Prilenia Therapeutics Development Ltd.

iStock/ dickcraft Misses from amyotrophic lateral sclerosis hopefuls Denali Therapeutics and partners AbbVie and Calico Life Sciences mark the latest setbacks for the controversial platform trial, the results from which have largely mirrored the dismal success rate in ALS overall. Launched in 2020 to expedite the development of an effective medicine for amyotrophic lateral sclerosis, the HEALEY ALS Platform Trial suffered two more disappointments this week as candidates from Denali Therapeutics and AbbVie and Calico Life Sciences missed the study’s primary endpoint, failing to significantly slow disease progression. Funded by Sean M. Healey—who died from amyotrophic lateral sclerosis (ALS) in 2020—and his global asset management firm, the HEALEY trial generated new hope for patients with the intractable neurological disease. Platform trials are a fairly new phenomenon, however, meaning successes have been limited and investigators are still refining the methodology. In a Monday investor note, Stifel analyst Paul Matteis called the trial “a very high-risk/high-reward option.” As with any novel venture, HEALEY has experienced challenges. In an earlier interview with BioSpace , Clene Nanomedicine CEO Rob Etherington noted certain inflexibilities in the trial’s protocol in addition to a six-month timeframe that is “too short of a window to prove efficacy.” For some drug developers, it is also an attractive business proposition. The HEALEY team recruited the first biotechs to the trial by covering some of their costs. “The good news was they paid for the drug, so we didn’t have to raise money for [that],” Prilenia Therapeutics CEO Michael Hayden told me in September. A platform trial also has the advantage of being patient-centric, using a shared placebo group between all regimens to boost the total number of patients receiving a potentially efficacious drug. But nearly five years on, the HEALEY trial has yet to produce a definitive success, instead serving up a string of failures. Hopefuls from Clene, Prilneia, Biohaven , UCB and Seelos Therapeutics all failed to hit the trial’s primary endpoint, and of these, only Prilenia and Clene saw enough positive signals to move their treatments forward. The other programs have all been terminated—a devastating development for the ALS community. It has also been hard, of course, on these companies. Seelos filed for bankruptcy in November after trehalose’s failure. That same month, Massachusetts General Hospital (MGH), which runs the HEALEY trial, sued Seelos over the company’s alleged failure to fully pay for the work MGH conducted on its candidate trehalose. Seelos, which has expressed disagreement regarding the data from its regimen in the HEALY trial, particularly concerning the use of Amylyx’s Relyvrio by some participants, is allegedly withholding payment as a result—to the tune of $2 million, according to the lawsuit. In a March 2024 update , Seelos stated that while the study did not meet statistical significance in the primary and secondary endpoint across all participants, it showed a potential signal of efficacy in a pre-specified subgroup not taking Relyvrio. These patients saw a 22% improvement in slope of change in the ALS Functional Rating Scale-Revised (ALSFRS-R) assessment adjusted for mortality, with an 89% success probability, at 24 weeks, according to the press release. “The HEALEY platform is designed to detect signals of efficacy and we believe the observed signal and success probability is competitive to other recently FDA-approved therapies for ALS which also failed to achieve statistical significance when measured for function and mortality on similar primary and efficacy endpoints,” Seelos CEO Raj Mehra said in the March statement. Relyvrio received approval in September 2022 as only the third-ever treatment for ALS. Given its subsequent withdrawal from U.S. and Canadian markets in April 2024 after failure to show efficacy in a Phase III trial, it would have been interesting to see how trehalose would have performed under different circumstances. Signals of Hope For followers of the HEALEY trial—and the ALS space in general—pulling signals of efficacy from the rubble is a familiar tune. For Prilenia and Clene, positive biomarker data supported moving their respective programs forward. In Prilenia’s case, a subgroup of patients with early-stage ALS who were rapidly declining had “substantially less decline” on the ALSFRS-R total score compared to the placebo group. Prilenia submitted a Marketing Authorisation Application to the European Medicines Agency that was accepted in September 2024. Certainly, there is precedent for moving a program forward based on patient subgroup data. “[ALS] is heterogeneous, and sometimes it’s really important, even when a drug doesn’t work in everybody, to look at if there’s a subset that might have benefited,” Merit Cudkowicz, director of the Healey & AMG Center for ALS, told me in 2021. Cudkowicz noted that results of the first trial for Radicava, developed by Mitsubishi Tanabe and approved by the FDA in May 2017, were also negative across the overall trial population. However, a subset of early fast progressors did respond, “and when they repeated the studies just in that group, it was positive and that led to marketing.” And embattled Israel and New York–based biotech BrainStorm Cell Therapeutics has consistently pointed to analysis from its Phase III trial of NurOwn showing that a prespecified subgroup of patients with early-stage disease, as determined by an ALSFRS-R baseline score of 35, saw a meaningful response across all primary and secondary endpoints. BrainStorm is now gearing up for a Phase IIIb study that president and CEO Chaim Lebovits said would be focused on these early-stage patients. After a 2024 campaign filled with disappointment, this is a space that desperately needs a break. ALS is uniformly fatal, typically claiming its victims within five years of diagnosis, and the disease continues to confound researchers. Given the dire need for effective treatments, patients, drug developers and journalists alike could be forgiven for celebrating signals of hope. As for the HEALEY trial, Cudkowicz shared that the team is currently considering amending the protocol based on learnings from the first five regimens. “My sense is that it is not a perfect clinical trial. It has its flaws,” Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told me . “But I think they’re trying to fix the situation at HEALEY.”

