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.
