With ‘great promise’ for treating Huntington’s disease, four drug programs press ahead (Part I)

 

At the recent 20th Huntington’s Disease Therapeutics Conference, four companies provided updates on their key clinical trial programs, demonstrating that they had overcome basic safety hurdles and revealing plans to have their drugs potentially approved as therapies (treatments) for delaying the progression of HD symptoms.

 

PTC Therapeutics, Roche, Wave Life Sciences, and uniQure made 15-minute presentations. This clinical trials update took place during the first session on February 25, the first day of the three-day event.

 

Sponsored by the nonprofit CHDI Foundation, Inc., the largest private funder of HD research, the conference took place in Palm Springs, CA.

 

Possible impact

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. Blocking the bad protein could help prevent the death of brain cells, a major driver of HD.

 

In a post-conference interview with me, CHDI Chief Scientific Officer Robert Pacifici, Ph.D., said that the companies’ plans to move their programs towards drug approval is “great news.”

 

“All of them expressed their commitment to moving forward with their interventions, and that’s not trivial,” Dr. Pacifici said. “That means a lot of time, a lot of money invested on their part. They wouldn’t be doing it if they didn’t think there was great promise there.”

 

Each firm has overcome the basic safety hurdles necessary for moving to a Phase 3 clinical trial, the final step before the U.S. Food and Drug Administration (FDA) approves a drug, Dr. Pacifici added.

 

This article, the first of two, focuses on trials from PTC and Wave. Part II will examine the Wave and uniQure updates.

 

Votoplam, a potential pill for HD

 

With 60 companies represented at the conference, CHDI selected those “that had something new to say” in terms of clinical development, Dr. Pacifici told the attendees.

 

Amy-Lee Bredlau, M.D., PTC’s senior medical director, began her talk on the company’s huntingtin-lowering drug by noting progress: the compound, PTC518, is now called votoplam, a nonproprietary drug name assigned by PTC’s new, larger partner on the project, the international pharmaceutical firm Novartis.

 

“I think this is a really great collaboration,” Dr. Bredlau said.

 

As Dr. Bredlau explained, votoplam is a huntingtin splicing modulator, reducing the production of both the mutant and normal huntingtin proteins.

 

In contrast with riskier delivery methods, some presented in the session, votoplam is a pill. That makes it easy for patients to take the drug.

 

CHDI and PTC started the search for a huntingtin-lowering pill with a joint project initiated in 2018.

 

A delay in HD progression

 

PTC ran a successful Phase 1 clinical trial of votoplam in 2020 and 2021, providing initial evidence of safety and the lowering of the huntingtin protein.

 

At the conference, in an interim analysis, Dr. Bredlau presented data from the first 32 of the 156 volunteers enrolled in PIVOT-HD, PTC’s one-year global Phase 2 trial, which has verified the safety and tolerability of the substance. The first group of participants in PIVOT-HD began in 2022.

 

PIVOT-HD demonstrated that, by the third month, votoplam enters trial volunteers’ brains and lowers the huntingtin protein, she said. At month 12, the lowering was sustained. The trial also showed no spikes in neurofilament light chain (Nfl), a protein whose presence indicates degeneration of brain cells in diseases like HD. Scientists hope that lowering huntingtin will limit Nfl.

 

Significantly, Dr. Bredlau observed that these volunteers had a delay in the progression of HD symptoms, as indicated by several key clinical measures.

 

She said PTC is “very excited” about those trends, which “look very promising,” adding that “we’re really hopeful that we’ll see a strengthening of the signal at the end of the 12-month study,” when results from the remaining volunteers will be studied.

 

PTC will release full results of PIVOT-HD in this (second) quarter of 2025, said Dr. Bredlau, adding that the firm hopes that the results secure permission for a Phase 3 trial, to be run by Novartis.

 

Dr. Amy-Lee Bredlau of PTC Therapeutics presents data from the PIVOT-HD clinical trial demonstrating trends of a delay in progression of Huntington's disease symptoms (photo by Gene Veritas, aka Kenneth P. Serbin).

 

GENERATION HD2 fully in progress

 

Peter McColgan, M.D, Ph.D., global development leader for Roche, updated the pharmaceutical giant’s HD program. He focused on the Phase 2 trial of the huntingtin-lowering drug tominersen.

 

Tominersen is an antisense oligonucleotide – a “laser-guided missile” against HD – originally developed by Ionis Pharmaceuticals, Inc. Like votoplam, tominersen lowers both the normal and mutant huntingtin protein.

 

After Roche’s unsuccessful trial of tominersen in 2021, the company redesigned a less ambitious and more focused trial of the drug in people less affected by the disease. Called GENERATION HD2, it started in early 2023.

