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).

New book by longtime advocate describes Milton Wexler’s incomparable contributions to Huntington’s disease research and beyond

 

A new book portrays the largely unexplored personal and psychological context of the quest to understand and defeat Huntington’s disease: a biographical memoir of Milton Wexler (1908-2007), the founder of the Hereditary Disease Foundation (HDF) and key mover in the discovery of the HD gene.

 

In late 2022, Wexler’s daughter, historian Alice Wexler, published The Analyst: A Daughter’s Memoir (Columbia University Press). She is a longtime Huntington’s disease advocate and chronicler of the cause.

 

The Analyst adds unique dimensions to HD history, building on Alice’s groundbreaking work. In 1995 she authored Mapping Fate: a memoir of family, risk, and genetic research (first published by Random House and Times Books, then reissued by the University of California Press). In 2008, she wrote The Woman Who Walked into the Sea: Huntington’s and the Making of a Genetic Disease (Yale University Press).

 

This year marks the 30th anniversary of the discovery of the huntingtin gene, announced in March 1993. Through the HDF and in collaboration with a global team of scientists, Milton and his neuropsychologist daughter Nancy, Alice’s sister, spearheaded the hunt for the gene, as recounted in Mapping Fate. In The Woman Who Walked into the Sea, Alice explored the social and medical history of HD in the 19th and 20th centuries, helping explain the stigma HD families still face.

 

The sisters’ mother Leonore was diagnosed with HD at the age of 53 in 1968. That led Milton to immediately start the HDF, which focused on the development of treatments.

 

In 1993 the discovery of huntingtin “immediately transformed Huntington’s research,” Alice writes in The Analyst. “Suddenly it was possible for researchers to make animal and cell models and study how the gene worked at the cellular and molecular level. They could test drugs and other molecules in mice and sheep, fish and flies, as well as in human beings.”

 

Milton was “ecstatic and also relieved,” Alice recalls. “We even allowed ourselves to imagine that a treatment, and possibly a cure, might be on the horizon.” HDF-sponsored researchers and other scientists around the globe are still striving to achieve that goal.

 

 

Meeting’s life’s difficult challenges

 

Drawing on access to her father’s extensive personal correspondence, her diary, and archival sources enabled Alice, with decades of hindsight, to present her father’s story – in which the fight against HD became his life mission – in intimate detail.

 

Describing Milton, Alice is meticulous, often critical, but always loving – a reflection of the complex relationship of a highly successful professional with daughters that he wanted the best for and whose lives he fought for. She adds a valuable feminist perspective, for example, interpreting her father’s friendships by analyzing masculinity and male intimacy in the 1950s.

 

In addition to Milton’s incomparable contributions to HD research, The Analyst depicts key aspects of American life in the second half of the 20th century. It delves into Jewish life in Brooklyn, which spurred Milton’s ambitions, taking him to Kansas and then to Los Angeles.

 

Portraying her father’s main career as a psychoanalyst, Alice helps to rescue the history of a field that has lost relevance with the emergence of other forms of therapy, though it continues as an intellectual field. Milton saw great value in psychoanalysis’s way of helping people understand their emotions but he increasingly practiced more direct forms of therapy, focused on the here-and-now. As he put it, “insight alone does not change behavior.”

 

Alice demonstrates how much of Milton's early career trying to understand and treat schizophrenia helped him to confront this other knotty problem, HD.

 

In an appendix, The Analyst lists “sayings of Milton Wexler” – including a 1998 note to a President Bill Clinton in crisis – regarding challenges such as the loss of a child, self-defeat, depression, personal identity, loneliness, and risk for a disease such as HD.

 

Milton’s embrace of talk therapy is a key reminder for HD families overwhelmed by the disease's  many social and personal challenges that help is available, and that individual and family therapy can make a difference. He believed that people should not have to struggle on their own.

 

In Los Angeles, Milton became a therapist for many in the arts and entertainment – a practice that he parlayed into significant donations for the HDF.

 

(Click here to read more about my own journey with psychoanalysis as an aid to fighting HD.)

 

‘The nightmare is the children’

 

With new material and perspective, Alice expands on the difficult moments described in Mapping Fate regarding  Leonore’s diagnosis, Milton’s deep fears that his daughters would be affected, and his  “frantic search for information” about HD and scientific contacts that in a matter of weeks spurred the concept of the HDF.

 

Leonore’s diagnosis and HD were “the great poison in my life,” Milton wrote his brother Henry in May 1968 in a letter uncovered by Alice. “But the nightmare is the children.[…] For me there is only dread in the air.”

