Tough news for Huntington’s, other neurological disease patients: Roche halts dosing in historic clinical trial on signs of inefficacy

 

Calling it “tough news to share” and “even more difficult to receive,” pharmaceutical giant Roche announced on March 22 that it has halted dosing in the firm’s historic Phase 3 Huntington's disease clinical trial of its gene silencing drug tominersen, GENERATION HD1, because of unfavorable efficacy data, as seen by an independent review committee.

 

“The committee recently met for a pre-planned review of the latest safety and efficacy data from GENERATION HD1 and made a recommendation about the investigational therapy’s potential benefit/risk profile,” wrote David West, Roche’s senior director, for Global Patient Partnership, in a letter addressed to the international HD community. “Based on the committee’s recommendation, we will permanently stop dosing with tominersen and placebo in the GENERATION HD1 study.”

 

GENERATION HD1 began in early 2019, paused for several months to recalibrate dosing, and became fully enrolled in April 2020. Volunteers were to receive the drug over 25 months, and Roche had expected to finish the trial and report results in 2022. Tominersen developer Ionis Pharmaceuticals, Inc., Roche’s partner, had completed a Phase 1/2a trial of the drug (testing for mainly safety and tolerability) in 2017. That trial was so successful that Roche skipped a full-blown Phase 2 and went directly to Phase 3, GENERATION HD1.

 

West noted that the review committee’s recommendations resulted not from “any new emergent safety concern, but on a broad assessment of the benefit/risk” for those receiving the drug as compared to those getting the placebo.

 

This means that the drug demonstrated an “unfavorable efficacy trend,” an official of U.S. Roche’s subsidiary Genentech wrote me in an e-mail. If successful, the trial would have demonstrated that tominersen could slow, halt, or even reverse HD symptoms.

 

“This is brutal and I am absolutely devastated for our patients and families,” 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, wrote me.

 

Trial participants in Dr. Corey-Bloom’s clinic were among those taking part in GENERATION HD1. “I am glad that Roche will continue following patients for safety and clinical outcomes,” she added.

 

Veteran HD physician LaVonne Goodman expressed a similar sentiment. “Hope has been so very high for this drug; our community will feel not just disappointment, but real grief,” Dr. Goodman wrote me. “However, we’re accustomed to grief, and are resilient.  I think part of the community message should be that supporting each other is vitally important now.”

 

HDSA Chief Scientific Officer George Yohrling, Ph.D., called the news “devastating.” “HD families around the world had their hopes held high that this experimental drug could one day soon become an effective therapy for HD,” Dr. Yohrling stated. “While this is clearly not the news we wanted to hear, I am confident that in the coming weeks the Generation HD1 data will help the scientific community understand why tominersen did not meet its desired outcome.”

 

Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the nonprofit virtual biotech dedicated to discovering HD therapies and a collaborator of Roche and Ionis, also commented on the development.

 

“Roche’s decision to discontinue dosing in most of its Huntington’s disease studies based on a recommendation from the unblinded [with access to data] Independent Data Monitoring Committee that periodically reviews study data is a very disappointing outcome,” Dr. Pacifici wrote. “However, knowing our colleagues at Roche we are confident that this decision has been made in good faith with the best interests of study participants uppermost in mind.”

 

 

No new safety concern caused the halt

 

The stop to the Roche trial underscores the fact that an effective treatment still eludes not only HD scientists, but also researchers of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and other neurological conditions.

 

The reviewers who recommended the halt to GENERATION HD1 work separately from Roche. The committee has not yet shared its specific reasoning or data with Roche.

 

“It is important to note that the recommendation is not based on any new emergent safety concern,” West’s letter stated.

 

Roche has notified the clinical trial sites in the 18 participating countries of the halt. The sites are contacting the 791 symptomatic volunteers who had enrolled in the program.

 

The participants were receiving intrathecal (spinal) injections of tominersen or a placebo. Participants in GEN-EXTEND (an extension study for participants coming from any Roche HD study) will also no longer receive doses.

 

“It is our intention to provide as much information as we can to the community, which at this time is limited until we have accessed and analyzed full data,” West’s letter explained.

