With ‘great promise’ for treating Huntington’s disease, four drug programs press ahead (Part I)

 

At the recent 20th Huntington’s Disease Therapeutics Conference, four companies provided updates on their key clinical trial programs, demonstrating that they had overcome basic safety hurdles and revealing plans to have their drugs potentially approved as therapies (treatments) for delaying the progression of HD symptoms.

 

PTC Therapeutics, Roche, Wave Life Sciences, and uniQure made 15-minute presentations. This clinical trials update took place during the first session on February 25, the first day of the three-day event.

 

Sponsored by the nonprofit CHDI Foundation, Inc., the largest private funder of HD research, the conference took place in Palm Springs, CA.

 

Possible impact

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. Blocking the bad protein could help prevent the death of brain cells, a major driver of HD.

 

In a post-conference interview with me, CHDI Chief Scientific Officer Robert Pacifici, Ph.D., said that the companies’ plans to move their programs towards drug approval is “great news.”

 

“All of them expressed their commitment to moving forward with their interventions, and that’s not trivial,” Dr. Pacifici said. “That means a lot of time, a lot of money invested on their part. They wouldn’t be doing it if they didn’t think there was great promise there.”

 

Each firm has overcome the basic safety hurdles necessary for moving to a Phase 3 clinical trial, the final step before the U.S. Food and Drug Administration (FDA) approves a drug, Dr. Pacifici added.

 

This article, the first of two, focuses on trials from PTC and Wave. Part II will examine the Wave and uniQure updates.

 

Votoplam, a potential pill for HD

 

With 60 companies represented at the conference, CHDI selected those “that had something new to say” in terms of clinical development, Dr. Pacifici told the attendees.

 

Amy-Lee Bredlau, M.D., PTC’s senior medical director, began her talk on the company’s huntingtin-lowering drug by noting progress: the compound, PTC518, is now called votoplam, a nonproprietary drug name assigned by PTC’s new, larger partner on the project, the international pharmaceutical firm Novartis.

 

“I think this is a really great collaboration,” Dr. Bredlau said.

 

As Dr. Bredlau explained, votoplam is a huntingtin splicing modulator, reducing the production of both the mutant and normal huntingtin proteins.

 

In contrast with riskier delivery methods, some presented in the session, votoplam is a pill. That makes it easy for patients to take the drug.

 

CHDI and PTC started the search for a huntingtin-lowering pill with a joint project initiated in 2018.

 

A delay in HD progression

 

PTC ran a successful Phase 1 clinical trial of votoplam in 2020 and 2021, providing initial evidence of safety and the lowering of the huntingtin protein.

 

At the conference, in an interim analysis, Dr. Bredlau presented data from the first 32 of the 156 volunteers enrolled in PIVOT-HD, PTC’s one-year global Phase 2 trial, which has verified the safety and tolerability of the substance. The first group of participants in PIVOT-HD began in 2022.

 

PIVOT-HD demonstrated that, by the third month, votoplam enters trial volunteers’ brains and lowers the huntingtin protein, she said. At month 12, the lowering was sustained. The trial also showed no spikes in neurofilament light chain (Nfl), a protein whose presence indicates degeneration of brain cells in diseases like HD. Scientists hope that lowering huntingtin will limit Nfl.

 

Significantly, Dr. Bredlau observed that these volunteers had a delay in the progression of HD symptoms, as indicated by several key clinical measures.

 

She said PTC is “very excited” about those trends, which “look very promising,” adding that “we’re really hopeful that we’ll see a strengthening of the signal at the end of the 12-month study,” when results from the remaining volunteers will be studied.

 

PTC will release full results of PIVOT-HD in this (second) quarter of 2025, said Dr. Bredlau, adding that the firm hopes that the results secure permission for a Phase 3 trial, to be run by Novartis.

 

Dr. Amy-Lee Bredlau of PTC Therapeutics presents data from the PIVOT-HD clinical trial demonstrating trends of a delay in progression of Huntington's disease symptoms (photo by Gene Veritas, aka Kenneth P. Serbin).

 

GENERATION HD2 fully in progress

 

Peter McColgan, M.D, Ph.D., global development leader for Roche, updated the pharmaceutical giant’s HD program. He focused on the Phase 2 trial of the huntingtin-lowering drug tominersen.

 

Tominersen is an antisense oligonucleotide – a “laser-guided missile” against HD – originally developed by Ionis Pharmaceuticals, Inc. Like votoplam, tominersen lowers both the normal and mutant huntingtin protein.

