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).

My Huntington’s disease sister – and a hero who strives for the unthinkable

Sharon Shaffer is my Huntington’s disease sister – and my hero.

Afflicted with progressively worse HD symptoms the past 15 years, San Diego area resident Sharon decided to once again attempt the unthinkable for someone heading into the final years of the fatal, incurable disorder: she rowed the equivalent of an aquatic marathon (26.2 miles) on a gym machine in six and a half hours.

The May 10 event, with loved ones and supporters cheering her on, was called “Sharon's Marathon Row for Huntington's Disease Awareness Month.” 

Sharon’s feat was captured in a five-minute video titled Magic on Marathon Row, produced by filmmaker Nathan Apffel, who also directed the feature-length documentary The Longest Journey, about the Shaffer nuclear family’s epic battle against Huntington’s.

A scene from Magic on Marathon Row

“When disease takes your health and mobility and will take your life, you have a choice,” the video’s overlying text says. “Meet Sharon, a real-life super woman. As Sharon’s body gives out, her determination grows. As her world contracts, her commitment to raising awareness intensifies. As her body breaks down, one thing remains consistent: her determination to fight.”

Sharon’s husband Renato told me in an e-mail that, despite her advanced HD symptoms, she did the "marathon" through “sheer perseverance.”

“It is the only exercise she is able to do without assistance,” he added.

“Sharon, you truly are an inspiration to so many,” wrote E.J. Garner, the chair of the board of the Huntington’s Disease Society of America, in response to my Facebook posting of the video. “Thank you for being such a beautiful example of persistence to fight and bringing awareness to Huntington's disease.”

“She completed a feat only few in the entire world, even healthy and athletic, would not dare approach, let alone finish,” observed LeeJ Razalan, a friend and the owner of Stay Classy CrossFit, the San Diego gym where the event took place. “Sharon's statement in life and in disease will forever ring: we shall overcome and we will finish this together."

Watch Sharon in the video below.

Advancing symptoms

The “marathon” exhausted Sharon. “She could barely move when we got home and took a good three days for full recovery,” Renato explained.

With her family’s help, Sharon has remained one of the most physically active HD-afflicted individuals I have encountered. The highly demanding CrossFit workouts have been one of her favorite activities.

Renato believes that CrossFit delayed Sharon’s need for a wheelchair.

“I also believe the people she worked out with gave her motivation,” he added. “She always looked forward to working out.”

However, Renato also described CrossFit as a “barometer” of HD progression.

In recent years she has become physically weaker, and the involuntary movements caused by HD have increased.

“We have witnessed a rapid decline in the past twelve months,” Renato wrote. “She is no longer able to walk unassisted, and her speech is becoming more labored every day. We have full-time in-home care and are so fortunate they are doing a really great job taking care of her.”

Sharon still exercises, but “it gets more difficult every week,” Renato added.

Renato allowed Sharon to row in the “marathon,” he wrote, because as symptoms worsen, exercise will become impossible. That moment will be "heartbreaking."

An upbeat family

I met Sharon about two decades ago at the HDSA-San Diego support group. With others in the breakout group for presymptomatic gene carriers like us and also the untested at-risk, we shared our fears about the disease and its consequences for our children and extended families.

The Shaffers became one of the most active supporters of the cause. Between 2005 and 2015, with Sharon, family members, and others following in support vehicles, Renato and three other riders competed four times in the Race Across America, a non-stop coast-to-coast bicycle race. They always completed the race in fewer than the required eight days.

The Longest Journey documentary chronicles the 2015 race. “In contrast with most presentations of HD I’ve witnessed in the two decades since my mother’s diagnosis for the disorder, this often emotionally wrenching film left me, an HD gene carrier, feeling upbeat,” I wrote in a review of a private screening of the film in 2016 (click here to read more). 

The closing words of Sharon’s rowing video ask viewers to learn more about Sharon’s story by watching The Longest Journey. (It’s on Amazon and free to Prime members.)

According to Renato, Amazon statistics reveal that the film has been viewed 200,000 times.

The essential goal: treatments

Sadly, I’ve witnessed how HD has overcome Sharon, transforming her from a healthy and vibrant woman into someone now dependent on a wheelchair and the assistance of others.

However, Sharon has demonstrated that, despite the ravages of the "devil of all diseases," the core of her personality has survived.

As we enter the final week of HD Awareness Month, Sharon’s gutsy fight reminds us all that we must not give up in the face of Huntington’s difficult challenges.

For me, Sharon’s devotion to exercise is a cue to spend more time swimming.

At the same time, exercise, although certainly important, has not stopped Sharon’s HD from progressing.

We need effective treatments – urgently.

In the HD movement, advocates create moments that capture the essence of the cause.

