Saturday, May 21, 2022

Surfing through life with the spirit of aloha

To persevere against neurological diseases such as Huntington’s and the aging we all face, I have learned that it is essential to develop meaning and purpose and perform mental exercise.

 

In May 1997, just seventeen months after learning that my mother had the devastating symptoms of Huntington’s, I confided for the first time in a medical professional who was outside my local support group. Explaining my family’s predicament, I revealed to a physician in Brazil, my second home, that I had a 50-50 chance of having inherited the HD mutation.

 

Thomaz Gollop, M.D., an OB-GYN, knew about the harm caused by genetic disorders such as HD and the enormous potential for psychological trauma involved when a family learned it was at risk: in Brazil he helped pioneer genetic counseling and testing, particularly for families who wanted to conceive.

 

I had gone to interview Dr. Gollop at his São Paulo clinic about abortion, a topic I was researching. Though Brazil, a fervently Catholic country, had outlawed abortion, millions of women found ways to terminate their pregnancies, often in precarious circumstances.

 

The disturbing history of this underground practice provides a cautionary tale for the U.S. as our Supreme Court prepares in June to apparently renounce five decades of protecting legal abortion. An affiliate of the American Society of Human Genetics and member of the American Association for the Advancement of Science, Dr. Gollop has been a leading advocate in Brazil for women’s health and legalization of abortion, emphasizing the medical – as opposed to religious ­– nature of the procedure.

 

I had not yet tested for HD. Because of my risk, my Brazilian wife Regina and I had postponed having children. I saw Dr. Gollop as a shoulder to lean on. I poured out my heart about my mother’s struggles and my fear of becoming like her.

 

Dr. Gollop told me: just keep doing what you like to do until the disease hits.

 

In my journey of risk – I tested positive for the mutation in 1999, followed by our daughter Bianca’s negative test in 2000 – I have frequently reflected on Dr. Gollop’s advice by imagining the simultaneous challenge and beauty encountered by a surfer riding a wave.

 

“Just keep surfing through life!” I tell myself.

 

Celebrating our 30th anniversary in Hawaii

 

During this, Huntington’s Disease Awareness Month, we must recognize the enormous caregiving and financial burdens imposed by HD. As a result, affected families must often relinquish their dreams. Regina and I did not have more children. We gave up buying a vacation condo in Brazil. I turned down an offer of a better job at a research university in another state so that, if I were unable to work, we could rely on Regina’s secure salary and pension from her job as a public school teacher.

 

My risk of becoming disabled means we have focused on saving, to bolster my long-term care insurance policy. So we usually take modest vacations.

 

This year, though, we splurged a bit. To celebrate our 30th wedding anniversary – which I had never expected to reach with the HD-free health I have enjoyed – we traveled to Hawaii for the first time. In late March we visited the islands of Kona (the Big Island) and Oahu.

 

We found Hawaii wondrous with its primordial, balmy setting: we saw molten lava flow in the crater of a volcano and heard a resounding chorus of birds sing at sunset. Along with newlyweds and other couples marking anniversaries, we were called to the stage at a luau to slow dance to a Hawaiian love song in celebration of “ohana,” the Hawaiian word for family.

 

Keeping alive the joy

 

I was introduced to the story of the father of modern surfing, Duke Kahanamoku (1890-1968), a native of the Waikiki neighborhood of Honolulu. A dark-skinned man competing in a world dominated by white athletes and sports officials, Kahanamoku impressed the world by winning gold and silver medals in swimming at the 1912, 1920, and 1924 Olympics.

 

Also active in rowing and water polo, Kahanamoku was one of the greatest athletes of his era. Always around beaches and pools, throughout his life he also saved many people from drowning.

 

I first read about Kahanamoku in a guidebook praising the popular Honolulu restaurant that he owned, Duke’s Waikiki. Powerful local interests had always capitalized on Kahanamoku’s fame to promote Hawaii as a tourist mecca but frequently abandoned him to struggle for economic stability on his own. He opened Duke’s late in life as a way to supplement his income

 

Regina and I visited Duke’s. It has Kahanamoku memorabilia, including one of his large wooden surfboards. Outside the restaurant Regina took a picture of me in front of a giant wall photo of Kahanamoku poised to take a dive.