 

Dr. McColgan reported that GENERATION HD2, by January, had fully recruited its target of 301 volunteers at 70 sites in 15 countries.

 

“This is a massive achievement,” he said.

 

The trial will assess tominersen’s safety, the use of biomarkers (signs of a disease and a medication’s efficacy), and the drug’s effectiveness.

 

Tominersen is not a pill. It is administered via a spinal tap.

 

Roche aims to complete the trial by the end of 2026.

 

Dr. Peter McColgan of Roche with a slide showing the global recruitment for the GENERATION HD2 clinical trial (photo by Gene Veritas)

 

Roche’s multiple approaches

 

Dr. McColgan also described how Roche has expanded its focus to include other possible HD treatments and related research.

 

“We believe the fastest way to get treatments to patients is to pursue multiple programs in parallel,” Dr. McColgan said.

 

In collaboration with its colleagues at Spark Therapeutics – acquired by Roche in 2019 – Roche scientists are exploring other potential molecules for targeting HD. Spark specializes in gene therapies.

 

HD researchers continue to weigh the approach of drugs such as votoplam and tominersen, which lower both the mutant and normal huntingtin protein, versus those that attack only the mutant. The latter types are known as allele-selective. They leave the normal protein to carry out its essential actions unhampered.

 

Dr. McColgan said that Roche and Ionis are investigating an allele-selective antisense oligonucleotide.

 

Roche is also participating in the HD Regulatory Science Consortium. Using data from the original tominersen trial and other patient data, this collaboration seeks to improve the measurement of clinical trial volunteers’ performance in clinical trials, said Dr. McColgan.

 

Roche is also collaborating with CHDI to improve the measurement of Nfl (neurofilament light chain) as a key biomarker.

 

“Nfl increases across the stages of HD,” Dr. McColgan observed.

 

The latest news on tominersen

 

All clinical trials are regularly checked by an independent data monitoring committee.

 

Volunteers in the tominersen trial not on placebo have received either 60mg or 100mg of the drug.

 

On April 17 Roche issued a letter to the HD community stating that the committee overseeing the tominersen trial has found “no concerns … regarding participant safety or signs of symptom worsening with either tominersen dose.”

 

In addition, the letter said, “the 100mg dose was found to be more likely than the 60mg dose to result in clinical benefit. Therefore for the remainder of the study only the 100mg dose will be tested against placebo, and the 60mg dose will be discontinued.” Those receiving 60mg will now get 100mg.

 

“We are incredibly grateful to the 301 participants and their companions enrolled in GENERATION HD2,” the letter stated. “Each study visit contributes to collecting data that helps the entire HD research community learn more about tominersen, Huntingtin-lowering strategies, and the further understanding of HD.”

 

In Part II of this article I will report on Wave’s and uniQure’s clinical trial updates

 

(Disclosure: I hold a symbolic amount of Ionis shares.)

More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.

At HDF symposium, a Huntington’s disease ‘hero’ who prays for scientists to find a cure

 

Recognizing the invaluable input from people living with Huntington’s disease, the Hereditary Disease Foundation (HDF) featured a conversation with Michael, a 62-year-old HD-affected Boston man, at its biennial conference of scientists seeking therapies for this incurable disorder.

 

Michael was interviewed about his HD symptoms by neurologist Diana Rosas, M.D., of Harvard University and Massachusetts General Hospital.

 

Titled “Living with Huntington’s Disease: Family Perspectives,” this HDF tradition of focusing on an HD-affected person took place on August 8 during HD2024: Milton Wexler Biennial Symposium. Convening some 300 researchers, biopharma officials, and advocates, the event ran August 7-10 at the Royal Sonesta Boston Hotel in Cambridge, MA.

 

HD usually impedes speech. I saw that affecting my mother. She died of the disorder at 68 in 2006, after two decades of symptoms, and I carry the HD gene.

 

Michael struggled but persistently formed words and sentences. “I pray for everybody,” Michael said, referring to the quest for therapies, during the Q&A after the interview.

 

Michael’s former wife attended in support of his advocacy, as did his two sons, both in their 20s.

 

Michael (left), who has Huntington's disease, and his physician, Diana Rosas, M.D. (photo by Gene Veritas, aka Kenneth P. Serbin)

 

A diagnosis in 2017

 

Born in Chicago, Michael grew up in Princeton, NJ. As a young adult he moved to Boston, where he studied to become a French chef. He spent a year traveling through France to master his profession. He worked in several restaurants in Boston and also at Gillette Stadium for the NFL’s New England Patriots.

