Saturday, March 02, 2024

Huntington’s disease community will 'get there' in search for therapies, CHDI chief scientist declares after ‘terrific’ conference


After presiding over a “terrific” research conference, CHDI Foundation Chief Scientific Officer Robert Pacifici, Ph.D., declared that the Huntington’s disease community will “get there” in the search for long-awaited therapies.


Dr. Pacifici commented in an interview with me on March 1, after the CHDI-sponsored 19th Annual HD Therapeutics Conference, held in Palm Springs, CA, from February 26-29.


The CHDI chief scientific officer (CSO) provided his optimistic assessment in referencing the featured presentation by David Altshuler, M.D., Ph.D., CSO of the Boston-based Vertex Pharmaceuticals.


“They’ve solved some unbelievably difficult problems,” Dr. Pacifici said of Vertex, noting that it found a cure for hepatitis C.


Vertex has also developed therapies for three tough diseases that, like HD, are genetic: cystic fibrosis, sickle cell disease, and transfusion-dependent beta thalassemia.


At future therapeutics conferences, “we would love for the last talk” to focus on a new drug that is “now going to be approved,’” Dr. Pacifici told me.


“We’re going to get there,” he continued. Dr. Altshuler, who Dr. Pacifici said carefully calibrates his optimism, “was very complimentary and very confident that if we stay on this path, we’ll actually achieve that. He felt that the collective efforts that CHDI is trying to catalyze throughout the community are going to be successful.”


Dr. Pacifici pointed out how CHDI has adhered to another key principle of drug discovery emphasized by Dr. Althsuler: studying HD in human cells, tissues, and postmortem samples.


Dr. Pacifici said he expects the HD field will hear more from Dr. Altshuler and welcomed Vertex’s possible revived involvement.


In 2010 I spoke on my family’s fight against HD at the Vertex labs in San Diego and chronicled its search at the time for an HD therapy, though so far without results reported by that lab.


Dr. David Altshuler presenting a timeline of Huntington's disease scientific landmarks at the 19th Annual Therapeutics Conference, February 28, 2024. Pictured in the slide is James Gusella, Ph.D., whose lab discovered the huntingtin genetic marker in 1983 and the gene in 1993 (photo by Gene Veritas, aka Kenneth P. Serbin, and posted with permission of CHDI Foundation). (Click on the image to make it larger.)


The need to celebrate milestones


“But I think what you will see is incremental successes,” Dr. Pacifici continued. “We’re going to have these new findings, these critical milestones and stepping stones along the way that we should embrace and celebrate and use those as a source of hope that, even though it never moves as fast as we would like, we’re making very real, tangible progress”


Dr. Pacifici described the 19th conference as “terrific,” noting that more than 450 people – a record – 50 companies, and 70 academic institutions took part. He recalled how no biopharma firms attended the first few conferences. Now such companies “come to a conference because they think an area is ripe for discovery,” he observed.


“Everybody commented on how quickly the conference went this year,” Dr. Pacifici said. “There was just so much information and so much happening and actually people were sad when it was over.”


I found this, my twelfth CHDI conference, particularly exhilarating because of the amount of new data and the high quality of the presentations.


A virtual nonprofit biotech, CHDI is the largest private funder of HD research. As in our interviews at past therapeutics conferences, Dr. Pacifici summarized the key findings of the scientists’ presentations. Watch our 39-minute interview in the video below.



Key developments


Dr. Pacifici explained several key developments.


The session on new data and insights into the basic biology of HD included presentations that help “to understand exactly how we can custom craft the profile of candidate drugs to make sure that they hit the right things and are as safe as possible,” Dr. Pacifici said. Such crafting would mean that drugs could effectively address the numerous specific problems in HD, he added.


Another session “shined a bright light” on DNA repair, modifier genes, and somatic instability, the tendency of the deleterious expansion of the DNA to worsen with age and therefore trigger disease onset, Dr. Pacifici said. The new findings can contribute to the ongoing effort to “manipulate” these processes to slow or stop instability and therefore prevent the disease, he explained.


Including talks detailing HD at the cellular and molecular level, the session titled “It’s a Brain Disease” was “unbelievably informative” about specifying how HD harms the brain, Dr. Pacifici said.


Clinical trial news and the importance of participation in research


The final session featured clinical trial updates from uniQure, PTC Therapeutics, and Roche. None of these has yet reached Phase 3, the definitive test of a drug.


Referring to the 2021 results of Roche’s first attempt at a Phase 3 trial, Dr. Pacifici noted that the firm’s scientists “have really gone to town and reanalyzed the samples, reanalyzed the data in a way that is hopefully going to teach us not only why that particular trial didn’t meet its endpoints” but also “what we can do differently.” Roche’s reassessment of its drug, tominersen, in a Phase 2 trial, GENERATION HD2, is in progress.


