were able to identify a molecule that provides only the high affinity, very selective isomer of [the metabolites] of tetrabenazine.”

 

Comparing hands

 

Dr. Grigoriadis illustrated the concept of an isomer by noting how left and right hands resemble each other but are positioned differently.

 

“An isomer is a molecule that is exactly the same, has the same structural components,” he said. “So, it's an identical molecule, but it's left-handed, right-handed orientation. Your hands are four fingers and a thumb. They're identical, but they are in a different orientation.”

 

Isomers work in a similar way, he continued.

 

“They fit differently,” he said. “Functionally, they are different, even though they look exactly the same. You could have two isomers of the same molecule, a left hand and a right hand, that fit into different proteins, that fit into different spaces because they are in a different orientation.”

 

As a result, the various qualities of a drug “could be different,” he continued, resulting in a “slightly different” way in which the chemicals produced by INGREZZA “function.”

 

Dimitri Grigoriadis, Ph.D. (left), Dietrich Haubenberger, M.D., and Gene Veritas (aka Kenneth P. Serbin) discuss INGREZZA at the Neurocrine offices (photo by Aimee White, Director, Corporate Communications, Neurocrine). (Click on an image to make it larger.)

 

Building on tetrabenazine

 

At the time of valbenazine’s discovery, Neurocrine did not know whether it could help patients with diseases like tardive dyskinesia or HD, because the research on valbenazine had not been done, emphasized Eiry Roberts, M.D., Neurocrine’s chief medical officer. No drug had been developed for tardive dyskinesia before valbenazine.

 

“So this was a totally new research project,” Dr. Roberts continued. “There were learnings from experience with tetrabenazine that made it important to find out how valbenazine could be a safe and effective treatment for patients with conditions not sufficiently addressed by other medications available at the time.” The company also did extensive research to prove valbenazine’s safety, she added.

 

In addition, Neurocrine determined that, besides showing promise in the lab and efficacy in clinical trials for the treatment of tardive dyskinesia and chorea associated with Huntington’s disease, valbenazine could be mass-produced, Dr. Grigoriadis said.

 

Benefits for patients

 

Dr. Haubenberger stressed that INGREZZA is unique because  it involves just “one capsule, once daily with no complex dose adjustments to get to an effective dose.”

 

The once-a-day quality results from valbenazine’s “very long half-life of its effectiveness” (the time it remains in the body), explained Grace Liang, M.D., a movement disorders neurologist and Neurocrine’s vice president of clinical development in neurology.

 

“We know that the long half-life is important not only for the convenience this provides, but it allows patients to take it consistently without forgetting a dose,” said Dr. Liang. “Everybody has a life to live.” The “long duration” in the body and the selectivity – that it doesn’t act on other receptors of the brain that may cause other effects – make INGREZZA “special” for patients, she added.

 

INGREZZA “gives that nice, smooth, and steady coverage,” in contrast with the other chorea drugs, which have multiple daily doses and a shorter half-life, Dr. Liang continued.

 

INGREZZA also takes effect faster than Xenazine and Austedo, Dr. Haubenberger pointed out. He added that “with the first dose and as early as at two weeks of treatment, the clinical trial showed a greater reduction of chorea in patients on valbenazine compared to placebo.”

 

Unlike medicines that purposely have a material on their capsule to cause an extended release, valbenazine needs no such modification to achieve its “inherent,” smooth, once-daily effect, Dr. Roberts added.

 

Looking to the HD community

 

The FDA approved INGREZZA for use in adults with HD chorea. Neurocrine has no plans for a clinical trial of the drug in juvenile HD patients.

 

“We do recommend that people just use INGREZZA as it's labeled,” Dr. Liang said. “Obviously the care providers, the physicians would need to evaluate what the best treatment options are for those children, and we're hopeful that future developments can also support their needs as well.”

 

“Data is still being collected,” said Dr. Haubenberger, referring to an ongoing three-year study of more than 150 adults with HD taking INGREZZA. “There's lots more to learn about the compound itself and that's really where we want to invest in, where we can even learn more, share that with the community and even learn from that to inspire future avenues of research in HD and also other conditions.”