 

After Roche’s unsuccessful trial of tominersen in 2021, the company redesigned a less ambitious and more focused trial of the drug in people less affected by the disease. Called GENERATION HD2, it started in early 2023.

 

Dr. McColgan reported that GENERATION HD2, by January, had fully recruited its target of 301 volunteers at 70 sites in 15 countries.

 

“This is a massive achievement,” he said.

 

The trial will assess tominersen’s safety, the use of biomarkers (signs of a disease and a medication’s efficacy), and the drug’s effectiveness.

 

Tominersen is not a pill. It is administered via a spinal tap.

 

Roche aims to complete the trial by the end of 2026.

 

Dr. Peter McColgan of Roche with a slide showing the global recruitment for the GENERATION HD2 clinical trial (photo by Gene Veritas)

 

Roche’s multiple approaches

 

Dr. McColgan also described how Roche has expanded its focus to include other possible HD treatments and related research.

 

“We believe the fastest way to get treatments to patients is to pursue multiple programs in parallel,” Dr. McColgan said.

 

In collaboration with its colleagues at Spark Therapeutics – acquired by Roche in 2019 – Roche scientists are exploring other potential molecules for targeting HD. Spark specializes in gene therapies.

 

HD researchers continue to weigh the approach of drugs such as votoplam and tominersen, which lower both the mutant and normal huntingtin protein, versus those that attack only the mutant. The latter types are known as allele-selective. They leave the normal protein to carry out its essential actions unhampered.

 

Dr. McColgan said that Roche and Ionis are investigating an allele-selective antisense oligonucleotide.

 

Roche is also participating in the HD Regulatory Science Consortium. Using data from the original tominersen trial and other patient data, this collaboration seeks to improve the measurement of clinical trial volunteers’ performance in clinical trials, said Dr. McColgan.

 

Roche is also collaborating with CHDI to improve the measurement of Nfl (neurofilament light chain) as a key biomarker.

 

“Nfl increases across the stages of HD,” Dr. McColgan observed.

 

The latest news on tominersen

 

All clinical trials are regularly checked by an independent data monitoring committee.

 

Volunteers in the tominersen trial not on placebo have received either 60mg or 100mg of the drug.

 

On April 17 Roche issued a letter to the HD community stating that the committee overseeing the tominersen trial has found “no concerns … regarding participant safety or signs of symptom worsening with either tominersen dose.”

 

In addition, the letter said, “the 100mg dose was found to be more likely than the 60mg dose to result in clinical benefit. Therefore for the remainder of the study only the 100mg dose will be tested against placebo, and the 60mg dose will be discontinued.” Those receiving 60mg will now get 100mg.

 

“We are incredibly grateful to the 301 participants and their companions enrolled in GENERATION HD2,” the letter stated. “Each study visit contributes to collecting data that helps the entire HD research community learn more about tominersen, Huntingtin-lowering strategies, and the further understanding of HD.”

 

In Part II of this article I will report on Wave’s and uniQure’s clinical trial updates

 

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

More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.

As a ‘biological being,’ I embrace science’s fight against disease

 

I am a biological being.

 

This phrase came to me about a decade ago, and I have been hoping to write about its meaning for a long time.

 

Now, with scientific research at key American institutions such as the National Institutes of Health and university labs under attack from the Trump administration, the phrase resonates with me stronger than ever.

 

From the time I was hospitalized in 1977 with two herniated discs after shoveling heavy snow through decades of participation in Huntington’s disease research studies, I have been acutely aware of my body as the object of biomedical observation.

 

Seeing scans of deteriorating HD brains at scientific conferences leaves me deeply worried about the shrinking of my own brain – the inevitable result of the fact that I carry the HD gene.

 

In March 2022 I observed preliminary data presented by Triplet Therapeutics from SHIELD-HD, a two-year research study of 70 presymptomatic and early-disease-stage carriers of the HD mutation. Triplet aimed to use SHIELD-HD to support plans for a groundbreaking clinical trial to attack a key driver of HD, somatic expansion, the mutant huntingtin gene’s tendency for continued expansion with age. The program was scuttled because the firm folded in October 2022 as it lacked investment funds.

 

The 2022 SHIELD-HD data showed deterioration in the brains of the gene carriers.

 

For the first time, I saw information about the impact of the HD gene on my own brain. I had volunteered for SHIELD-HD, undergoing MRI brain scans and cognitive tests and giving samples of blood and my cerebrospinal fluid (CSF) at the HD clinic at the University of California, San Diego.

