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.