 

In these studies that reflect more “real-life settings, there’s much that can be learned from a broader data set than what could feasibly be done in a controlled clinical trial,” added Dr. Liang.

 

Other valbenazine projects

 

Previously, a Neurocrine clinical trial program of valbenazine for Tourette’s disorder did not show efficacy, Dr. Roberts said.

 

Neurocrine currently has a Phase 3 program for “valbenazine as an adjunctive treatment for schizophrenia, adjunctive to the antipsychotics that those patients take right now,” Dr. Roberts said. The drug is also in a Phase 3 study for the “commonest movement disorder in children, dyskinetic cerebral palsy,” she added.

 

In March Neurocrine announced the start of a Phase 1 clinical trial with their next-generation VMAT2 inhibitor, NBI-1065890, to study the safety and tolerability in healthy volunteers.

 

“We’re excited to bring this next-generation, internally discovered, highly potent, oral, selective VMAT2 inhibitor into the clinic with the hope of providing differentiated benefit in treating certain neurological and neuropsychiatric conditions,” Dr. Roberts stated in a press release. 

 

Gene Veritas (left) with Eiry Roberts, M.D., Chief Medical Officer, Neurocrine (photo by Aimee White, Neurocrine)

 

Aiming for disease-modifying therapies

 

Our November interview concluded with Dr. Roberts’ reflections on Neurocrine’s commitment to seek disease-modifying therapies for neurological conditions such as HD, including its new partnership with Voyager Therapeutics, a key player in the development of next-generation gene therapies. Voyager has experience in HD research.

 

“While symptomatic treatments are incredibly important for patients living with the diseases that we're seeking to serve, like Huntington's, for us to be a true innovator as well in this field, we need to be focused on understanding disease modification and cures,” Dr. Roberts said. “And so the collaboration with Voyager is one that gets us into the gene therapy space for potential curative or disease-modifying treatments. And we have other efforts that are very early in our research to look at different ways of coming upon disease modification.”

 

“It's really a focus area for us as we look at some of these novel platforms that we're coming forward with,” Dr. Roberts concluded.

 

Those research platforms are getting a boost: Neurocrine is moving to a new, state-of-the art 535,000-square-foot research campus. The lab space is scheduled for completion by year’s end.

 

Neurocrine's new research campus (photo courtesy of Neurocrine).

Adding to arsenal of movement disorder drugs approved by FDA, Neurocrine pledges to seek anxiously awaited therapies to slow progression of Huntington’s disease

 

Neurocrine Biosciences, Inc., announced on August 18 that the U.S. Food and Drug Administration (FDA) has approved its drug INGREZZA to treat chorea, a debilitating movement disorder suffered by people with Huntington’s disease.

 

INGREZZA is the third FDA-approved HD chorea drug.

 

Like the two previously approved, similar drugs for chorea made by other drug companies, INGREZZA does not fulfill what the HD community of scientists, advocates, and affected families anxiously await: development and FDA approval of a drug to slow, halt, or reverse the progression of the disease.

 

INGREZZA is easier to take, requiring just one daily dose, and its availability could deliver a therapy to those suffering chorea, many of whom do not take the two other drugs.

 

Recognizing the need to go beyond treating just chorea, Neurocrine’s scientific leadership has pledged to seek the development of so-called disease-modifying therapies for HD, which other clinical trials have failed to achieve.

 

“We have had an interest and a focus on HD and other rare neurological disorders at Neurocrine for a long time,” Eiry Roberts, M.D., Neurocrine’s chief medical officer, told me in a Zoom interview on August 25, recalling that the San Diego-based biotech firm was founded in 1992. “Now, that is not only focused on symptomatic treatments for rare neurological disorders, but also on that very, very important area of disease modification and cures.”

 

Huntington’s disease is “right front and center in our neurology therapeutic area efforts on the research side,” Dr. Roberts added. “Those obviously take a while to come through into the clinic. But we really have a significant interest there, and understand the importance to the community, as the community has been let down several times by failures in this space. But the science is evolving very rapidly, and we want to be a part of that as we move forward.”