Ultimately, the field needs a “conveyor belt” of new drug possibilities to develop the multiple kinds of drugs necessary for treating different aspects of HD, Dr. Pacifici concluded. Not all those new drugs will be successful, he said, but the more produced, the greater likelihood for successful therapies.


Dr. Pacifici pointed out that many of the discoveries discussed at the meeting resulted from the human data collected from tens of thousands of research volunteers.


Future projects and breakthroughs will continue to rely on large numbers of participants, he said. Some individuals may carry unique genetic characteristics revealing new kinds of therapies.


“Hang in there,” Dr. Pacifici said in his closing comment for the HD community. “I hope that next year at the 20th [conference] we’ll have some more good news to communicate.”


Stay tuned for further news from the conference!

Tuesday, February 27, 2024

At CHDI conference, advocates inspire acceleration of quest for Huntington’s disease therapies


With a record 420-plus participants, the 19th Annual Huntington’s Disease Therapeutics Conference got under way on February 26 with the aim of speeding the quest for therapies to slow, halt, or reverse the symptoms of this incurable disorder.


Sponsored by CHDI Foundation, Inc., the largest private funder of HD research, the event runs through February 29 at the Parker hotel in Palm Springs, CA, and will feature three days of scientific and clinical presentations.


“In recent years the quest for HD therapeutics that will make a real difference to affected families has accelerated and deepened,” CHDI Chief Scientific Officer Robert Pacifici, Ph.D., wrote in a welcome letter to the participants. “Accelerated in the sense that every week seems to bring new scientific insight, whether from publications or reports on new and ongoing clinical initiatives. Deepened in the sense of the sophistication of our understanding of the underlying HD biology that informs our drug development work.”


HD research has also “broadened,” Dr. Pacifici added, noting that participants are displaying a record 140-plus posters. Representatives from 55 pharmaceutical and biotech companies and 69 academic institutions will take part.


In his letter and opening remarks to the conference, Dr. Pacifici outlined how CHDI has reorganized its scientific-thematic approach to “better align” its activities “with this burgeoning body of knowledge.”


The conference, following such themes, will focus on new research into the roles of mutant huntingtin DNA, RNA, and protein in HD. Conference-goers also will focus on the hot topic of somatic instability, the tendency of the deleterious expansion of the DNA to worsen with age and therefore trigger disease onset.


A caregiver’s moving keynote and a vital TED Talk


Following Dr. Pacifici’s overview, the audience watched a deeply moving 80-minute keynote speech, not to be shared publicly, by Cheryl Sullivan Stavely, RN. Stavely recounted her 30-plus years as an advocate and caregiver to her late husband John and daughter Meghan, who both succumbed to HD.


Stavely thanked the scientists for their dedication and said she hoped that 30 years from now HD conferences will become unnecessary with the development of treatments.


Choking up at Stavely’s recollections of Meghan, I found the keynote highly effective in summing up the many health and social challenges faced by HD-affected people and their families such as the affected person losing the ability to work and making insurance and end-of-life arrangements.


Scroll to the end of this article for photos of Stavely’s presentation and others.


Earlier, I interviewed leading HD global advocate, Emmy Award winning television journalist, and fellow HD gene expansion carrier Charles Sabine about his compelling TED Talk “The Unlimited Capability of Every Human.” Launched on February 1, the talk already has had 4,500 views.


Sabine stressed the importance of making the presentation “gather viral momentum” and transform the way HD is viewed by the general public everywhere. I will explore the implications of Sabine’s vital talk in a future article.


Stay tuned for further coverage of the therapeutics conference. 


Displaying a slide of daughter Meghan, Cheryl Sullivan Stavely delivers the keynote address at the 19th HD Therapeutics Conference, February 26, 2024 (this and the photos below by Gene Veritas, aka Kenneth P. Serbin).

The audience watching Stavely's presentation

Cheryl Sullivan Stavely and husband Kevin Stavely


Leslie Thompson, Ph.D., of the University of California, Irvine, greeting Kevin and Cheryl Stavely


Stavely with Karen Anderson, M.D., of Georgetown University


Stavely (left) with Haiying Tang, Ph.D., of CHDI and Wenzhen Duan, M.D., Ph.D., of Johns Hopkins University

Monday, February 12, 2024

Scientists interacting with Huntington’s disease patients in the quest for therapies


In the quest for Huntington’s disease therapies, scientists have found key intellectual fuel for understanding the genetics of this fatal neurodegenerative disorder and developing therapies.