 

West acknowledged “the tremendous contribution of the families who are participating in these studies, as well as the broader Huntington’s community for their collaboration.”

 

Next steps depend on the data

 

Although Roche has stopped giving tominersen to the volunteers, the trial has not yet ended.

 

“The studies will remain ongoing (without further dosing in GENERATION HD1 and GEN-EXTEND) and it is intended that study participants will be followed by their physicians for safety and clinical outcomes,” West stated. Roche has not provided a timeline for the remainder of the work to be completed.

 

A Q&A appended to West’s letter states that “Roche remains committed to the HD space and our studies are continuing,” and data from GENERATION HD1 “will advance our understanding of tominersen and inform research for other disease modifying treatments.” It adds: “In addition to tominersen, the Roche family of companies is investigating gene therapy approaches to treating Huntington’s disease.”

 

The conclusions about GENERATION HD1 – and possible next steps by Roche and Ionis­­ – will depend on the analysis of the independent reviewers’ explanations and all of the massive data from the Phase 3 trial.

 

As Dr. Pacifici noted, only when data from the independent review committee has been “shared with the wider HD community” will it become possible to “form a scientific opinion” about the halting of the trial.

 

A perplexing result

 

Ionis held a public conference call on March 22 to answer questions about the Roche announcement.

 

“This is the largest Huntington’s trial ever conducted,” stated Ionis CEO Brett Monia, Ph.D. “It was conducted on a wealth of information.”

 

Monia stated that, “while we are saddened by today’s outcome, we are committed to the HD community and focused on delivering treatments for this and other devastating neurological diseases.”

 

Monia added, “Although this is a disappointing setback for Ionis and the HD community, we are confident in the potential of our technology platform to address many neurological diseases.”

 

Various questioners on the call asked Dr. Monia and Ionis scientists to speculate about the reasons for the halt and future potential approaches using the company’s technology (antisense oligonucleotides, or ASOs), but the Ionis officials emphasized that answers are premature without access to the data.

 

“We are still strong believers in the ASO approach,” Dr. Monia asserted.

 

However, Ionis Chief Scientific Officer Frank Bennett, Ph.D., the long-time coordinator of the firm’s HD program, added that the news of the potential ineffectiveness of using an ASO to reduce the amount of huntingtin protein in patients was “perplexing and disappointing to us,” leaving many unanswered questions.

 

Eric Swayze, Ph.D., Ionis’s executive vice president for research and one of the developers of the ASO, reminded the participants on the call of a fundamental reality of HD: “It’s a complex disease.”

 

Dr. Monia added that “one silver lining” in the halt to GENERATION HD1 was that it did not, as noted above, result from a concern about safety.

 

Diversification necessary

 

Although the pioneering Roche-Ionis program had electrified the HD world with the hope of the first effective treatment, the HD research community has also deliberately diversified the approaches to treating HD.

 

Thus, companies like Triplet Therapeutics, Inc. have leveraged publicly available knowledge gained from the Roche/Ionis program and others to plan their own, unique drug development strategies.

 

Triplet aims to start a clinical trial in the second half of this year for a potential drug targeted at stopping the mutant huntingtin gene’s tendency for continued expansion with age. That expansion compromises brain cells and triggers disease. In this respect, HD is known as a repeat expansion disorder (RED), with the triplets of the genetic code CAG recurring too many times and thus causing disease.

 

As a Triplet scientist explained last year, the Roche/Ionis approach is like “putting a brake” on the disease, whereas Triplet’s ASO will target the expansion of the gene and therefore seek to “remove the foot on the gas.” (Click here to read more).

 

Using the same mechanism, in addition to HD, Triplet hopes to develop transformative treatments for many of the more than 50 other REDs. For REDs of the central nervous system, it would use the same drug as for Huntington’s.

 

Although unavailable for comment on the Roche announcement, Triplet executives offered encouragement in an e-mail to me: “Triplet’s thoughts are with the HD community, and our clinical development plans in HD and other repeat expansion disorders remain on track and unchanged.”