 

Clockwise from upper left: Aimee White, Neurocrine director of corporate communications, Gene Veritas (aka Kenneth P. Serbin), Dr. Eiry Roberts, Neurocrine chief medical officer, and Dr. Dietrich Haubenberger, Neurocrine executive medical director and clinical lead for the KINECT-HD clinical trial during a Zoom call on August 25, 2023 (screenshot by Gene Veritas).

 

A drug earning large revenues

 

In 2008, introduced into the U.S. by Lundbeck, Xenazine (tetrabenazine) became the first FDA-approved HD-specific drug of any kind and is used to reduce chorea. In 2015 Xenazine/tetrabenazine became a generic drug.

 

In 2017, the FDA approved Austedo (deutetrabenazine), a very similar but improved chorea drug developed in San Diego by Auspex Pharmaceuticals but ultimately licensed by Israel-based pharma giant Teva, which had acquired Auspex and the rights to the drug.

 

In 2017, INGREZZA was approved by the FDA for the treatment of tardive dyskinesia, an irreversible involuntary movement disorder unrelated to HD.

 

INGREZZA – the compound valbenazine – has a different chemical makeup than its predecessors. Like them, however, it is a VMAT2 inhibitor, designed to reduce involuntary movements like chorea. VMAT2 inhibitors help regulate dopamine, a chemical messenger in the brain that affects movements.

 

INGEZZA’S prior approval by the FDA allowed Neurocrine to skip the early phases of a clinical trial program and take the drug directly into a definitive  Phase 3 trial run in partnership with the Huntington Study Group, the world’s largest HD clinical research network, with deep experience in running drug trials, including for Xenazine and Austedo.

 

Xenazine requires three daily doses, Austedo two, but INGREZZA just one – although in anticipation of Neurocrine’s entry into the market with INGREZZA, Teva received permission from the FDA in February to reduce the daily dose to just one. Nevertheless, Austedo requires titration, that is, slowly increasing the dosage over weeks. INGREZZA is always just one pill.

 

Both Teva and Neurocrine have earned hundreds of millions of dollars annually with their respective drugs (on INGREZZA, for example, click here to read more).

 

 

Life with HD in the U.S. before anti-chorea drugs

 

“Most people with HD experience chorea, an abnormal involuntary movement disorder, characterized by irregular and unpredictable movements,” the Neurocrine press release observed.  “Chorea can affect various body parts and interfere with motor coordination, gait, swallowing and speech.”

 

In the U.S., before the approval of Xenazine, at least some HD families got tetrabenazine from Canada, where the drug was legal.

 

My mother, who died of HD in 2006 at the age of 68 – two years before the Xenazine approval –was never able to take tetrabenazine for chorea. Instead, she was prescribed haloperidol, although we heard from HD advocates and family members that this drug could have very negative side effects. My mother switched to Zyprexa (olanzapine), an antipsychotic medication.

 

Early in my family’s journey with HD – I tested positive for the HD mutation in 1999 – I took Zyprexa for depression and anxiety.

 

Thankfully, at 63 I have reached an age about 15 years beyond my mother’s age of HD onset and have not experienced chorea.

 

Changing the treatment landscape, providing options

 

In the U.S., the availability of three chorea drugs in a span of just 15 years has vastly changed the treatment landscape.

 

“Chorea associated with HD can significantly affect the quality of life of a person living with HD by impacting their daily activities, social life, independence and overall well-being,” said Louise Vetter, President and CEO of the Huntington's Disease Society of America (HDSA). “The approval of INGREZZA for HD chorea means that people living with HD have a new treatment option to help manage their chorea symptoms, which is a welcomed milestone in efforts to improve care for families affected by HD.”

 

“The convenience of once-a-day dosing will make it appealing to patients and families,” Martha Nance, M.D., director of the HDSA Center of Excellence at Hennepin Health Care, wrote me in e-mail on August 23. “And remember, everyone is different – some people will prefer one of the older drugs, while others will likely respond better to the new one. It is wonderful to have options!”