A brainstorming strategy became the trademark of the HD-focused Hereditary Disease Foundation (HDF), founded in 1974 by leading Los Angeles psychoanalyst and HD activist Milton Wexler as an offshoot of the Huntington’s Disease Society of America (HDSA).


Wexler organized multidisciplinary small workshops of scientists aimed at spontaneous discussion – as opposed to dry scientific presentations with slides – to search for the HD gene and develop treatments (click here to read more).


Allan Tobin, Ph.D., the former director of the Brain Research Institute at the University of California, Los Angeles (UCLA), ran hundreds of workshops for the HDF and later for CHDI Foundation, Inc. (CHDI), today the main private funder of HD therapeutic research.


Involving the affected


Many scientists have had little or no contact with HD families, so the HDF has included individuals from those families in its workshops. I was exposed to this approach in 2012, when Dr. Tobin transformed my desire to simply blog about a CHDI workshop into an event that included a 90-minute discussion of HD’s health and social ramifications based on my family’s story.


On the morning of January 30, I once again interacted with HD scientists, answering an invitation from HDF CEO Meghan Donaldson to offer my “perspective as both a family member and someone who is gene-positive,” aiming to help connect researchers “to the patients and the disease and to strengthen their resolve for finding a treatment.”


I not only spoke about my HD journey but also exchanged ideas with the scientists about their mission of developing therapies and also the many challenges faced by the HD community.


For me, exploring science with researchers serves as both mental enrichment and coping mechanism as I strive to forestall what research predicts will be my inevitable HD onset. Of course, I hoped to contribute to the scientific mission.


At the workshop: seated, from left to right, Mahmoud Pouladi, M.Sc., Ph.D., Osama Al Dalahmah, M.D., Ph.D., Ashley Robbins, Gene Veritas (aka Kenneth P. Serbin), Sarah Hernandez, Ph.D., William Yang, M.D., Ph.D. Standing, from left to right, Xinhong Chen, Andrew Yoo, Ph.D., Anton Reiner, Ph.D., Baljit Khakh, Ph.D., Nicole Calakos, M.D., Ph.D., Ed Lein, Ph.D., Beverly Davidson, Ph.D., Nathaniel Heintz, Ph.D., Harry Orr, Ph.D., Leslie Thompson, Ph.D., Myriam Heiman, Ph.D., Shawn Davidson, Ph.D., Steven Finkbeiner, M.D., Ph.D., Roy Maimon, Ph.D. (photo by Julie Porter, HDF) (Click on the image to enlarge it.)


Pondering modifier genes and a proactive approach


My 80-minute encounter with 20 scientists kicked off the two-day HDF Milton Wexler Interdisciplinary Workshop, held at the Huntley Hotel in Santa Monica, CA.


To provide background, before the meeting HDF Director of Research Programs Sarah Hernandez, Ph.D., sent the participants a copy of my article “Striving for a Realistic and Unapologetic View of Huntington’s Disease” from the Journal of Huntington’s Disease.


With the HDF’s permission, I recorded my remarks and Q & A with the scientists. As is customary, the confidential, scientific portion of the workshop was not recorded, to encourage uninhibited brainstorming.


After Dr. Sarah Hernandez introduced me, I gave an overview of my family’s fight against HD, including my mother’s diagnosis with the disorder in 1995, the genetic test revealing my risk in 1999, my gradual exit from the “terrible and lonely HD closet,” and strategies for delaying onset.


I discussed the possible key role of modifier genes in enabling me to reach the age of 64 still fully functioning – in contrast with my mother, whose symptoms began in her late 40s, ending with her death at the age of 68 (click here to read more).


Just before the meeting, I had discussed with two of the scientists that “maybe I should get my genome sequenced and find out if I actually have any of those modifier genes,” I told the scientists.


I noted, however, that no routine genetic tests exist for these genes and that establishing them might “open a whole new Pandora's box of bioethical considerations,” given the potential for unsettling messages. We'd have to have new protocols.”


“So, yes, I think it might be good to have those tests, but we've got to think very carefully about jumping into that,” I said. “But maybe for science, I could do my own whole genome sequence and write a blog article about it and analyze my modifier genes.”


I stressed that a “proactive approach is absolutely essential.” That option was unavailable to my mother, the first person to develop HD in an extended family with no knowledge of the disease.


Seeking to manage HD


The scientists probed various facets of my family’s HD experience and my advocacy.


I explained the importance of the HDSA-San Diego support group in providing vital information about such matters as genetic testing and obtaining long-term care insurance. I also discussed my timeline for testing and how I did so anonymously. I reflected on how my colleagues at the University of San Diego reacted positively to my exit from the closet and the full-throated advocacy that I could now pursue.


The concerns about discrimination led me to underscore the importance of the Affordable Care Act and the Genetic Information Nondiscrimination Act in eliminating discrimination against those with preexisting conditions.