 

Milton divorced Leonore but nevertheless cared for her impeccably and guaranteed her financial security. Leonore died in 1978 at 63, ten years after her diagnosis..

 

Providing intellectual fuel

 

With his background in psychology and prior experience as an attorney, Milton advocated for a multidisciplinary approach to solving HD and other neurological disorders. He championed the interplay of psychoanalysis and neuroscience in a move critical for HD research. He also grasped the growing importance of molecular genetics and its potential value for Huntington’s.

 

From this perspective Milton developed unique HDF workshops involving informal, spontaneous discussion – as opposed to dry scientific presentations with slides – as the main driver of the search for the HD gene and the quest for treatments. The first took place in 1971. Held in hotel rooms or at universities, these gatherings typically involved 15 to 20 participants.

 

As Alice reports, Milton believed that real creativity resulted from “casual conversation and carefree association among people in the same or related disciplines.”

 

While finding prestigious veteran scientists for HDF’s advisory board, Milton recruited younger researchers, including women, as the organization’s intellectual fuel.

 

As Alice observes, the HDF formed part of a trend in which “philanthropy assumed an increasingly influential role in funding science and meeting social needs.” Contributions to the HDF swelled. It established an endowment to fund future workshops and critical research grants.

 

The challenges of genetic testing

 

Alice reflects on her family’s monumental role in finding the gene and also the irony that neither she nor her sister chose to get the genetic test – a test which “opened a Pandora’s box of legal, social, and ethical challenges and raised many personal questions for Nancy and me.”

 

The test developed shortly after the 1993 discovery of huntingtin enabled 100 percent accuracy in detecting the HD mutation. Prior to this, research had established that each child of an affected parent has a 50-50 chance of inheriting that mutation. As Alice showed in The Woman Who Walked into the Sea, deep stigma and discrimination increased around HD in the 1900s.

 

“None of us considered the possibility of the genetic test to resolve the uncertainty,” Alice writes, referring to the time when she began noticing subtle changes in Nancy. “For all our knowledge of psychology, we turned to denial, that most primitive of defenses. We worried, we wondered, and then we denied. It simply could not be.”

 

Indeed, to this day, only about ten percent of persons at risk for HD choose to be tested.

 

At 81, Alice has not developed symptoms. In 2020, Nancy revealed her HD diagnosis to the New York Times. At 78, she bravely struggles with HD symptoms yet keeps abreast of the latest scientific developments. She now works with a writer on her memoir.

 

Solidarity and hope

 

Along with Mapping Fate and The Woman Who Walked into the Sea, Alice’s warm portrayal of her father in The Analyst shows how he helped the HD community advance in understanding the disorder and seek anxiously awaited treatments to slow, stop, or reverse the disease.

 

Milton lived a full, fascinating, and challenging life, dying peacefully in 2007 at age 98, at Alice and Nancy’s side. In multiple ways, he serves as a model – especially for the idea that when faced with an enormous and difficult challenge, becoming an activist can be the best form of  therapy.

 

The legacy of the discovery of huntingtin, as well as HDF’s scientific leadership, help build solidarity and hope for a better future for HD and all other neurodegenerative diseases.

 

 

Milton Wexler flanked by daughters Nancy (left) and Alice in 1992 (photo by Mariana Cook)

After a difficult year for the Huntington’s disease cause, CHDI chief scientist feels ‘reinvigorated’ and ‘optimistic’ about quest for therapies

 

Having faced negative results in two key clinical trials a year ago while battling the coronavirus pandemic, the Huntington’s disease community has renewed the quest for therapies (treatments).

 

A vital sign of this: despite initial fears about the omicron variant of COVID-19, the 17th Annual HD Therapeutics Conference took place ­from February 28-March 3 at the Parker Palm Springs hotel in Palm Springs, CA. The 305 fully vaccinated attendees gathered under a massive tent, which allowed social distancing and provided good ventilation.

 

Shortly after the March 2020 conference, much of the world went on lockdown to avoid the ravages of the virus, pushing the 2021 conference online.

 

“I don't think it's hyperbole to say that coming here for this conference in person feels like a rebirth,” said Robert Pacifici, Ph.D., in a half-hour interview with me on March 4. “It's been a hard couple of years for everybody, but for the Huntington's disease community in particular.”

 

Dr. Pacifici is the chief scientific officer of the conference sponsor, CHDI Foundation, the nonprofit virtual biotech entity geared solely towards finding HD therapies. CHDI is the largest private funder of HD research.