In defying seemingly insurmountable obstacles, the Shaffers remind us of the immense scientific, financial, political, and social challenges that the HD community faces in seeking to find the first effective treatment – and perhaps even a cure – for a neurological disorder.

How to make law enforcement a friend – not a foe – of people with Huntington’s disease (and other disabilities)

Encounters with misinformed, sometimes insensitive police are one of the most vexing and tragic problems faced by people disabled by Huntington’s disease. So HD advocates and organizations are proactively trying to help law enforcement officers understand symptoms of the disorder and properly handle individuals in distress.

“We want them to be a friend, not a foe,” Doug Schulte, a long-time caregiver to his HD-afflicted wife Dorlue, said of the relationship between HD-affected people and police officers.

Doug, a retired fire captain with the San Diego Fire-Rescue Department, has joined HD advocates in the area and around the country in raising awareness about the disease. Its many behavioral disorders have often been misinterpreted as drunkenness, drug usage, or intentional hostility. People with HD often have an unsteady gait, involuntary movements, slurred speech, aggressiveness, and other difficulties that hamper social interaction. But those are warning signs for police untrained for such interactions.

An informal survey, which I conducted among HD families on Facebook recently, revealed that police misunderstanding and harsh treatment of affected individuals continue, but also that some officers respond with respect. (Click here and here to read about two previous controversial cases, in West Virginia and Pennsylvania.)

The survey also showed that some HD families are taking the initiative to contact the local police to educate them about the disease and their loved ones.

At the same time, thanks to both disease advocates and changing perceptions of police officers’ responsibilities, some law enforcement agencies have established programs to increase officers’ sensitivity when encountering or responding to calls involving the cognitively disabled and the mentally ill.

On October 3, California Governor Jerry Brown signed into law a bill mandating that police officers receive more in-depth training for helping citizens with mental illness or developmental disabilities, or who are under the influence of certain substances.

‘Take Me Home’

Doug recently registered Dorlue in the “Take Me Home” Program of the San Diego County Sheriff’s Department. Under the program, people with Huntington’s, Alzheimer’s disease, autism, and other cognitive disabilities or their loved ones can register their information online. Registrants can upload a photo of the disabled individual and provide a description of the person and symptoms that officers should know about.

Dorlue Schulte (family photo)

Lt. Mike Knobbe, a 24-year veteran of the sheriff’s department and the coordinator of Take Me Home, said that the program aims for good relations between the police and the disabled.

“The whole goal of this program is to build that partnership and to build that understanding, to allow you to tell us what you want us to know about your individual with special needs,” said Lt. Knobbe in a December 2 interview at sheriff’s headquarters.

Lt. Knobbe runs Take Me Home as part of his work as head of the department’s search and rescue unit. He also represents the department at the ambitious Alzheimer’s Project established by the San Diego County Board of Supervisors to seek treatments and improved care for that disease. The region has some 60,000 people affected by Alzheimer’s, some of whom dangerously wander from home and need a program like Take Me Home, Lt. Knobbe said.

Advocates for the disabled and affected families might not trust the police, he said, if officers don’t understand the dynamics of a disorder and the difficult situations that can result.

A display table with items from and about the "Take Me Home" Program (photo by Gene Veritas)

“So this is our opportunity to say, ‘Hey, we want to understand,’” he said. “What do you want to tell us, so when we get a call referencing your loved one, or to your residence, it will automatically come to our deputy, and we can have that knowledge ahead of time.”

With more than 500 individuals registered in the sheriff’s department’s countywide database, Take Me Home allows the department and other local police agencies to send to patrolling officers’ computers a photo of the disabled individual, medical information, and an explanation of unusual symptoms or behaviors. So far, the department has not tracked results, but may do so in the future. It is actively promoting the program to other law enforcement agencies in San Diego County and with disability organizations.

As Lt. Knobbe explained, typically misunderstood HD symptoms such as aggressiveness can “absolutely” go into the database.

“That’s something we want to know,” he said. “We still have a duty and a responsibility as a law enforcement officer to respond, yet it gives us a chance to have some information as to why might this be occurring.”

To register, go to www.sdsheriff.net/tmh/. You can listen to Lt. Knobbe introduce the program to the HD community in the video below.

'Take Me Home': A Police Aid for Assisting the Disabled from Gene Veritas on Vimeo.

An online database

The San Diego Sheriff’s Department adopted Take Me Home in 2010 at the initiative of Brian Herritt, a former Palomar College officer with an autistic son who once wandered from the family car and encountered a policeman. The boy was unhurt, but the incident prompted Herritt to think about why officers should understand the behaviors resulting from autism, Lt. Knobbe said.

In advocating for the program in San Diego, Herritt studied the Take Me Home program of the Pensacola (Florida) Police Department. Other departments around the country have similar programs.

In San Diego, Take Me Home first relied on patient advocacy groups such as the local Alzheimer’s association to provide a list of individuals for the database.