iStock, dani3315 A fatal, highly hereditary illness with no disease-modifying treatments, Huntington’s is long overdue for a therapeutic win. Here, BioSpace looks at five candidates that could change the trajectory for patients. Huntington’s disease has perplexed researchers for decades . Despite being one of the first genetic neurodegenerative illnesses for which science was able to pinpoint the causative gene, modern medicine is still searching for a disease-modifying treatment for this formidable foe. “Here we are, decades later, and we still don’t know what to do with that information to prevent people from having decline from all the different functions of the brain and ultimately dying from the illness,” David Shprecher, movement disorder director at Banner Sun Health Research Institute, told BioSpace . Huntington’s, which is caused by a CAG repeat in the first exon of the huntingtin ( HTT ) gene, generates a triad of symptoms: motor, cognitive and behavioral. While patients can develop severe issues with anxiety and obsessive-compulsive disorder, it is complications from the motor symptoms—including difficulty swallowing and falls—that are usually the cause of death, according to Shprecher. “The problem is we don’t fully understand why the gene mutation causes damage to the brain,” he said. Clinical trials are another challenge, he continued, with only about 41,000 symptomatic patients in the U.S. and many not at a stage where they’re eligible to participate. Geographic barriers are also significant as most trials are conducted at major academic centers and require in-person assessments. “There’s been a real push to use a lot more telehealth and biometric remote technology” to allow more access to these important trials, Shprecher said. While the Huntington’s community has experienced multiple letdowns over the last four years, biopharma is not giving up. Several companies, including Prilenia Therapeutics, uniQure and Sage Therapeutics are hopeful that their approaches can make a tangible difference for patients. Here, BioSpace reviews five investigational drugs that could change the trajectory for patients with Huntington’s disease. Prilenia Therapeutics Pridopidine Prilenia Therapeutics announced in September that the European Medicines Agency has accepted its Marketing Authorisation Application for pridopidine, a “highly selective and potent” agonist of the sigma-1 receptor. Topline results reported in April 2023 from the Phase III PROOF-HD study revealed a miss for pridopidine, which failed to meet the primary and key secondary endpoints. However, further analysis of the data showed that the candidate elicited clinically meaningful efficacy in patients not taking anti-dopaminergic and chorea medications. The Huntington’s community had been hopeful of pridopidine’s potential to treat Parkinsonian symptoms experienced by patients, Shprecher said, as these are not addressed by any current treatments. However, he added, “there would be very few Huntington’s disease patients eligible for a trial if it excludes both of those types of medications.” Sage Therapeutics Dalzanemdor Sage Therapeutics is developing dalzanemdor, a potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s. The Cambridge, Mass.–based biotech reported data in June from a small, Phase II trial in which there was a “small numerical difference” between dalzanemdor and the placebo as measured by the HD-Cognitive Assessment Battery composite score on day 28, with the company also noting that other “prespecified analyses” showed potential positive signals. Huntington’s watchers, however, were not impressed. In a note to investors at the time, William Blair analysts called the results “underwhelming” and said they “remain cautious” on dalzanemdor and “do not view the small numerical changes as definitive” based on the results of this study. Sage is gearing up to report data from the Phase II DIMENSION study of dalzanemdor in Huntington’s later this year, a win it needs after the drug failed to show efficacy in Alzheimer’s and Parkinson’s . uniQure AMT-130 Dutch biotech uniQure is developing a microRNA gene therapy, AMT-130, which is delivered deep inside the brain to inhibit the production of the mutant HTT (mHTT) protein. In July 2024, the company reported 24-month interim data from its Phase I/II trial of AMT-130 in 29 patients showing a dose-dependent slowing of disease progression. “We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration,” Walid Abi-Saab, chief medical officer of uniQure, said in the press release at the time. AMT-130 has been