 

 

Gene Veritas, aka Kenneth P. Serbin, standing in front of photo of Duke Kahanamoku in Honolulu (photo by Regina Serbin)

 

I was intrigued by Kahanamoku. Returning home to San Diego, I wanted to keep alive the joy I had felt in Hawaii. Exploring Hawaiian culture and history, I thought, might build for me new dimensions of meaning and purpose.

 

Surfing king Duke Kahanamoku and aloha

 

I delved into journalist David Davis’ Waterman: The Life and Times of Duke Kahanamoku, the first comprehensive biography of Kahanamoku (and the source of my observations here). By coincidence, the moving documentary Waterman, based on Davis’ book, premiered in theaters in April. I saw it on opening day.

 

In Hawaii Regina and I were frequently greeted with “aloha,” and people used “mahalo” to say “thank you.”

 

As an official greeter of visiting dignitaries (including President John F. Kennedy) and global ambassador for Hawaiian culture, Kahanamoku spent his life spreading the spirit of aloha.

 

Davis writes that Kahanamoku “suffused” visitors “with aloha because he believed that promoting Hawaii was beneficial for fellow Hawaiians.”

 

 

Regina Serbin at Chief's Luau with flowers presented in celebration of our 30th wedding anniversary (photo by Gene Veritas)

 

Kahanamoku printed his personal philosophy on his business card:

 

In Hawaii we greet friends, loved ones or strangers with ALOHA, which means with love. ALOHA is the key word to the universal spirit of real hospitality, which made Hawaii renowned as the world’s center of understanding and fellowship. Try meeting or leaving people with aloha. You’ll be surprised by their reaction. I believe it, and it is my creed.

 

(I have also frequently encountered sincere hospitality in my years of traveling and residing in Brazil and other Latin American countries.)

 

Although highly competitive in athletic contests, Kahanamoku’s embodiment of aloha gained him a reputation as a humble victor and cooperative teammate.

 

He refused to respond to the many racist epithets he endured. He suppressed his feelings when personally attacked or taken advantage of by others so much that he developed ulcers.

 

Nevertheless, with his athletic prowess and aloha, Kahanamoku entered areas of society normally reserved for whites.

 

As Davis observes, “Many years before nonwhite athletes like Joe Louis, Jesse Owens, and Jackie Robinson fought racism with courageous performances, Kahanamoku was a groundbreaking figure who was able to overcome – some would say transcend ­– racism.”

 

The wisdom of a waterman and his people

 

For Native Hawaiians, Kahanamoku’s plight symbolized the unwanted but steamroller-like annexation of the independent nation by the U.S. (in 1893); the adulteration of the environment by settlers from the mainland; the imposition of mainland culture and language on the locals; and, ultimately, the commercialization of society in favor of tourism, plantation agriculture, and the establishment of Hawaii as a major military installation.

 

In the words of another fine documentary, Hawaii is a “stolen paradise.”

 

Not surprisingly, Kahanamoku’s extended family retained no ownership in Duke’s Waikiki, which expanded to include restaurants on two other Hawaiian islands and also in three California coastal cities.

 

Despite this history, Hawaii fortunately has maintained much of its connection to nature and cultural traditions. With aloha and their intimate ties to the land and water, Kahanamoku and his fellow Native Hawaiians (along with natives elsewhere) offer a connection to premodern humanity and the importance of solidarity.

 

That spirit resonates with the fight for human well-being fundamental to the Huntington’s cause. As I tweeted in March, “Fortitude, collaboration of #HuntingtonsDisease movement embody opposite of aggression of war in @Ukraine: caregiving, alleviation of suffering, and harnessing of science for cures. #IStandWithUkraine.”