This process proved cumbersome, lengthy, and inconvenient, and the program was falling into disuse, Lt. Knobbe said. In early 2014, Sheriff Bill Gore tasked him with revamping the program.

“You can now register online on your own,” Lt. Knobbe said of the most important change in the program. “If you’re a caregiver, and you want to register your loved one, you can access our website and the Take Me Home registry and you can actually do you own online registration via your Android device, your iPhone, your iPad, your home computer, attach your own photograph, give us the information you want us to know, and do it from the comfort of your home.”

People register voluntarily, but the information remains confidential, he explained.

A screenshot of the Take Me Home webpage, December 9, 2015

Encouraging participation

Lt. Knobbe credited Doug Schulte with introducing him to HD and getting the disorder listed in the registry.

Before the introduction of the online option, Take Me Home “wasn’t utilized,” said Jamie Jirik, the board secretary for the San Diego Chapter of the Huntington’s Disease Society of America (HDSA). “The information wasn’t being updated effectively.”

“We want this to stay around,” Doug said, adding that he and Jamie are encouraging all San Diego County HD families to participate. “We want this to be something that law enforcement is used to using for people not only with Huntington’s, but Alzheimer’s, autism, and other mental illnesses. People who are deaf, too. It’s equipped with photo recognition software.”

Take Me Home gives law enforcement a good option: contacting a family member instead of arresting an HD person, Doug continued. “It’s what law enforcement wants to do,” Doug said. “They don’t want to take someone down and detain them. It’s a big waste of time for them.”

“If we have a lot of individuals in the database, we’ll have more resources available to us from law enforcement and other first responders,” Jamie added.

“There’s no risk to it,” said Doug. “It’s all reward. There’s no way that putting the information in there is going to be a detriment.”

Jamie Jirik and Doug Schulte (photo by Gene Veritas)

A problem ‘easy to fix’

Using HDSA’s Law Enforcement Toolkit, Jamie and Doug have teamed up to raise awareness about HD among police agencies, paramedics, and other first responders in the San Diego region. They have made presentations at training sessions and other departmental-sponsored events.

Doug calls on his personal experiences as a caregiver to get across the message about HD.

“When you explain how it unfolds in a person’s life, it brings a new dimension of understanding,” he said.

Dorlue has not experienced difficulties with the police, but Doug recognizes that the potential exists, as it does for many HD-afflicted people. He’s also listened to the sufferings of other families.

“The problem of police detention of HD-affected individuals is an awareness issue that is easy to fix,” he said. “We want the resources that society puts in place to protect the HD community to work with us, not against us. My background in fire was to help solve people’s emergencies. Police want to be there helping us, not detaining us if it isn’t warranted. I understand, because I have worked beside law enforcement. They have an extremely difficult job – they just are not aware of HD.”

Teaching response teams about HD

Jamie, 28, watched the disease kill her father in her home state of Illinois when she was 12. “He suffered from a lot of the behavioral aspects of HD,” recalled Jamie, who has tested negative for HD. “We saw his personality change greatly as the disease progressed.”

Jamie’s father was “confrontational at times” with the police and arrested several times, but her mother “actually had a great relationship with law enforcement,” Jamie said. “They did a really good job because they didn’t beat him up and respected him as much as possible.”

In addition to promoting Take Me Home to the local HD community, Jamie and Doug have explained the disease to local police agencies’ Psychiatric Emergency Response Teams (PERT). Such teams act as a liaison between law enforcement and health resources.

“They have the training and experience to interact with individuals with psychological difficulties,” she said. Departments activate PERT when people become a threat to themselves or to others, cannot communicate, or cannot clothe or bathe themselves, Jamie explained. PERT gets a trained clinician inserted into a police situation.

Raising awareness about HD: Jamie Jirik (left), Dr. Mark Marvin, director of the San Diego County PERT, Lt. Debra Farrar of the San Diego Police Department, and Doug Schulte (personal photo)

Feeling safer

Jamie and Doug are promoting other ways of insuring the proper treatment of HD people, including the newly standardized Huntington’s Disease ID Bracelet sold by HDSA.

“It’s a tool for law enforcement,” Doug explained. “They can pop this open and get the specific information about the person’s medical situation. When a paramedic has an interaction, they need to see the medical history and medications. There’s a piece of paper in here where you can write all that.”

Other resources can be viewed at HDSA’s Law Enforcement Education webpage.

The HD advocacy organizations HDCare.org and WeHaveAFace.org have announced a cooperative effort to provide a new medical ID alert bracelet for HD people. (Click here to read more.)

“There’s not one way that’s going to work for everyone, but having all these [resources] available for HD families to utilize will allow people to feel safer and just communicate with first responders,” Jamie observed.

Jamie Jirik displays the Huntington's Disease ID Bracelet (photo by Gene Veritas).