 

In March 2021, the community “learned that two of the really well thought-out and very rational clinical trials for Huntington's disease had been halted and it dashed a lot of people's hopes,” recalled Dr. Pacifici, referring to GENERATION HD1, the largest clinical trial in HD history, run by Roche, and two smaller trials with a similar drug run by Wave Life Sciences.

 

Those results “must have been devastating” for people awaiting an “efficacious treatment,” Dr. Pacifici continued. “But we do what the Huntington's community always does: we persevere, we lift ourselves up by our bootstraps, and we go forward.”

 

Witnessing a “bunch of reasons” for hope about therapies at the conference, Dr. Pacifici declared, “I'm reinvigorated and very optimistic.”

 

For an overview of the conference and my interview with Dr. Pacifici, watch the video below.

 

 

Above, HD Therapeutics Conference attendees view scientific posters presenting new research, and, below, watch one of the many presentations at the four-day event (photos by Gene Veritas, aka Kenneth P. Serbin).

 

 

Learning from last year’s setbacks

 

At the Therapeutics Conference, Roche elaborated on new data from GENERATION HD1 and its plans to develop an improved clinical trial. Wave provided an update on its new early-stage trial, SELECT-HD.

 

Both firms use gene silencing drugs to attempt to reduce the amount of the toxic huntingtin protein in the brain (called huntingtin lowering). Both seek to build on the lessons learned from the 2021 setbacks.  (Click here to read about Roche’s recent announcement and here about Wave’s new trial.)

 

“I'm heartened that there's still a lot of enthusiasm for the huntingtin-lowering approach,” Dr. Pacifici observed. “There's actually a very impressive portfolio of other companies, therapeutic modalities, and approaches to huntingtin-lowering.”

 

Other plans to attack the mutant protein

 

PTC Therapeutics and Novartis Pharmaceuticals presented updates on their respective ongoing clinical trials using different huntingtin-lowering approaches. Whereas Roche and Wave drugs were administered via an uncomfortable spinal tap done at a clinic, PTC and Novartis use so-called small molecules: pills.

 

Besides the obvious convenience, such small-molecule drugs offer other key advantages, Dr. Pacifici explained.

 

“We know that mutant huntingtin is expressed everywhere [in the body] and so it’s good to know that you can lower it everywhere with a small molecule,” he said, noting that dosages can then be calibrated to achieve different lowering effects.

 

A higher dose creates more lowering, while a lower dose lessens it, Dr. Pacifici explained.

 

“From a safety perspective, if we ever found a long-term problem with huntingtin lowering, you can stop taking the compound and let the huntingtin come back so that then you can decide,” he continued, referring to a practice called picket-fence dosing, in which patients stop and restart dosing as needed.

 

Triplet gears up to test its approach

 

With no guarantee that reducing the toxic protein will result in an effective treatment, the Huntington’s field has purposefully diversified.

 

A key example is the work of Triplet Therapeutics. Triplet focuses on somatic expansion (also known as somatic instability), the tendency in HD of the already expanded (and therefore mutant) huntingtin gene to continue growing in length with age. The greater the expansion, the earlier the impact of the mutation on brain cells. This process is governed by recently discovered modifier genes that slow or hasten disease onset. (Click here and here to read more.)

 

“That's what actually causes the cells to malfunction, to die, and eventually leads to the underlying physiology of Huntington's,” Dr. Pacifici said. “So, not surprisingly, that gives us another therapeutic handle. Can we slow down that somatic instability?”

 

At the conference, two Triplet scientists presented a preliminary analysis of data from SHIELD-HD, a research study of 70 presymptomatic and early-disease-stage carriers of the HD mutation. SHIELD-HD is furnishing data for a clinical trial of Triplet's drug candidate, TTX-3360, aimed at blocking somatic expansion and, therefore, potentially delaying or avoiding HD onset.

 

Triplet Therapeutics scientists Irina Antonijevic, M.D., Ph.D., the chief medical officer (right), and Peter Bialek, Ph.D., senior director of translational science, after their presentation at the HD Therapeutics Conference (photo by Gene Veritas)

 

Founded in 2018, Triplet has used the science of somatic expansion and HD modifier genes to move with “record-breaking speed” towards a clinical trial, Dr. Pacifici said.

 

In a brief interview after the Triplet presentation, Irina Antonijevic, M.D., Ph.D., the company’s chief medical officer, confirmed that it will file a Clinical Trial Application this summer for permission to start a Phase 1 dose escalation clinical trial of TTX-3360, mainly to test safety and tolerability. Regulatory agencies can take a few months to review the application, after which the firm could start recruiting people with HD.