 

A “waterman,” Kahanamoku felt most at home in the sea, the source of life and the substance inhabiting our inner parts.

 

In a time of global warming, political strife, and warfare, the world has much to learn from the wisdom of aloha and Hawaiians’ immersion in nature.

 

 

Kenneth and Regina Serbin with Waikiki Beach and Diamond Head volcanic cone in the background (family photo)


 

Negotiating the waves of life

 

Modern surfing emerged from Hawaii. The greatest surfer of his time and global popularizer of the activity, Kahanamoku did not see it as a sport. It was about his love for, and relationship with, the sea. And about pure fun.

 

“The best surfer out there is the one having the most fun,” he said. After World War II, with the worldwide explosion in surf culture, competitions, and surfboard technologies, Kahanamoku marveled at ­– and was deeply proud of ­– how it took hold. He did want to see it included in the Olympics, which finally occurred in the 2020 games.

 

I tried surfing once in my 20s but did not pursue it. At 62 and still healthy, and with the example of Kahanamoku, I have thought of perhaps trying again, if I can find a patient instructor!

 

More importantly, Dr. Gollop’s advice rings true: to stave off Huntington’s onset, I need to keep doing what I like ­– including exploring Hawaiian culture and history.

 

The thought of Kahanamoku flawlessly negotiating the waves on his board also reminds me of the need ­– with aloha ­– to find in life “the right balance between striving and chilling.”

 

This week I am balancing my disappointment over a professional roadblock with the joyous celebration of Bianca’s graduation from the University of Pennsylvania.

 

I hope that those of us in the Huntington’s community and beyond can all learn to surf through life like Duke Kahanamoku ­– and always with aloha.

 


Regina (left), Bianca, and Kenneth Serbin during graduation weekend at the University of Pennsylvania in Philadelphia (family photo)


Monday, April 11, 2022

CHDI keynoter Charlotte Raven reflects on her fight against Huntington’s disease and the dashed hopes of a clinical trial

 

Like many affected by Huntington’s disease, renowned British journalist Charlotte Raven longed for the chance to participate in a clinical trial of a potential treatment for the incurable disorder.

 

Charlotte was diagnosed with Huntington’s in 2005. She inherited the genetic mutation from her father, who, after a long battle, died from HD in 2016.

 

In 2019 Charlotte had her wish fulfilled in London. As part of its HD clinical trial program to evaluate the efficacy of tominersen – the historic first attempt to attack the disease at its genetic roots – the pharmaceutical giant Roche was recruiting volunteers for GEN-PEAK, a small, Phase 1 study run in tandem with the larger, main, Phase 3 study.

 

Charlotte became “patient 1,” the first individual in GEN-PEAK to receive tominersen. If successful, the main trial would result in all participants in the program, including GEN-PEAK volunteers, receiving the treatment.

 

In her keynote speech at the recent 17th Annual HD Therapeutics Conference, Charlotte recalled the immense hope she felt about tominersen, shared by HD families around the globe: “Ever since I’d been picked to be on the trial, I’d woken up every morning thinking about the drug. It was like being in love. It was what I needed, wanted, looked forward to.”

 

A heartrending presentation

 

Those hopes were dashed on March 22, 2021, with Roche’s announcement that it was halting dosing of tominersen because of unfavorable efficacy data.

 

“Now that pinprick of light had been blacked out,” Charlotte told the 300 researchers, biopharma executives, and advocates gathered at the conference, held in Palm Springs, CA, and sponsored by CHDI Foundation, the nonprofit virtual biotech firm dedicated to developing HD therapies. “The world ended again; it felt exactly the same as the moment of my original diagnosis.”

 

Struggling with HD symptoms and assisted by her twelve-year-old son John, Charlotte bravely delivered a heartrending presentation, reading from a computer screen. Because Charlotte’s speech is slurred, the audience was provided access to an online script. She received a standing ovation.

 

Despite the bad news of 2021, drug hunters expressed renewed optimism about potential therapies. As reported in my previous article, the ensuing three days of scientific talks focused on multiple approaches. Indeed, Roche said it would test tominersen again in an improved clinical trial.