 

Both Xenazine and Austedo are extended release; they offer gradual introduction into the system over time. They are also tablets, making it difficult for patients and caregivers to crush for use in food or a feeding tube.

 

As Dr. Roberts explained, breaking a medication can lead a patient to experience a very different effect from the one intended.

 

In contrast, INGREZZA is a capsule and non-extended, potentially providing physicians and patients greater flexibility in dosing. It can be crushed and given in different quantities.

 

INGREZZA’S one capsule, once-daily dose “may be of huge benefit to patients with swallowing difficulties or those in need of reminders to take medication,” Jody Corey-Bloom, M.D., Ph.D., observed in an e-mail on August 25. She added that the approval of the new drug “may also be helpful in curbing the price point of anti-chorea agents,” given the competition.

 

 

Was a third chorea drug necessary?

 

In the absence of disease-modifying therapies, the INGREZZA approval has raised the question of whether a third chorea drug was necessary.

 

At an August 22 online meeting of Neurocrine officials, HSG clinical trial administrators, and HD advocates from North America and Europe, I expressed this concern, asking whether developing INGREZZA was “the best way for the community to focus its efforts.”

 

Katie Jackson, the president/CEO of Help4HD International, echoed that concern from the community. With a strong online presence and connections with the HD-focused biopharma firms, Help4HD widely announced the INGREZZA news on social media.

 

Jackson, who lost her husband to HD and has three at-risk children, said that the response from the HD community was “exactly what we're talking about today: we already have Austedo. Why is this [the development of INGREZZA] important?”

 

“I couldn’t agree more, in that, right, this is the third VMAT-2 inhibitor,” said Erin Furr Stimming, M.D., the HSG principal investigator for the Phase 3 trial, KINECT-HD, referring to my question. “We absolutely acknowledge that this is a symptomatic treatment. This is not a disease-modifying therapy. Chorea is only one of the many symptoms that our patients struggle with on a daily basis.”

 

 

Nevertheless, Dr. Furr Stimming stated that it “is really important for the community to have another drug available.” The INGREZZA approval will help to build further awareness about HD and “provide hopefully resources to our patients and families,” she added.

 

Dietrich Haubenberger, M.D., the executive medical director at Neurocrine and clinical lead for the firm on KINECT-HD, stressed the importance of INGREZZA/valbenazine as a “unique molecule.”

 

So far researchers have not done a head-to-head study of Xenazine, Austedo, and INGREZZA.

 

The scientist-written site HDBuzz cautioned that, “like all drugs, valbenazine has some downsides. VMAT2 inhibitors have common side effects, like sleepiness. They can also have very serious side effects which include depression as well as suicidal thoughts or actions.”

 

The site recommended that “people with HD who are considering INGREZZA accurately relay their past medical history to their healthcare provider and alert them as soon as possible if they experience any side effects.”

 

Success in reducing chorea

 

The FDA approval was based on the favorable results from KINECT-HD and KINECT-HD2, a related open-label extension trial, still ongoing. These trials measure the safety and tolerability of INGREZZA and the efficacy of the drug in alleviating chorea.

 

KINECT-HD enrolled 128 adults 18 to 75 years of age in the U.S. who were diagnosed with motor-manifest HD (had onset of movement disorder) and who had sufficient chorea symptoms to meet study protocol criteria.

 

KINECT-HD2, a three-year study, will enroll more than 150 adults,  with the same inclusion criteria as KINECT-HD. Whereas half the volunteers in KINECT-HD got a placebo, in KINECT-HD2 every participant will receive the drug.

 

KINECT-HD had sites in the U.S. and Canada, and KINECT-HD2 is taking place at some of those same sites.

 

According to the Neurocrine press release (and also a June 2023 scholarly article reporting on KINECT-HD in Lancet Neurology), INGREZZA demonstrated a decreased chorea severity three times better than placebo.

 

As explained by HDBuzz, in the trial, INGREZZA “improved the Total Maximal Chorea (TMC) score, a metric clinicians use to monitor chorea symptoms.”