 

“We’re very excited,” Dr. Pacifici said. “The whole area of somatic instability is a great complement to huntingtin lowering. It's possible that eventually, if God forbid, huntingtin lowering turns out not to be viable, we've got a great backup plan. But even if it is, these things could actually synergize with each other. I could imagine people in the future being treated with a combination of therapies that address both of these things – lowering the huntingtin protein, but also preventing additional somatic instability.”

 

A future article will explore the SHIELD-HD presentation and Triplet’s clinical trial plans.

 

The value of family participation

 

Most of the conference presentations focused on human data, as opposed to research in animals. Dr. Pacifici pointed out that many advances in HD research result from the participation of thousands of gene carriers in studies and clinical trials.

 

“I appreciate that families are willing to give their time, their blood, their urine, and the travel, the poking, the prodding they're going through,” Dr. Pacifici said. “I want to express my heartfelt gratitude. This year, more than ever, I guess I'm happy to say I told you so, meaning that I always encourage people to participate and we're now seeing the fruits of that participation. We now have the evidence that those samples are being used judiciously and are providing unparalleled value.”

 

Dr. Pacifici also pointed to the steadfast commitment of both scientists and families to HD research during the pandemic, which “required people taking risk and going into the clinics and the labs.”

 

“Hang in there, be resilient, participate when you can,” Dr. Pacifici concluded, because a “really talented, committed global group of passionate drug discovery professionals would love nothing more than to deliver what you need so desperately, which are effective treatments for Huntington's disease.”

 

For my coverage of the start of the conference, click here.

 

For additional coverage, visit HDBuzz.

History, Huntington’s disease, and the survival of the human race

 

With thousands of people continuing to die from the COVID pandemic and the planetary climate crisis worsening, the Russian attack on Ukraine and the dictatorial Vladimir Putin’s threats of nuclear war have brought the world to a turning point.

 

Either we strive to end war or, by failing to unite globally to solve environmental and health challenges, we risk destroying ourselves. From biological history we know that millions of species have gone extinct. No one but us prevents our extinction, as well.

 

The war has produced searing images of Ukrainian families living underground or fleeing their country by the hundreds of thousands.

 

While the U.S., the North Atlantic Treaty Organization (NATO) countries, and many other key nations have sought to counteract Putin’s actions without sending in troops, around the world citizens and governments have protested and shown solidarity with the Ukrainian people.

 

As I drove yesterday from my home in San Diego to Palm Springs, CA, for the 17th Annual Huntington’s Disease Therapeutics Conference, I thought once again of how the quest for effective treatments for this devastating disease has embodied fortitude and collaboration.

 

Along the way I listened to The Tipping Point, the new, long-awaited album by Tears for Fears, one of my favorite bands, and pondered the poignant interview they gave about their album’s relevance to the present moment.

 

What I have termed the “Huntington’s disease movement” has highlighted caregiving, the alleviation of physical and mental suffering, and the harnessing of science for societal good.

 

These sentiments are especially appropriate at the start of the conference, February 28, Rare Disease Day.

HD Therapeutics Conference keynote speaker and journalist Charlotte Raven (seated) and, from left to right, Dr. Ed Wild, Charlotte's daughter Anna, and son John, February 28, 2022 (photo by Gene Veritas, aka Kenneth P. Serbin). Read more below about Charlotte's heartrending but brave presentation.

 

Writing the history of the HD movement

 

As an HD mutation carrier and advocate, I have shifted my focus as a professional historian from the country I consider my second home, Brazil, to the history of science, technology, and medicine.

 

On January 31, I submitted an application for a grant to support new research for a book to be titled “Racing Against the Genetic Clock: A History of the Huntington’s Disease Movement and the Challenges of the Biomedical Revolution.”

 

“Huntington’s disease research stands at the forefront of the biomedical revolution,” I wrote in the application. “The search for the huntingtin gene, finally achieved in 1993, contributed to the concept of the Human Genome Project. Huntingtin was one of the first disease-causing genes discovered. Yet, thirty years later, the experience of living with Huntington’s has not changed dramatically.”

 

In this project, building on my quarter-century of advocacy and tracking of scientific progress, I will seek to chronicle and interpret the HD movement in the period since the huntingtin breakthrough.

 

A visit with scholar Alice Wexler

 

To gather documentation and exchange ideas about the project, on February 21 I traveled to Santa Monica, CA, to meet with the preeminent historian of HD, Alice Wexler, Ph.D., the sister of Nancy Wexler, Ph.D., a key figure in the search for the huntingtin gene.