 

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

 

‘Feeling your personality crumble’

 

Charlotte’s keynote traced her career as an ambitious and controversial journalist and social commentator, her family’s fight against HD, and her efforts to cope with the symptoms and resulting limitations on her work and life.

 

The speech echoed Charlotte’s book Patient 1: Forgetting and Finding Myself, published last November. CHDI gave each conference attendee a copy.

 

In Patient 1, Charlotte provides a detailed, hauntingly beautiful portrait of the challenges posed by HD to both her and her extended family. Writing with help from her brother Daniel, as yet untested for the mutation, Charlotte intimately describes the toll HD has taken on her, robbing her of her memories and producing crippling anxiety.

 

“I wanted this book to be an accurate record of what it is like to exist with HD and to feel your brain and personality crumble,” Charlotte writes.

 

It also includes the first published account of the Roche program from a patient perspective.

 

‘A new leaf of hope’

 

During her CHDI keynote, to rest, Charlotte took two short breaks.

 

In the first interlude, with Charlotte looking on, her daughter Anna, 17, took the stage to speak of the special bond she has developed with her mother because of HD.

 

“Growing up under the shadow of Huntington’s has meant I’m often not the only priority, and sacrifices need to be made to make sure that my mom is properly looked after,” said Anna, who helps care for her mother.

 

Untested, both Anna and John have a 50-50 chance of inheriting the HD mutation. HD genetic testing protocols recommend against testing before age 18.

 

“Seeing and hearing about all these people working and researching to find treatments amazes me every day and makes everything seem a little less bleak,” Anna said. “The future for me, my brother, and my mom is unknown, but we have a new leaf of hope, and for that I would like to say thank you from the bottom of my heart.”

 

In the second interlude, Charlotte’s neurologist and clinical trial physician, Ed Wild, M.D., Ph.D., described her intellectual mettle. Dr. Wild wrote the Afterword to Patient 1. At the conference, he also recalled how “injecting 120 milligrams of tominersen into Charlotte’s spine in 2019” was one of his “proudest moments” in his career of helping HD patients.

 

Watch the entire keynote presentation in the video below, which includes the option of closed captioning.

 


 

The best team for defeating HD

 

Charlotte finished the speech with a tribute to researchers and a reflection on how confronting HD has “humbled me, and helped me connect more with the people around me, which is a new skill that I’ve been working on with commitment and persistence.”

 

“GEN-PEAK may have turned out to be a blind alley, but it was still a step on the journey towards a cure, and I still feel proud to have been part of it,” she said. “I’ve lived a fairly selfish life in lots of ways, so it seems oddly fitting that this last thing I did to save myself, might end up saving others instead.”

 

Charlotte noted an irony: she could write Patient 1, with its portrayal of HD's impact, only because the disease had mentally “compromised” her.

 

“I feel like I’ve finally been able to portray my family and friends as they really are instead of as I’d like them to be,” she added. “They are coming to life.”

 

She concluded: “Anna and I cannot get over how HD is such a rare disease, yet somehow attracts so many of the world’s brightest and best scientists. In my complicated journey with empathy, this is the most striking gift I can imagine.”

Wednesday, March 09, 2022

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.

Monday, February 28, 2022

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).

Tuesday, January 18, 2022

After setback, Roche to run new clinical trial with Huntington’s disease gene silencing drug

 

After halting dosing in the historic Phase 3 clinical trial for its Huntington’s disease gene silencing drug tominersen last March, pharmaceutical giant Roche announced today that it will start a new, less ambitious Phase 2 trial, limited to younger adult patients with “less disease burden.” The goal is to measure tominersen’s efficacy against the progression of HD.

 

Disease burden is calculated using a person’s age and degree of genetic mutation: the higher the sum of those two factors, the higher the burden. Roche, after initial testing of the drug, skipped Phase 2, which typically tests safety and efficacy of different doses, to pursue a Phase 3 trial, which confirms safety and efficacy in a larger population. Now it is proceeding in a more typical manner.