 

A “significant gap” in getting people treated with chorea

 

With my questions to Dr. Roberts and Dr. Haubenberger on August 25, I wanted to explore why Neurocrine had not sought a “potentially far more transformative drug.” With the FDA approval for INGREZZA for chorea, I also wanted to learn about the company’s plans for developing disease-modifying therapies.

 

Dr. Roberts, Dr. Haubenberger, and I explored these themes in greater depth in our interview.

 

Neurocrine, the HSG, and other clinicians, according to Dr. Roberts, saw a “significant gap” in treating chorea: 90 percent of patients have chorea, but less than 20 percent were taking either Xenazine or Austedo. Making INGREZZA available could help fill this unmet need.

 

Another key factor in favor of INGREZZA was that in the “clinical trial we saw benefits as early as two weeks,” Dr. Roberts said.

 

The approval of INGREZZA provides Neurocrine with an opportunity to partner more closely with the HD community – including in the search for disease-modifying therapies, Dr. Roberts continued.

 

“We're very interested in learning from the community, including researchers in the area and key opinion leaders and other individuals about what are the areas of science that we should be doubling down on,” she said.

 

Just the start

 

For Neurocrine, a drug approval is not the conclusion but just the start of a relationship with a community of affected individuals and their families, Dr. Haubenberger stated.

 

Moving beyond the clinical trials, the researchers need to learn “how this translates into the real world,” he explained.

 

“This goes back to your first question about symptomatic versus more transformative, disease-modified,” Dr. Haubenberger said. “I don't necessarily see there quite an either/or. I think it's about what is important to patients and their caregivers.”

 

Now the researchers following INGREZZA need “to actually drill down on the clinical meaningfulness,” for example, by examining what an improvement in a score signifies in affected persons’ daily lives or how chorea may be impairing their activities in ways unseen by doctors, he said.

 

This approach can inform the search for treatments not just for HD, but other neurological disorders, Dr. Haubenberger said.

 

Next steps for HD

 

Dr. Roberts said that, for business reasons, she cannot discuss specific biological processes to be examined in the search for HD disease-modifying therapies. She added that currently there are no plans for clinical trials.

 

“I will say that we are interested in a broad range of different biological processes that could have an impact for patients with HD, and I think that our research colleagues are working very hard on that right now,” she said.

 

“I think specifically for HD these are, from a scientific point of view, exciting times,” Dr. Haubenberger said, noting the advances in biology as well as the lessons from clinical trial programs with negative results.

 

A focus on neuroscience

 

With the evolution of the company and the financial success of INGREZZA, Neurocrine may be well-positioned to research disease-modifying therapies for HD and other neurological disorders.

 

It has been leaving its mark on the biotech world.

 

STAT News in 2018 praised Neurocrine for its focus on central nervous system disorders – one of the toughest nuts to crack in biomedicine – and having an ambitious research and development budget.

 

In 2019, pharma giant Biogen contemplated a takeover of Neurocrine, at the time valued at $8 billion.

 

In 2020, Neurocrine signed a statement by global biopharma leaders to ensure affordable access of medicines for patients.

 

That year Neurocrine was represented at an exclusive screening of the film Dancing at the Vatican – about Pope Francis’ historic 2017 audience with the HD community in Rome – at the University of San Diego

 

In a new partnership that could eventually have a key impact on the search for HD therapies, Neurocrine and Voyager Therapeutics – which has focused on HD in the past – formed a strategic collaboration in January for developing next-generation gene therapies for neurological diseases such as Parkinson’s disease.

 

“We're a company that's focused on neuroscience in its broadest sense,” Dr. Roberts observed. “We have therapeutics in neurology, psychiatry, neuroendocrinology and the emerging area of neuro immunology, which may well be very important in the context of disease-modifying and curative treatments.”

 

A big applause for the trial participants and caregivers

 

INGREZZA is available now for the HD community. The company has promised to schedule webinars and conduct additional educational efforts to provide information about the drug and answer questions and concerns.

 

For now, Neurocrine has no plans to seek approval for INGREZZA for chorea associated with Huntington’s outside the U.S. Participants in KINECT-HD in Canada will get access to the drug.