 

Alice Wexler wrote Mapping Fate, the key historical account about the discovery of the gene. She also authored The Woman Who Walked into the Sea, which describes the of development of medical understanding of HD in the 20th century and the stigma and discrimination associated with the disease.

 

In October, Columbia University Press will publish her latest work, The Analyst, a memoir of her late father Milton Wexler. A psychoanalyst, he founded the Hereditary Disease Foundation (HDF) in 1968 after his wife Leonore was diagnosed with HD.

 

Until the early 2000s, the HDF was the main private funder of HD science. From her personal archive, Dr. Wexler provided me with HDF newsletters, scientific reports, and other important documents.

 

Dr. Wexler also shared with me news clippings and other documents related to the HD movement.

 

Over lunch and then on a long walk along the Santa Monica beach, Dr. Wexler and I bonded over stories of our beloved Latin America (she, too, began her career studying that region), our families’ respective fights against HD, and my goal of building on her work as I embark on my new research.

 

Alice Wexler and Gene Veritas, aka Kenneth P. Serbin, in Santa Monica, CA, February 21, 2022 (personal photo)

 

My eleventh CHDI meeting

 

This will be my eleventh HD Therapeutics Conference, which is sponsored by CHDI Foundation, the nonprofit virtual biotech firm that grew out of the HDF and is dedicated solely to developing HD therapies. I keynoted the 2011 meeting. Because of the pandemic, the 2021 conference was held online. This year the conference will take place in person at its traditional location, the Parker Palm Springs, but under a tent on one of the hotel’s large lawns instead of inside.

 

As a pre-meeting reception on February 27 held by CHDI at the Villa Royale, I saw many veterans of the CHDI staff. I also spent time telling a new CHDI researcher staff member, who was attending her first Therapeutics Conference, about my family’s HD story.

 

I also conversed at length with Daniel Claassen, M.D., M.S., a professor of neurology at the Vanderbilt University Medical Center.

 

I was thrilled to hear Dr. Claassen describe his experience of lecturing via Zoom to about 150 Brazilian neurologists last year about Huntington’s disease, with the assistance of a Portuguese-speaking interpreter.

 

Fighting for human well-being

 

We also discussed the unique interpretations that each HD family can develop about the symptoms, especially in cases such as that involving my family, which had no prior knowledge of HD before it struck my mother.

 

I recalled for Dr. Claassen an especially painful moment from around Christmas of 1989. I had been doing research in Brazil for well over a year and was very happy to see my parents upon visiting their home in Ohio.

 

At one point, I heard my mother on the phone crying and complaining to a friend that she could not stand having me around.

 

At the time, I attributed her reaction to moodiness. In retrospect, as Dr. Claassen and I concluded, my mother’s reaction probably represented the start of the psychiatric and behavioral disorders that are often the first HD symptoms to appear.

 

My mother was diagnosed with HD six years later, in 1995.

 

“It wasn’t my mother’s fault!” I said with great sadness about her emotional difficulties.

 

At the Therapeutics conference, we will all be renewing our commitment to defeat HD and other neurodegenerative conditions.

 

For me, this is our contribution to human well-being.

 

 

Dr. Daniel Claassen (left) and Gene Veritas (photo by Simon Noble, Ph.D., director, scientific communications, CHDI)

 

Charlotte Raven, a brave keynote speaker

 

The conference got under way the evening of February 28 with a profoundly moving presentation by keynote speaker Charlotte Raven, a renowned British journalist, commentator, and author whose work has appeared in The Guardian, New Statesman, and Modern Review.

 

Charlotte is affected by HD. She was the first participant in the Roche GEN-PEAK trial, a small Phase 1 study run in tandem with the Roche Phase 3 GENERATION HD1 trial. These trials sought to measure the effects of the gene silencing drug tominersen.

 

In March 2021, Roche halted dosing in GENERATION HD1 because of lack of efficacy. In January, Roche announced that it will start a new, less ambitious Phase 2 trial to test tominersen’s efficacy (click here to read more).

 

Joined in the presentation by her son John, daughter Anna, and her neurologist, Ed Wild, M.D., Ph.D., Charlotte spoke bravely about her struggles with HD. She echoed the deep sadness and frustration of the HD community in the wake of the March 2021 news.

 

With many of the nearly 300 conference participants crying at the end, Charlotte received a standing ovation.

 

Roche will present two reports on its efforts on the conference’s final day, March 3.

 

A future article will feature Charlotte’s story, including a video of her keynote.

 

Assisted by son John, Charlotte delivers her keynote address (photo by Gene Veritas).