 

As one scientist wrote me (and as I also felt), the Roche announcement was like a punch to the gut. However, I am also heartened by the potential of other clinical trials like Triplet’s. (I will further explore the implications of the Roche trial halt in upcoming articles.)

 

To echo Dr. Goodman’s words, our community and its scientists are indeed resilient.

 

(For more on the Roche announcement, see the article in HDBuzz).

 

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

Blog article No. 300: who exactly is Gene Veritas?

 

On January 10, 2005, I began the first post in this blog with a simple but consequential sentence: “My name is Gene Veritas and I am at risk for Huntington’s disease.”

 

Today, 16 years and two months later, after my mother’s death from Huntington’s at age 68 in 2006 and my own long struggle to avoid disease onset, I am writing my 300th post.

 

Now 61, I never expected to get this far. Starting in her late 40s, my mother’s symptoms left her progressively unable to care for herself and ultimately bedridden. And I inherited from her the same degree of mutation in the huntingtin gene – which I long thought portended the same fate.

 

As I have noted often in recent years, I feel extremely lucky to remain asymptomatic. Although there is (as yet) no genetic test available to individuals to pinpoint the reason, researchers have discovered key modifier genes that slow or hasten onset among people with identical mutations (click here to read more). Also, as doctors and researchers have observed, my efforts to lead a healthy lifestyle likely have also helped.

 

In the early years of the blog, writing under the protection of my Gene Veritas pseudonym, I focused mainly on my family’s struggles with the many medical and psychosocial ramifications of HD. More recently, with the tremendous advances in HD research of the past decade, I have emphasized the science and the advent of crucial clinical trials. Those trials have brought unprecedented hope for the HD community.

 

However, in the whirlwind of HD advocacy and writing, I have not paused to reflect on the deeper meaning of my alias. Even after I went fully public as Kenneth P. Serbin nine years ago in an article in The Chronicle of Higher Education, I am still widely known in the HD community as Gene Veritas.

 

I have relished explaining a pen name that has become my trademark. In my HD work, I actually prefer the pseudonym, which not only intrigues people but also instantly focuses our interaction on the profound implications of Huntington’s.

 

To mark my blogging milestone, I thus want to clarify two things: who exactly is Gene Veritas? And what does that name mean?

 

A college professor and family man

 

Huntington’s, as a 100-percent genetic disorder, always involves stories about families.

 

After the news of my mother’s diagnosis blindsided my wife Regina and me in late 1995, our life plans changed dramatically. A future as my potential caregiver has loomed over Regina ever since. She is ever thankful about my delayed onset.

 

We forged ahead as best we could. Over the past two decades, we have brought our HD-free daughter Bianca to the threshold of adulthood. Bianca expects to graduate from college in 2022.

 

I am in my 28th year as a history professor at the University of San Diego, and Regina works as an instructional coordinator for the San Diego Unified School District.

 

As a family, we have been active in the local chapter of the Huntington’s Disease Society of America. In 2017, we traveled to Rome for one of the most extraordinary moments in our journey with HD, “HDdennomore: Pope Francis’ Special Audience with the Huntington’s Disease Community in Solidarity with South America.”

 

In the doctor-recommended enrichment and exercise that I practice, I have included the canine member of our family, our cockapoo Lenny, with long walks on diverse routes through our neighborhood.

 

Gene Veritas (aka Kenneth P. Serbin) with wife Regina, daughter Bianca, and dog Lenny (family photo)

 

Representing our common struggles

 

I began this blog under “Gene Veritas” because I lived in the “terrible and lonely HD closet,” fearing discrimination on the job and in healthcare and insurance matters. I built what I have described as an “absolute firewall” between my HD reality and the rest of my life.

 

In February 2011, I took a major step out of that closet by delivering the keynote speech at the “Super Bowl” of HD research, the Sixth Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech solely dedicated to finding HD treatments. It was held in Palm Springs, CA.

 

About 250 prominent scientists, physicians, drug company representatives, and others listened to my speech, which was titled “Blog Entry 85 … Unmasking the World of Gene Veritas: An Activist Copes with the Threat of Huntington’s Disease.” (I referred to an “entry” instead of “post,” because of the diary-like nature of the blog in the early, anonymous years. Now I use the term “article,” because the posts have become more in-depth and sometimes run several thousand words or more.)