 

(Neurocrine has not announced pricing for INGREZZA but noted that the approval for chorea for HD will not affect the price. Currently, INGREZZA coverage is approved for more than eight out of ten patients nationwide regardless of insurance. For information about Neurocrine’s Copay Savings Card or the INBRACE Support Program, call 1-84-INGREZZA (1-844-647-3992) 8 AM to 8 PM ET, Monday through Friday or visit the INBRACE Support Program website:  https://inbracesupportprogram.com/ingrezzapatient/)

 

At the conclusion of our interview, Dr. Roberts renewed Neurocrine’s invitation – the pandemic thwarted an earlier plan – for me to visit the company’s labs to learn more about the key areas of research. This will be the focus of a future article.

 

I echo Dr. Haubenberger’s words at the August 22 meeting with advocates:

 

“The biggest applause needs to be given to all the participants and their caregivers that tirelessly committed their time, their commitment to participating in this clinical program.”

 

Disclosure: My travel expenses were partially covered by the HSG for attendance at its 2019 annual conference.

Huntington’s disease advocates, scientists generate hope after a difficult year in the search for treatments

 

In one of the most difficult years emotionally in the fight to conquer Huntington’s disease, advocates, scientists, and HD-affected individuals have generated hope as 2021 draws to a close.

 

The “heartbreaking” news in March about the disappointing results of the greatly anticipated Roche and Wave Life Sciences clinical trials was compounded by the devastating, ongoing coronavirus pandemic.

 

Last year at this time, leading global HD advocate Charles Sabine, a British former international correspondent for NBC-TV, launched his inspiring film Dancing at the Vatican, about Pope Francis’ embrace of the global HD community, on YouTube.

 

Like the pope’s 2017 special audience with the HD community in Rome, Dancing at the Vatican brought great hope and joy.

 

Now Sabine has just released another heartening film, Hoping Machine, a 60-minute documentary that, he says, “encapsulates many core principles” of the pope’s declaration that it is time for HD to be “hidden no more”: the “corrosive nature of denial and hidden secrets” and the “empowerment that springs from knowledge, understanding, collaboration and community.”

 

“I truly believe Hoping Machine offers the most important perspective that anyone involved in HD right now – researchers, clinicians or families – could hear,” Sabine wrote me by e-mail.

 

You can watch Hoping Machine for free by clicking on this link.

 

Powerful HD journeys

 

Hoping Machine takes its title from the song by American folk music giant Woody Guthrie, who died from HD in 1967, the year his former wife Marjorie founded the Huntington’s Disease Society of America (HDSA).

 

The film depicts the gripping recollections of HD family members, and also several scientists, of their experiences as keynote speakers at what I have called the “Super Bowl” of HD research, the annual Huntington’s Disease Therapeutics Conference. Beginning in 2006, the conferences are sponsored by CHDI Foundation, Inc., the abundantly funded, nonprofit virtual biotech aimed solely at developing HD therapies.

 

These speakers have all told powerful stories about their HD journeys, including using the keynote to go public about their HD status for the first time (my case in 2011) and exploring the most intimate and difficult aspects of life with HD.

 

Inspired by the scientists’ dedication

 

They have also sought to both inspire and thank the scientists.

 

“Here I am, affected by Huntington's disease, and I'm relying on all of you guys, all of the scientists, everybody working in the HD community,” keynoter Amy Merkel recalled of her talk in Palm Springs, CA, in February 2020. “I'm relying on you for life.”

 

Sometimes, when she has experienced symptoms, “I just kinda wanted to crawl under the covers and stop trying,” Merkel continued. “That speech and that time in Palm Springs kind of lifted me a little. You can do this.”

 

A licensed practical nurse, Merkel had abandoned her “dream” of becoming a registered nurse (RN) “because I knew I was gene-positive” for HD, she said. However, “the advances that all of the scientists have made in Huntington’s research” convinced her to study to become an RN.

 

Amy achieved her goal: "I'm a registered nurse, and I currently am working as a sexual abuse nurse examiner in southern Arizona."