 

Michael believes his father had HD, although he was never formally diagnosed, due to the limited knowledge about the disease as Michael grew up in the 1970s. His father was also an alcoholic. Michael’s aunt also suffered from HD and went into a care home.

 

Michael was diagnosed with HD in 2017.

 

It became ‘too dangerous and messy’ to cook

 

Dr. Rosas is Michael’s physician. As she noted, many lab researchers have little contact with HD-affected individuals. The interview aimed to inform them of the complex triad of symptoms and many psychosocial challenges posed by HD.

 

Dr. Rosas asked Michael to address questions about the first type of symptoms: movement disorders, including involuntary movements.

 

These symptoms, Michael explained, caused him to stop cooking: it had become “too dangerous and messy.” It also became harder to dress himself.

 

Typical of HD patients (including my mother), Michael has suffered several serious falls, leading to a broken wrist, ribs, neck, a punctured lung, and a subdural hematoma (a serious injury to the head). Though he had participated in research conducted by Dr. Rosas, the hematoma has prevented him from participating in clinical trials, because of a restriction by pharmaceutical companies.

 

“I like helping out however I can,” he said of his participation in research.

 

Michael, who lives alone, does have a chocolate labrador retriever that he walks.

 

Michael used to drink alcohol daily and smoke heavily. The drinking caused one of his falls, he said. He quit both habits. Alcohol was a “big part” of his life, he recalled, adding that he doesn’t “miss the days of drinking.”

 

A greatly modified daily routine

 

Dr. Rosas brought up another part of the HD triad: cognitive loss, executive dysfunction, and failing memory.

 

Michael observed that his loss of executive function prevented him from cooking, which had required preparing items and “lots of multitasking.”

 

Though he “can remember my bank card number,” he has ongoing difficulties with memory. He pays his cable and phone bills but has an accountant to assist with his overall finances. He still cares for two salt-water fish tanks, an activity he took up in his 20s.

 

Michael arises at 6 a.m., when he takes his medications: risperidone, an antipsychotic, twice daily; deluxotine for depression; and a multi-vitamin. He also takes medical marijuana.

 

After some small accidents, Michael stopped driving, now relying on Uber.

 

Overcoming impulsiveness and depression

 

Regarding the third part of the triad, psychiatric and mood disorders, Dr. Rosas observed that HD-affected individuals can become fixated or impulsive.

 

Michael agreed that this has affected him, recalling that his drinking also led him to be “very impulsive.” He also suffers from depression. Many HD-affected people become angry when faced with unexpected changes in their daily routine. Michael has also experienced this type of anger. Getting over the anger can take time, he added.

 

Like many of the affected, Michael also has difficulties sleeping. His drinking had exacerbated this problem.

 

“It’s like your mind and body are always on with HD,” he observed.

 

Indeed, HD-affected individuals burn lots of calories. Dr. Rosas recommends five meals per day, although Michael said he eats three to four. 

 

Dr. Rosas interviews Michael about his HD symptoms (photo by Gene Veritas).

 

‘You are a hero!”

 

In the Q&A following the interview, Michael expanded on aspects of his life.

 

One has involved his relationship with his ex-wife and sons. Michael said that the divorce occurred around the time of his diagnosis and was “probably” the result of it.

 

Michael saluted his former spouse as “one of my huge supporters. I haven’t had a girlfriend after my divorce. We were married for 24 years.”

 

He said that he has “two great kids” who are “successful and happy.”

 

Michael also socializes with friends, some of them also divorced.

 

Asked about the work of the researchers, Michael said, “I love them to death.” He added that he is looking forward to new advances.

 

Dr. Rosas asked what most worries Michael about HD.

 

“I suppose going to a home, going to an assisted living situation,” he said.

 

His capacity to manage on his own prompted praise. “You are a hero!” declared Tacie Fox, a family advocate and co-trustee of The Fox Family Foundation (which supports HD research), leading the audience to applaud enthusiastically.

 

“It feels like you have somehow navigated in a way that brings you joy in your life,” she added. “We’re struggling with that with my little sister. She watches a lot of TV. I’m in awe that you, living on your own, have marshaled that inner strength.”

 

The key role of modifier genes

 

At 64, I have been extremely fortunate to have not been diagnosed with HD. It is likely that I have benefited from modifier genes and other factors.

 

Like the rest of the audience, I was deeply moved by Michael’s courage and perseverance in living with HD.

 

I hope that when the inevitable symptoms arrive, I will have the same strength as Michael.

 

Stay tuned for upcoming articles on the conference proceedings, including deep discussion of the key role of modifier genes in the search for therapies.

 

Disclosure: the Hereditary Disease Foundation covered my travel expenses.

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).