 

Below are photos of me in the clinic in August 2022, just two months before the Triplet shutdown. The first shows a neurologist injecting an anesthetic to prepare for the drawing of my CSF. In the second photo the doctor draws a small amount of my CSF. It was the last of my several CSF drawings over the course of SHIELD-HD. Scientists see analysis of CSF, which bathes the brain, as a major tool in the search for therapies for HD. 

 

Having CSF drawn is a safe procedure but can be painful. Each time I drove home by myself within a couple hours of the drawing. I am very glad I did it.

 

 

 

 

Analysis of SHIELD-HD

 

With the end of Triplet, final analysis of the key SHIELD-HD data was completed by CHDI Foundation, Inc., the largest private funder of HD research. The analysis was presented at the 19th Annual HD Therapeutics Conference, sponsored by CHDI, in February 2024.

 

A future article will further explore my participation in SHIELD-HD and the importance of that program for HD research.

 

The 20th Therapeutics Conference: a sign of collaboration

 

As a biological being, I embrace science, not useless conspiracy theories. At the University of San Diego, where I teach and research, I began a new course this month called “A History of the Brain: Examining Huntington’s Disease.” One key lesson from the history of brain science: reliance on superstition was replaced with scientific observation – the key to solving neurodegenerative disorders like HD.

 

On a large scale, so has the HD community participated in and supported science – from the start of the hunt for the gene in the 1970s to programs today such as Enroll-HD. Tens of thousands of individuals from around the world have taken part, despite the fact that HD is a rare disease, with about 40,000 affected individuals in the U.S.

 

CHDI, the Huntington’s Disease Society of America, the Hereditary Disease Foundation, Help4HD International, and other HD organizations also rely on science and cooperate with scientific institutions.

 

A magnificent example of scientific collaboration will take place starting this evening in Palm Springs, CA, as the 20th HD Therapeutics Conference gets under way at the Parker hotel.

 

Stay tuned for reports about the meeting.

Savoring 20 years of my Huntington’s disease blog

 

This month I am celebrating the 20 years of this blog.

 

I began At Risk for Huntington’s Disease on January 10, 2005, wanting to “squeeze as much life into my days as possible” before experiencing the debilitating HD symptoms that led to my mother’s death a year later. Because I lived in what I called the “terrible and lonely HD closet” – fearful of genetic discrimination – I used the pseudonym “Gene Veritas,” “the truth in my genes.” That name reflected the fact that I had tested positive for the HD gene in 1999.

 

My mother died at 68, after two decades of debilitating symptoms, which was very painful to watch.

 

I turned 65 last month. By this age, I had expected to have full-blown HD, which would have left me unable to work, drive, or write.

 

But, according to my latest neurological checkup, I don’t yet have apparent HD symptoms!

 

In general, the more abnormal the gene, the earlier the age of disease onset. My mother and I have the same gene mutation, suggesting a similar disease path. However, although my mother’s symptoms started in her late 40s, one or more modifier genes, the functions of which were discovered a decade ago, have perhaps delayed my disease onset.

 

This article is number 336. Each day of good health is a blessing.

 

Gene Veritas (aka Kenneth P. Serbin) with his blog (photo by Regina Serbin)

 

The impact

 

In 2012, I exited the HD closet by publishing an essay – and using my real name, Kenneth P. Serbin – in The Chronicle of Higher Education. It was titled “Racing Against the Genetic Clock.” Going public opened new vistas of advocacy and enabled me to blog with greater transparency.

 

In December 2022. I published a detailed analysis of the blog in “Striving for a Realistic and Unapologetic View of Huntington’s Disease” in the Journal of Huntington’s Disease. It described how the blog has helped give voice to the HD community by exploring the major challenges faced by HD families, becoming a key reference for those families, and chronicling the quest to defeat the disorder.

 

As I observed, the blog has also “helped document the new and harrowing experience of living in the gray zone between a genetic test result and disease onset.”

 

At Risk for HD has addressed multiple topics including advocacy, caregiving, family trauma, coping strategies, genetic testing, discrimination, leaving the HD closet, participation in research and clinical trials, as well as religion, faith, and spirituality.

 

When my mother was diagnosed with HD in 1995 – two years after the discovery of the gene – little hope existed for treatments that could slow the progression of HD. However, in the past decade, advances in academic labs and biopharma firms have led to key clinical trials that show potential for affecting the course of HD and perhaps even a cure (click here to read more).

Telling the story of those complex developments has become a major focus of At Risk for HD. With the growing number of research projects, I have necessarily highlighted those that appear closest to producing actual drugs such as the Roche gene silencing program, which I have covered extensively.