Some wanted to know about the very difficult social and psychological challenges involved in genetic testing, and how to convince those worried about HD to reach out to medical professionals. 


Given how devastating the discovery of HD in a family can be, I advocated a “gentle” and gradual approach to getting people involved, recalling that research studies such as Enroll-HD allow people to participate anonymously and without knowing their genetic test results.


I pointed out that, despite the fear and devastation associated with HD, today the HD community has real hopes for clinical trials of HD-specific remedies. Such hope did not exist a quarter-century ago. As I tell younger people just starting their struggle against HD, although “there may not be the magic bullet,” HD might ultimately be “managed like other diseases are managed like heart disease, diabetes, and HIV.”


Involving presymptomatic people in trials


I was both humbled and thrilled that the scientists wanted my observations on various aspects of the search for therapies.


In my opening remarks, I had stated that, in comparison with the start of my HD journey in the late 1990s, thankfully it has been harder for me to track the progress because of so many research and clinical trial programs. In her introduction, Dr. Hernandez noted that I am at work on a biosocial history of the HD movement.


UCLA neuroscientist Baljit Khakh, Ph.D., asked whether I could identify “errors” to be avoided or “strengths” to be reproduced, as well as trends worth noting.


In response, I expressed my frustration about the lack of opportunity for presymptomatic gene carriers like me to participate in clinical trials. The now defunct Triplet Therapeutics, Inc., had planned such a trial, I observed, and that the Alzheimer’s disease field has had such a trial.


“We're a valuable resource,” I said, recognizing that such trials require approval by the U.S. Food and Drug Administration and also involve bioethical and financial considerations.


However, I also observed that “the field's done a great job of trying to diversify [drug] targets,” because of the many types of approaches under research.


Addressing the cognitive deficit


Nathaniel Heintz, Ph.D., of The Rockefeller University asked about the importance of clinical trials to test drugs to treat just symptoms, without modifying the course of the disease. Treatments developed for other diseases, like Parkinson’s, benefit millions, he noted, but does HD as a rare disease face a greater challenge to attract trial volunteers?


I observed that HD now has three treatments for chorea, the involuntary, dancelike movements experienced by many of the affected.


However, I also pointed out that HD clinical trials are very U.S.- and Europe-based, avoiding important countries such as Brazil, which was not included in Enroll-HD. I observed how HD families in Brazil and other parts of the world are “desperate to participate in clinical trials.”


Xinhong Chen, a lab researchers at the California Institute of Technology, touched on another facet of Dr. Heintz’s question: what symptoms do people most want treated to improve their quality of life?


I pointed to the importance of reducing the “cognitive deficit” that occurs with HD and prevents people from engaging in daily functions, caring for themselves, and communicating with others. I added that I had hoped to take pridopidine, a pill developed for this purpose. Sadly, the pridopidine trial failed in April 2023.


Andrew Yoo, Ph.D., of Washington University in St. Louis, wanted to know how to overcome the lack of interest in HD and related research in his native South Korea.


The leadership of the HDF, CHDI, HDSA, and the Huntington Study Group (HSG) should push for greater “diversity” on the international level, I said, suggesting that the HSG could send a delegation to South Korea. Also, advocates and medical personnel can spur action on HD, Alzheimer’s, and other neurodegenerative diseases by alerting people to the caregiving crisis, which is global, I observed.


The scientists get down to business


I was energized by my exchange with the scientists.


After my session, the workshop participants took up the main business of the rest of that day and the next: “cell type specific biology in Huntington’s disease.”


That activity was chaired by William Yang, M.D., Ph.D., of UCLA, Myriam Heiman, Ph.D., of the Massachusetts Institute of Technology, and Steven Finkbeiner, M.D., Ph.D., of the University of California, San Francisco.


Through their brainstorming – the first session of which I observed – the participants aimed to advance ideas for HD therapies.


On January 29, I lunched with Dr. Yang, gave a slide presentation on my advocacy to his research team, and toured his lab. I also interviewed Dr. Yang on his latest research.


Stay tuned for my next article: Dr. Yang’s long interest in HD and his enthusiastic outlook for potential therapies.


Disclosure: the Hereditary Disease Foundation covered my workshop travel expenses.


Gene Veritas (left) with Dr. William Yang in his UCLA office. In the background: a medium spiny neuron, one of the brain cells most affected by Huntington’s disease (photo Nan Wang, Ph.D., of the Yang Research Group).

Wednesday, November 08, 2023

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)

Tuesday, August 29, 2023

Adding to arsenal of movement disorder drugs approved by FDA, Neurocrine pledges to seek anxiously awaited therapies to slow progression of Huntington’s disease


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:


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.