 

 

Amy Merkel poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (far right), at the 15th HD Therapeutics Conference, held in in Palm Springs, CA, February 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

Good news from the KINECT-HD trial

 

Another glimmer of hope – and a sign that HD science marches on – came on December 7 with the release of “positive” data from the KINECT-HD phase 3 clinical trial to test the efficacy, safety, and tolerability of Neurocrine Biosciences’ drug valbenazine. The initial trial data demonstrated that valbenazine, as intended, reduced chorea, the involuntary, dance-like movements that are the principal motor symptom of HD.

 

Marketed by San Diego-based Neurocrine as Ingrezza and already approved by the U.S. Food and Drug Administration (FDA) for the neurological disorder tardive dyskinesia, valbenazine is the same type of drug as the two other FDA-authorized drugs for chorea, Xenazine (2008) and Austedo (2017).

 

According to the Neuocrine press release, Ingrezza reduced the total motor score (a measure of the severity of chorea) by 3.2 points versus placebo in the trial participants.

 

This result was very close to reduction of the 2.5 points in Austedo and the 3.5 points in Xenazine.

 

As the release explained, the total motor score is part of the motor assessment of the research tool known as the Unified Huntington’s Disease Rating Scale (UHDRS®) and “measures chorea in seven different body parts, including the face, oral-buccal-lingual region, trunk and each limb independently.” The total motor score is the sum of the individual scores and ranges from 0 to 28.

 

Like Xenazine and Austedo, valbenazine is a VMAT2 inhibitor.

 

Initial data about Austedo (deutetrabenazine) indicated that patients “felt better” overall after taking this drug. In addition, Austedo requires only two daily doses, versus Xenazine’s three (click here to read more).

 

Ingrezza is even more convenient: the KINECT-HD trial used just one daily dose.

 

Critical: no suicidal behavior observed

 

Critically, and also in contrast with the other two drugs, “no suicidal behavior or worsening of suicidal ideation was observed in the valbenazine-treated subjects in this study,” the Neuocrine statement said.

 

Neocrine partnered in KINECT-HD with the Huntington Study Group (HSG), the leading HD clinical trial administrator and research platform. In a first for the HSG, KINECT-HD trial participants used wearable sensors for continuous monitoring of their movements and other biological functions, even at home. (Click here to read more.)

 

In 2022, after a complete review of the trial data, Neocrine will report its findings in greater detail at a medical conference, and it will submit the drug for FDA approval for use in HD.

 

“The positive results of the KINECT-HD study are very exciting for the HD community,” Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence at the University of California, San Diego, wrote me on e-mail. “Although valbenazine is not a disease-modifying therapy, it will clearly be a highly effective therapeutic option for one of the most common symptoms in HD – chorea.”

 

“Completing ANY clinical research trial successfully in the midst of the COVID-19 pandemic is cause for excitement, and a testament to the tenacity of HD patients, families, and research teams,” wrote Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN. “The favorable results are not terribly surprising, since two other similar drugs have been approved previously – but they are certainly reassuring.”

 

Maintaining the commitment to patients

 

The “holy grail” for the HD field – and other neurological diseases – is a treatment that prevents people from ever developing symptoms.

 

Comparing Ingrezza’s success with this bigger challenge, Dr. Nance offered a partial explanation to what she described as a large and complex challenge.

 

“It only takes a few weeks or months to document that a drug reduces the severity of a symptom (chorea, depression, insomnia), but takes years to show that a drug is slowing the progression of a disease that progresses slowly over years,” she wrote. “We have not gained a toehold on slowing nerve cell loss in any of these conditions.”

 

However, because the scientists have advanced to attempting treatments aimed at the disease’s roots ­– DNA and RNA – “there is good reason to hope.”

 

“Building on the unsuccessful trials that were so disheartening to the global HD community earlier this year, I counted no fewer than thirteen companies moving towards clinical trials of DNA/RNA-directed treatments at our recent HSG research conference in November,” she noted.

 

Dr. Nance wrote that we should be “thrilled” that 2021 has ended on a favorable research result and “maintain our commitment to work together to find better treatments for the HD patients of the future.”