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.

After abrupt shutdown of Triplet Therapeutics, Huntington’s disease community regroups in the fight for therapies

 

Triplet Therapeutics, Inc., a Cambridge, MA-based start-up that aimed to transform the treatment of Huntington’s disease and related disorders, has shut down, citing a lack of new investment partners and the discovery that its proposed HD drug caused adverse effects in animal tests.

 

On October 11, Triplet CEO Nessan Bermingham announced the company’s closure on his LinkedIn page. The abrupt closure was another piece of tough news regarding potential therapies for HD.

 

In March 2021, Roche and Wave reported negative trial results for drugs aimed at reducing the toxic mutant huntingtin protein in patients’ brains. These drugs are antisense oligonucleotides (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

Triplet’s strategy

 

Triplet had designed its own ASO, but with a different strategy: to stop the deleterious expansion of the mutant huntingtin gene (click here to read more). Known as somatic expansion, this process drives the disease and can hasten the onset of symptoms. By slowing this expansion, Triplet had hoped that its drug would head off the disease early.

 

Triplet scientists and others have viewed this approach as a more effective alternative to the “huntingtin lowering” strategy devised by Wave, Roche, and others.

 

Capitalizing on recent groundbreaking HD genetics research, Triplet, founded in late 2018, developed the only clinical trial program to slow or stop somatic expansion in HD. Triplet also had hoped to develop treatments for others among the 50 rare conditions with somatic expansion, which, like HD, are called repeat expansion disorders.

 

 

Brian Bettencourt, Ph.D., Triplet's former senior vice president for research, explains a slide illustrating the firm's pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference, 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

“It is with great sadness we announce the closure of Triplet Therapeutics,” Bermingham wrote on LinkedIn.

 

The “underlying science of targeting repeat expansion disorders” remains “a viable approach from our vantage point,” Bermingham wrote. However, crucially, in animal studies, the data from Triplet’s HD drug “reflected prior experiences” with ASO toxicity in the central nervous system – a reference to the Roche and Wave results.

 

Specifically, the ASO showed signs of harming neurons (brain cells). “As a therapeutic modality, given Roche’s data, our data, lack of efficacy from Wave products, our belief is that neurons may be particularly sensitive to antisense oligonucleotides,” Bermingham told STAT.

 

Triplet secured $59 million in initial financing and investment. After the bad news in 2021 from Roche and Wave, Triplet struggled to raise the money needed for its planned next step: an early phase clinical trial of its ASO. “The clinical data really put a chill on the overall interest or risk perceived within Huntington’s disease,” Bermingham noted.

 

SHIELD HD continues to provide key data

 

To provide data about the disease for the clinical trial it was planning, Triplet has run a separate, two-year study, without a drug, of approximately 70 presymptomatic and early-disease-stage carriers of the HD mutation. Called SHIELD HD, the study involves cognitive testing, brain MRI scans, blood tests, and examination of cerebrospinal fluid drawn from spinal taps (click here to read more). The sites are Canada, France, Germany, the United Kingdom, and the U.S.

 

In March, Triplet scientists presented a preliminary analysis of this data at the 17th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the virtual nonprofit biotech focused exclusively on developing HD therapies. CHDI is the largest private funder of HD research.

 

SHIELD HD may end in the next few months. In Bermingham’s announcement about the closure of Triplet, he said that CHDI, “a great partner and patient advocate,” stepped in to help SHIELD HD sites complete their work.

 

Triplet’s representatives are now seeking potential partners to continue the company’s research, including a new plan for a clinical trial.

 

Assessing risk

 

In an online interview with me on October 21, Irina Antonijevic, M.D., Ph.D., the former chief medical officer of Triplet, explained that discovering toxicity of the ASO in the animal studies surprised the firm’s researchers. However, she emphasized that the toxicity was “minimal” at therapeutic dose levels, with the animals not suffering any functional loss.

 

As noted publicly, Triplet had also developed several, more potent backup ASOs, Dr. Antonijevic said. The more potent the drug, the smaller the dose needed, therefore reducing the chance of toxicity or an adverse effect, she added.

 

Nevertheless, in a more risk-averse investment climate, Triplet could not find the necessary partners to carry on its clinical trial program with the added concern about the toxicity, Dr. Antonijevic observed.

 

“I think that they are just sort of very different risks,” she said. “Somebody takes maybe a risk to say, ‘Maybe this drug has a risk, but I have a disease, and I know what this disease will do to me.’”

 

For a drug company, the risk involves “investing millions” and waiting years to see if there is a return on investment, she said.

 

Tweaking drug safety, efficacy, and delivery

 

Triplet’s experience revealed how the field of HD drug development needs to tweak the safety, efficacy, and delivery of ASOs into the brain. Despite the challenges, a number of other firms and many researchers believe ASOs merit more study and clinical trials.

 

Roche has developed a revised clinical trial plan, including lower and thus potentially less toxic doses of its ASO. It will start a second trial of that ASO in early 2023.