granted orphan drug, Fast Track and Regenerative Medicine Advanced Therapy designations from the FDA, and uniQure has scheduled a Type B meeting with the regulator for later this month to discuss the potential for an accelerated development pathway, according to its Q3 earnings report . Wave Life Sciences WVE-003 Wave Life Sciences is developing the first allele-specific silencing therapy for Huntington’s. An antisense oligonucleotide, WVE-003 targets a nucleotide polymorphism present on the mHTT mRNA while leaving healthy huntingtin intact. In June 2024, Wave reported that the candidate significantly and selectively reduced levels of the mHTT protein in a Phase Ib/IIa trial. After 24 weeks, treatment with WVE-003 led to a 46% drop in mHTT levels in patients’ cerebrospinal fluid versus placebo. While the program was initially partnered with Takeda, the larger pharma stepped back from the collaboration last month. Now taking WVE-003 forward itself, CEO Paul Bolno told BioSpace that Wave has “initiated engagement” with regulators regarding a clinical development path that could support accelerated approval. Roche and Ionis Tominersen Roche and Ionis Pharmaceuticals are partnered on the development of tominersen, which is currently being studied in a Phase II clinical trial of patients with prodromal and early manifest Huntington’s disease. In previous clinical trials , tominersen was shown to lower levels of toxic mHTT by blocking its production. The antisense oligonucleotide is administered through a lumbar puncture into the cerebrospinal fluid. Tominersen’s development journey has not been without challenges. In March 2021, Roche discontinued a Phase III trial of the candidate in manifest Huntington’s disease after a pre-planned data review by an unblinded Independent Data Monitoring Committee. The recommendation was related to tominersen’s potential benefit/risk pro patients, Ionis said at the time. Roche and Ionis are going all in on Huntington’s. In addition to the mid-stage tominersen trial, Roche paid its longtime partner last year for two RNA-targeting programs targeting Huntington’s and Alzheimer’s disease.

NAARDEN, Netherlands & WALTHAM, Mass.--( BUSINESS WIRE )-- Prilenia Therapeutics B.V. , a biopharmaceutical company focused on developing novel therapeutics to treat neurodegenerative and neurodevelopmental diseases, today announced the presentation of five scientific abstracts and an oral presentation focused on pridopidine, the company’s investigational medicine for the treatment of Huntington’s disease (HD), at the upcoming 31 st annual meeting of the Huntington Study Group to be held in Cincinnati, Ohio, November 7-9, 2024. “To provide truly meaningful change for people living with HD, we need to shift the paradigm from treating symptoms to addressing progression. The data we will present at HSG reinforce pridopidine’s benefits across function, cognition and fine motor skills measured by validated assessments and sustained for up to two years,” said Dr. Michael R. Hayden, Chief Executive Officer of Prilenia. “The European Medicines Agency has accepted our MAA submission for the treatment of HD, and it is currently under review. This is the first submission seeking approval for a potentially first-in-class investigational new treatment that can impact these measures of clinical disease progression in HD.” Dr. Hayden will present clinical data on pridopidine during the Contemporary Trials and Next Steps (Clinical Trial Roundup) session (10:45–12:15 ET, Friday, November 8), additional to presentation of the five abstracts. The data demonstrate pridopidine’s effect and implications for HD management and clinical trial design: The Phase 3 PROOF-HD Trial Demonstrates Significant Benefits of Pridopidine on Progression, Cognition, and Motor Function in Huntington’s Disease Overview : Pridopidine shows consistent, sustained, and clinically meaningful benefits across multiple endpoints, including function, clinical disease progression (as measured by cUHDRS), cognition, motor and quality of life in patients not receiving antidopaminergics (ADMs) and on low doses of ADMs. Integrated Efficacy Analysis of Four Randomized Placebo-Controlled Trials Supports Pridopidine’s Treatment Benefits Across Key Clinical Measures of Huntington’s Disease Overvie w: The integrated efficacy analysis from four clinical trials supports PROOF-HD findings, showing consistent, sustained and clinically meaningful benefits of pridopidine in HD in patients not receiving ADMs. Pridopidine Demonstrates Consistent Improvements in Q-Motor Measures, and Early