 

In 2021, the first Roche trial showed lack of efficacy. In 2023 Roche started enrolling volunteers in a more focused trial to see if the drug might work at least in some patients. Other key trials are in progress or being planned.

 

Hoping for an HD-free world, savoring life

 

Writing the entries of At Risk for HD has given me great meaning and purpose, which researchers have identified as increasing well-being and positively impacting the course of the disease.

 

For now, I plan to continue blogging as long health permits – and until the quest for a cure is complete.

 

In February, I hope to attend the crucial 20th Annual HD Therapeutics Conference at the Parker Hotel in Palm Springs, CA. The conference is sponsored by CHDI Foundation, Inc., the largest private funder of HD research.

 

In 2011, I delivered the conference keynote speech before 250 scientists, physicians, and biopharma reps – a decisive step towards my complete exit from the closet in 2012 and chronicled in this blog.

 

I have described the conference as the “Super Bowl of HD research,” covered in many blog articles and videos of scientists (see, for example, this one).

 

With the rest of the HD community, I hope for the announcement of effective treatments. I very much look forward to reporting on progress.

 

Just as important is the need to savor life – another key lesson of my journey with the HD community, this blog, and my friends and family.

‘Striving for a cure’: highlights from the 19th Annual Huntington’s Disease Therapeutics Conference

 

Progress towards effective treatments for Huntington’s disease relies on the affected families’ collaboration with researchers exploring the frontiers of science.

 

The potentially pathbreaking findings featured at the recently completed 19th Annual HD Therapeutics Conference, sponsored by the nonprofit CHDI Foundation, Inc., led CHDI Chief Scientific Officer Robert Pacifici, Ph.D., to declare that the community will achieve therapies.

 

In this article I highlight the scientists’ work with a photo essay on their conference presentations and some of their key observations.

 

I cover most of the presentations. For detailed reports on the conference, see the articles in HDBuzz by clicking here, here, and here. Later CHDI will post videos of the presentations on its website. It is also preparing a video “postcard” of the event.

 

In recent decades, Huntington’s breakthroughs have resulted from the increasing amount of human data, which Dr. Pacifici and other scientists say is the best way to study the disease and develop potential therapies. The presentations at this conference especially reflected this trend. Researchers such as Matthew Baffuto, B.S., of the Heintz Lab at The Rockefeller University (in the photo above), recognized the importance of postmortem donations of HD-affected individuals’ brains and other human samples for their research. Baffuto’s final slide included a dedication: “To the HD patients and families who make this human research possible and for whom we continue to strive for a cure.” (All photos by Gene Veritas, aka Kenneth P. Serbin) (Click on an image to make it larger.)

 

The first wave of attempts by pharmaceutical companies to defeat Huntington’s has involved attempts to lower the amount of the abnormal huntingtin protein (HTT) in patients’ brains. In many of these approaches, this also means lowering the amount of normal HTT. The lab of Jeff Carroll, Ph.D., a scientist at the University of Washington and a HD gene expansion carrier like me, has extensively studied huntingtin lowering in mice. Normal huntingtin is necessary for adult mice to function, Dr. Carroll observed. Huntingtin lowering is not a “bad idea, just that there’s a floor between 50 percent and zero percent HTT,” he said.

 

Tony Reiner, Ph.D., of the University of Tennessee Health Science Center, presented the latest findings of his work comparing HD mouse brains to human tissue from deceased HD-affected individuals. He also focuses on how HD affects the various regions of the brain differently. This photo illustrates how Dr. Reiner uses antibodies to measure the complications that arise in HD mouse brains.

 

Sarah Tabrizi, M.D., Ph.D., of University College London, discussed her lab’s research on somatic expansion, the tendency of the abnormal huntingtin gene to expand with time and become more harmful to the brain. She presented data on developing drugs to interact with modifier genes, which can impact somatic expansion and therefore the age of disease onset. Dr. Tabrizi focused on the modifier gene MSH3 as an ideal therapeutic target. For this research, the Tabrizi lab has utilized stem cells, CRISPR gene editing techniques, and antisense oligonucleotides, used in huntingtin lowering drug programs and other HD research projects.

 

Ricardo Mouro Pinto, Ph.D., of Harvard University Medical School, presented his lab’s work on genetic modifiers of somatic expansion. Dr. Pinto has implicated the so-called DNA mismatch repair pathway as a critical driver of somatic expansion. His lab is also developing CRISPR-based strategies as potential therapies. Dr. Pinto’s team was recently awarded a grant from the Hereditary Disease Foundation to continue the search for therapies.