 

Wave, building on its failed 2021 early stage trials of two ASOs, put a third drug into another small, early phase trial. Unlike the previous drugs, this Wave ASO successfully reduced the mutant huntingtin protein. Also, for the first time, it did this without lowering the level of the healthy protein – something that occurs with the Roche drug.

 

“This is, as far as we know, the first time anyone has ever selectively lowered only one copy [of a total of two] of a protein inside of a human body,” the HD science site HDBuzz commented on Sept. 30.

 

The method of delivery is important for all drugs, especially for ones introduced into the brain. The Roche and Wave trials use spinal taps (intrathecal injections). Triplet had projected using an

injection via a small reservoir implanted on the top of the brain. The firm uniQure is injecting its drug using brain operations.

 

Developing a pill

 

Drug developers point out that the most convenient HD drug would be a pill – taken orally, at home, and without medical assistance. These drugs are known as small molecules.

 

Several firms have embarked on small molecule clinical trial programs for HD.

 

An important trial of one of these small molecule drugs, a huntingtin-lowering pill developed by Novartis, was halted in August for safety reasons. Some of the trial volunteers on the drug developed problems with their nerves, known as peripheral neuropathy.

 

FDA requests more data from PTC

 

On October 18, another firm enrolling people in a clinical trial for a small molecule, PTC Therapeutics, Inc., was asked by the U.S. Food and Drug Administration (FDA), to provide further information before allowing a clinical trial of its HD drug, PTC518. PTC announced that enrollment is ongoing for the planned 12-month Phase 2 trial in several European countries and Australia.

 

Both branaplam and PTC518 are so-called splicing molecules.

 

“PTC pioneered the development of splicing molecules and we have learned about the essential elements to successfully develop these molecules,” Jeanine Clemente, the senior director of corporate communications at PTC, wrote me in an October 20 e-mail in response to my questions about the FDA decision. “We cannot comment on the FDA’s thoughts regarding branaplam or splicing molecules, in general.”

 

However, Clemente pointed out that PTC518 is highly specific and selective for the huntington gene.” She added that, in many important ways, “PTC518 is different than branaplam.”

 

HDBuzz also noted that PTC518 “may have more ideal drug properties, compared to branaplam.”

 

The FDA has asked PTC for additional data to support the dose levels and duration proposed in the trial, Clemente wrote.

 

Clemente added that PTC enrolled its trial entirely with patients outside of the U.S., including approvals to conduct the study at all proposed dose levels. “There have been no treatment-associated adverse events reported to date,” she stated. “We will continue to work with the FDA to potentially enable enrollment of U.S. patients in the trial.”

 

Keeping perspective in a difficult fight

 

Triplet will host a podcast later this year to discuss the “birth, life and death” of the firm, CEO Bermingham stated in his announcement of the closure.

 

The HD community must keep the Triplet shutdown – and all news regarding the ups and downs of the search for HD therapies – in perspective, noted Martha Nance, M.D., the director of the Huntington’s Disease Society of America Center of Excellence at Hennepin County Medical Center in Minneapolis.

 

“We would not do research if we already knew all the answers,” Dr. Nance wrote me in an October 18 e-mail. “HD patients and families have bravely faced their difficult disease for generations, and the doctors and scientists are doing their best, along with patients and families, to find a brighter path.”

 

As an asymptomatic HD gene expansion carrier who has not yet participated in a clinical trial, I had high hopes for the Triplet program, with its focus on attacking the disease in the early stages. I was deeply saddened to hear that the firm closed. I also felt in the gut once again the hard reality of marshalling resources – including financial support – for combating rare diseases.

 

Companies like Triplet are venture capital-funded businesses pursuing high-risk, high-reward endeavors, and many such endeavors fail. So we are fortunate to have a nonprofit like CHDI as a backstop.

 

Dr. Nance’s wisdom reminded me of the need to join with my fellow HD and rare disease advocates to regroup in the fight for therapies.

 

“Finding a solution to brain cell death in HD is not easy,” she observed. “And as we edge closer to an answer, each failure seems more dramatic. It would be nice if the answer would just reveal itself, if the answer to HD was simple and easy, but we will not let the setbacks of the last two years prevent us from moving forward.”

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.

Roche confirms tominersen as ineffective, while Triplet provides key details for trial of drug to slow major driver of Huntington’s disease

 

Following up on news that it had halted dosing, Roche has confirmed that its historic GENERATION HD1 clinical trial, aimed at the genetic causes of Huntington’s disease, failed to improve symptoms in study participants.

The disappointing trial outcome for the drug candidate tominersen was revealed on April 27 by Scott Schobel, M.D., M.Sc., Roche’s medical leader of GENERATION HD1, at the virtual 16th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech focused solely on developing HD treatments and a collaborator in the effort.

 

More than 1,000 people registered for this greatly anticipated meeting.

 

“Nobody wanted this result,” Dr. Schobel said in his online talk, the first scientific presentation describing why an independent review committee had recommended, and Roche accepted, that GENERATION HD1 be halted. “This is a setback, and it’s a setback which is emotional. It’s a setback which we all feel, because, after being able to lower the huntingtin protein for the first time, there’s a lot of hope in that.”