 

As I wrote in an article about that key moment, despite revealing my real name to the audience, my penname “‘Gene Veritas’ will still live on in cyberspace.[…] Through its anonymity and universality, it symbolizes the common struggles of families threatened by HD and numerous other neurological and genetic diseases.”

 

Indeed, in many talks since then I have introduced myself with both my real name and pseudonym.

 

‘The truth in my genes’

 

I explain to people that “Gene Veritas” means “the truth in my genes.”

 

A “gene” is a sequence of DNA, the code that programs our development as humans and gives us particular characteristics. “Veritas” is Latin for “truth.”

 

The truth of my future lies in the mutant huntingtin gene that I inherited from my mother.

 

I also have a personal connection to “veritas”: it forms part of the motto “lux et veritas” (light and truth) on the seal of my alma mater, Yale University.

 

The connection to Yale bubbled up from my subconscious while I was searching for a pseudonym. Surely Yale also came to mind because of the solidarity, advice, and assistance I have received from fellow alumni (click here, here, and here to read more).

 

As one observed, because of the devastation caused by HD, the pseudonym can also represent a grim pun on the school motto.

 

We are all Gene Veritas

 

On March 8, I participated in an online interview conducted by HD global advocate Charles Sabine and Simon Noble, Ph.D., CHDI’s communications director. They wanted to learn more about the Gene Veritas facet of my life.

 

Dr. Noble asked me whether I had an alter ego and other identities, in line with the ideas of 2010 keynoter and graphic novelist Steven Seagle, who has addressed his family’s way of confronting Huntington’s by juxtaposing the reality of disabling HD with the fantasy of Superman.

 

“Gene Veritas” is my alter ego, I said.

 

So, Dr. Noble wanted to know, how did the Gene Veritas alter ego protect me? Did it allow me to do other things? Did I become a different person in some respect? Were there positives to being Gene Veritas?

 

“Absolutely,” I responded. “Being anonymous for so many years allowed me to be completely honest about Huntington’s disease. Those first years of the blog were a complete explosion of HD honesty – talking about the feelings, talking about the discrimination, talking about the anger, the hurt, the pain, worrying about my mother, seeing my mother die from the disease. Those early years were really, really hard.”

 

This blog and “Gene Veritas” have also served as coping mechanisms, I added, and they allowed me to build awareness about HD.

 

“But how to build awareness anonymously?” I continued. “It’s like a contradiction in terms. That’s why ‘Gene Veritas’ became so important, because I was somebody. I couldn’t be Ken Serbin, but I could be Gene Veritas.”

 

Pondering further the universality of my pseudonym, I observed: “It’s my story, but it’s really the story of the HD community. Anybody could be Gene Veritas in the HD community. Because I think we’ve all been at one point or another a kind of Gene Veritas, at least when we first find out about Huntington’s. It’s representative. It’s something that has a broad meaning to it.”

 

Writing the history of the HD movement

 

In this blog, my CHDI keynote, and other speeches, I have documented the new and harrowing human experience of living in the gray zone between a genetic test result and onset of a disease.

 

In my CHDI speech, I showed a slide with a simple breakdown of main blog topics to that point. Information about the disease and research was the leading topic, followed by articles on my mother, fear of onset, and coping.

 

I will do a more fine-grained content analysis of posts for an academic article on the blog as a coping mechanism, fount of information for the HD community, and source of insight into the fight against HD and the search for therapies. I will submit the article to a scientific or medical journal.

 

I am also planning a book on the history of the Huntington’s disease cause, tentatively titled “Racing Against the Genetic Clock: A History of the Huntington’s Disease Movement and the Biomedical Revolution.” The blog will serve as a considerable primary source (a document or other material produced by a participant in a historical event) for my research and/or future historians of the HD cause.

 

In academic year 2021-2022, I will dedicate an expected sabbatical (a leave from teaching and other on-campus duties) to the book project. I will consult researchers, physicians, and members of the HD community about the key themes.

 

I earnestly hope to recount in this blog and my book the achievement of effective treatments for HD.