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.
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