 

An opportunity to learn

 

Dr. Schobel displayed a series of slides demonstrating tominersen’s lack of effect on trial volunteers, who showed “progressive decline,” reflected in key measures of cognition and control of bodily movements. Observations by physicians also showed “increasing severity” of disease in the participants, Dr. Schobel said.

 

Still, he said the researchers established a “new setpoint for the field”: reducing the level of the mutant protein in the early-stage tominersen clinical trial.

 

That achievement was a historic first, and many HD scientists still believe that this strategy can lead to an improvement in symptoms. However, it now remains for potential future trials to demonstrate that huntingtin-lowering can actually help patients.

 

Roche is “compelled” to use the trial results “as an opportunity to learn,” Dr. Schobel said. The company still has a “wealth of data” to analyze regarding tominersen and its implications for the huntingtin-lowering approach. The firm will share results with the HD community.

 

The Huntington's Disease Society of America will hold a webinar at noon Eastern time on April 29 with an update for the community on the Roche results. (Click here to register.)

 

 

Dr. Scott Schobel of Roche displays slide demonstrating decline in volunteers' condition in the GENERATION HD1 clinical trial at the 16th Annual HD Therapeutics Conference (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Drug candidate’s target chosen

 

On this first day of the three-day conference, Irina Antonijevic, M.D., Ph.D., the chief medical officer at Triplet Therapeutics, Inc., revealed key details of the firm’s drug program to develop a genetic strategy that contrasts sharply with the idea of lowering the huntingtin protein. The firm also issued a press release.

 

Dr. Antonijevic focused on Triplet’s efforts to slow or stop a key driver of HD, somatic expansion, the mutant huntingtin gene’s tendency for continued expansion with age.

 

Triplet’s research exploits continuing breakthroughs in HD genetics, also the topic of this year’s Therapeutics Conference. Those advances have revealed that so-called modifier genes linked to the speeding or slowing of somatic expansion can hasten or delay the age of HD onset by just a few years or by as many as 40.

 

Triplet scientists and others believe that the longer that expansion, the more toxic the gene and its product, the huntingtin protein, become.

 

Building on these developments, in 2020 Triplet announced its drug candidate TTX-3360, aimed at slowing or stopping somatic expansion.

 

In her conference presentation, Dr. Antonijevic announced that the specific biochemical target of TTX-3360 is the modifier gene MSH3, involved in the maintenance and repair of DNA.

 

In studies of mice, Triplet has demonstrated safe and effective lowering of MSH3 using TTX-3360. Additional safety studies were done in nonhuman primates.

 

Injection directly into the brain

 

Like the Roche drug, TTX-3360 is an antisense oligonucleotide (ASO), a synthetic modified single strand of DNA. Both the early-stage trial of tominersen and GENERATION HD1 delivered ASOs via spinal tap.

 

However, Dr. Antonijevic announced that TTX-3360 will be introduced into the brain using an intracerebroventricular (ICV) injection. The ICV device is a small reservoir implanted at the top of the head with a catheter going into the brain. ICVs have been used in medical treatments since the 1960s, including injection of anti-cancer drugs.

 

Dr. Antonijevic explained that, in contrast with the spinal tap – whereby an ASO had to travel along the spine before entering the brain – the ICV will permit Triplet to get its drug deeper into the brain, including areas severely affected by HD.

 

With spinal taps, patients can experience pain and inflammation during dosing because of scarring that results from repeated dosing, Dr. Antonijevic asserted. The ICV permits easy withdrawal of cerebrospinal fluid (which bathes the brain) for monitoring of drug safety and efficacy, she added.

 

The ICV also allows for rapid dosing – perhaps even at home – whereas the spinal tap requires a visit to a doctor’s office, Dr. Antonijevic pointed out.

 

(According to one scientific article, an ICV can remain in place for life. However, long-term usage is not well understood. The device should be monitored for leakage or failure. If necessary, the device can be removed or replaced.)

 

At the HD Therapeutics Conference, Dr. Irina Antonijevic of Triplet Therapeutics discusses a slide comparing two methods of drug delivery: spinal taps (intrathecal injections) and intracerebroventricular injection (screenshot by Gene Veritas)

 

Triplet aims to file an investigational new drug application with the U.S. Food and Drug administration (and/or a clinical trial application in Europe or Canada) by year’s end for a Phase 1/2a study of TTX-3360, which will address primarily the safety and tolerability of the compound. Triplet will recruit presymptomatic and early symptomatic individuals for the trial.

 

Triplet also announced a pledge of one percent of its equity to a “patient support fund,” to be managed independently, to support patients suffering from HD and other, similar disorders, known as repeat expansion disorders. The fund will help patients and families secure access to care and therapies.

 

(For background on the Triplet clinical trial program, click here. Stay tuned to this blog here for further coverage of the conference.)

 

(For additional coverage of the conference, click here).

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.)