 

Mark D. Bevan, Ph.D., of Northwestern University, spoke on his lab’s latest findings in HD mice, in particular the dysregulation and rescue of subthalamic nucleus, involved in the suppression of movement. Dr. Bevan highlighted the need for both huntingin-lowering and somatic expansion therapies to have widespread delivery into the brain.

 

Osama Al-Dalahmah, M.D., Ph.D., of the Columbia University Irving Medical Center, discussed the major role of astrocytes in HD. There are over 100 different brain cell types. Astrocytes are cells that provide physical and chemical support to other cells such as neurons, key in the brain. As a neuropathologist, Dr. Al-Dalahmah analyzes post-mortem brain tissues. Among other observations, he noted that astrocytes can be neuroprotective. His lab is working on ways to protect neurons in HD.

 

Scientist Baffuto’s wide-ranging presentation focused on specifying cell types in unraveling both the molecular mechanisms underlying somatic expansion and also the path of the disease. The Rockefeller team developed what it describes as an “innovative methodology” for deep profiling of cellular processes in the brain. The technique is fluorescence-activated nuclear sorting (FANS). As shown in one of Baffuto’s slides, they used FANS to detail the disease process in key areas of postmortem HD-afflicted brains: the striatum, cortex, thalamus, hippocampus, amygdala, and cerebellum.

 

Scientists continue to debate exactly what triggers Huntington’s. Assessing the impact of somatic expansion, the Harvard University Medical School team studying HD proposed a new model for how somatic expansion contributes to HD pathology. Bob Handsaker, B.S., explained that, until recently, scientists thought that the DNA triplet repeat creates a toxic protein whenever the CAG repeat length is greater than 40 and that HD pathology arises from lifelong exposure to this toxic protein, similar to how smoking damages the lungs. (The abnormally repeated DNA word CAG is the genetic root of HD.)

 

New research has challenged this idea in three important ways: First, there is much more somatic expansion than had been appreciated, with affected neurons expanding to reach over 400 CAG repeats. Second, this somatic repeat expansion starts slowly and then accelerates over time, like a "slowly ticking DNA clock” in each individual neuron. Third, the evidence suggests that modest somatic expansion, up to a repeat length of 150 CAGs, does not create a protein that is toxic - the toxic effect in each individual neuron only begins above this longer repeat-length threshold. Along with other research presented, this finding underscored that there may be a longer window of opportunity than had previously been appreciated for any therapeutic interventions that act to slow or block somatic expansion. This is because in the first few decades of life in a person with HD, the DNA in most neurons has typically not expanded to reach this toxic threshold.

 

Darren G. Monckton, Ph.D., of the University of Glasgow, presented his new research on biomarkers, signs of a disease and indicators of whether a drug has efficacy. Dr. Monckton focused on biomarkers in areas of the body outside the brain such as blood, in particular regarding the degree of somatic expansion and measuring it over time.

 

Carlos Bustamente, Ph.D., a Venezuelan American geneticist and the founder and CEO of Galatea Bio, Inc., advocated for enabling precision medicine around the globe. Dr. Bustamante observed that new technological advances have made it faster and less expensive to understand human genomes but most of such resources have gone to understanding predominantly northern European communities. He pointed out the need to expand the genetic dataset to other parts of the globe. Dr. Bustamante also explained how genetic differences in the global population have contributed to differences in the geographic prevalence of Huntington's.

 

David Margolin, M.D., Ph.D., the vice president for clinical development at uniQure, presented an update on the early-stage (Phase 1/2) clinical trial of the company’s gene therapy drug, AMT-130, involving 39 trial volunteers in the U.S. and Europe. Dr. Margolin reported that, relative to baseline, volunteers treated with AMT-130 showed evidence of preserved neurological function. So far, the drug has proved to be safe.

 

Amy-Lee Bredlau, M.D., the senior medical director at PTC Therapeutics, presented interim safety and biomarker data for the company’s huntingtin-lowering pill, PTC-518, in PIVOT-HD, a Phase 2 trial. At this stage, the drug has been shown to be safe and has achieved a lowering of huntingtin in the blood – although data do not yet show whether the lowering is also occurring in the brain.

 

From left to right, Roche researchers Jonas Dorn, Ph.D., Peter McColgan, M.D., Ph.D., and Marcelo Boareto, Ph.D., reanalyzed the data from the firm’s first attempt at a Phase 3 huntingtin-lowering trial program, which in 2021 ended without the drug tominersen showing the necessary efficacy for approval as a drug. The scientists discussed ways to improve clinical trial design, including for GENERATION HD2, a less ambitious, Phase 2 trial of tominersen in a smaller number of volunteers. GENERATION HD2 is in progress.