 

Roche informed the global HD community about the new trial in a letter released today. Roche’s partner Ionis Pharmaceuticals, Inc., the original developer of tominersen, also issued a press release.

 

“New exploratory post hoc analyses of GENERATION HD1 suggest that low exposure (less frequent dosing) tominersen may benefit younger adult patients with lower disease burden,” the Roche letter stated.

 

 

Low dosing meant volunteers received the drug every 16 weeks, while high dosing was every eight weeks.

 

“These findings, together with safety data of low exposure tominersen, support the continuation of the development program with a new Phase II clinical trial in younger adult patients with lower disease burden,” the letter continued. “While the findings are encouraging, confirmation in a randomised, placebo-controlled study is important.”

 

Post hoc analyses involve criteria set after data is seen, and “therefore they are not definitive,” the letter said. Because the trial was not specifically designed to run these analyses, the number of patients in the subgroups are small and the differences to placebo are not "statistically significant" and "could represent a chance result."

 

Even so, “these findings are promising and warrant a new study designed to test tominersen in this specific patient group,” stated Frank Bennett, Ph.D., Ionis' executive vice president, chief

scientific officer and franchise leader for neurological programs, in the press release. “This is an encouraging development for the HD community. We and Roche are grateful to the HD community's continued partnership, which has led to these important insights and a new scientific hypothesis [about tominersen].”

 

Maximizing benefits for HD patients

 

“It’s very exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at the University of California San Diego.

 

One of the GENERATION HD1 trial investigators, Dr. Corey-Bloom participated in a Roche-sponsored videoconference about the GENERATION HD1 findings that are serving as the basis for plans for a Phase 2 trial.

 

“They’ve analyzed the data in a very thoughtful manner,” Dr. Corey-Bloom said. “They’re hoping to really maximize benefits for at least a specific group of patients with HD, based on the results of their post hoc analysis.”

 

Roche is still planning the new trial. Therefore, it has not yet announced a timeline, sites, eligibility criteria, or information about dosing.

 

“This is just the news that should instill hope – a clear demonstration of the researchers’ commitment to regroup, redirect, and bravely move forward with its work on tominersen even after the challenges of 2021,” Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN, commented by e-mail. “HD families, research scientists, and clinicians will need to work together in the coming years to determine when, whether, and how this drug can be delivered safely, effectively, and ethically to people in the earliest stages of HD.”

 

Representatives of Roche will present public updates on tominersen in previously scheduled webinars on January 20 for the European Huntington’s Disease Network (click here to register) and HDSA (click here to register). Another webinar, hosted by the European Huntington Association, will take place on January 24 (click here to register).

 

Roche is “resurrecting” tominersen in the “right way,” wrote Evaluate Vantage biopharma analyst Madeleine Armstrong. “Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant.”

 

With “no approved therapies for Huntington’s,” Roche “looks justified in trying again,” she added.

 

More results at upcoming conference

 

In an initial trial completed in 2017, Ionis had demonstrated that tominersen had successfully lowered the amount of the mutant, purportedly toxic huntingtin protein in the cerebral spinal fluid of a small group of volunteers.

 

Those impressive results led Roche to skip the standard Phase 2 trial and enter directly into Phase 3 (click here to read more). The GENERATION HD1 trial started in early 2019, enrolled a total of around 800 participants globally, and was to end in 2022.

 

However, in March 2021 a monitoring board conducting a standard review of trial data recommended that all dosing of tominersen in GENERATION HD1 be stopped. Roche decided to also stop dosing in a supporting trial. The following month Roche confirmed that trial data indicated that tominersen was ineffective and, in some cases, actually caused volunteers to worsen.

 

Roche is expected to present a detailed scientific update on tominersen at the 17th Annual HD Therapeutics Conference February 28-March 3 in Palm Springs, CA.

 

(Disclosure: I hold a symbolic amount of Ionis shares.)