Benefits in Q-Motor Predict Long-Term Changes in Function and cUHDRS in PROOF-HD Overview : Pridopidine demonstrated improvements in Q-Motor assessments at all timepoints irrespective of ADM use, with strongest and most significant effects in patients not receiving ADMs. Early improvements in Q-Motor were predictive of long-term benefits on key clinical outcome measures of disease progression. Low Dose Antidopaminergic Medications do not Mask the Beneficial Effects of Pridopidine in Huntington’s Disease Overview: Participants on low dose ADMs maintain the positive and clinically meaningful benefits of pridopidine in HD. These observations may guide the use of ADMs for the treatment of chorea and behavioral disorders together with pridopidine. The Effect of Antidopaminergic Medications on Huntington’s Disease Overview: Analyses of data from the ENROLL-HD database demonstrate that use of ADM’s was associated with worse outcomes in clinical outcome measures typically used in HD for function, cognition, cUHDRS and motor performance. These observations have important implications for the conduct and interpretation of investigational studies of disease-modifying agents in HD and for medical practice. About Pridopidine Pridopidine (45 mg twice daily) is a potent and highly selective, orally administered, sigma-1 receptor (S1R) agonist, that has the potential to alter treatment paradigms in neurodegenerative diseases. S1R regulates several cellular neuroprotective mechanisms commonly impaired in neurodegenerative diseases, such as HD and ALS. Pridopidine has an extensive clinical development program encompassing efficacy and safety data. In the PROOF-HD Phase 3 clinical trial, pre-specified analyses that excluded patients receiving antidopaminergics (ADMs) showed benefits in people taking pridopidine across multiple measures, including clinical disease progression as measured by cUHDRS, cognition (Stroop Word Reading Test, SWR) and motor (Q-Motor). The primary and secondary endpoints in the full population were not met. Importantly, an integrated efficacy analysis from four Phase 3 and Phase 2 studies supports and validates the PROOF-HD findings, showing consistent, sustained and clinically meaningful benefits of pridopidine in HD in patients not receiving ADMs as measured by cUHDRS (excluding SWR as PRIDE-HD did not measure SWR), Q-Motor Finger Tapping (FT) and Pronation/Supination (PS). In clinical studies to date, pridopidine (45 mg twice daily) has been well-tolerated with a safety and tolerability profile similar to placebo. The European Medicines Agency has accepted our MAA submission for the treatment of HD, and it is currently under review. In parallel, Prilenia is also in discussions with the U.S. Food and Drug Administration (FDA) to determine next steps for HD in the United States. The Company will also consider regulatory submissions elsewhere globally following the regulatory review process in Europe. Prilenia holds Orphan Drug designation for pridopidine in HD and ALS in the U.S. and EU. In addition, pridopidine has received Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of HD. About HD Huntington’s disease (HD) is a rare, inherited, autosomal dominant, neurodegenerative disease that results in functional, motor, cognitive and behavioral symptoms. HD is caused by a mutation in the huntingtin gene, and each child of a parent with HD has a 50 percent chance of developing the disease. HD affects about 100,000 people around the world with an additional 300,000 people at risk of developing HD. It is usually diagnosed between the ages of 30 and 50, although HD can occur at any age, including in children and young adults (known as juvenile onset HD or JHD). The disease progresses slowly over 15 to 20 years, with patients slowly losing their ability to work, communicate, manage day-to-day life and take care of themselves. This increasing disability leads to full reliance on a caregiver and, ultimately, death. The only currently available treatments for HD focus on symptomatic relief and palliative care, with nothing impacting measures of overall disease progression. About Prilenia Prilenia Therapeutics is a biopharmaceutical company focused on developing novel therapeutics to treat neurodegenerative and neurodevelopmental diseases like Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Our team has an unwavering dedication to scientific excellence, and we are driven by our passion and commitment to patients and their families, caregivers, and communities around the world affected by these diseases. Based on the collective data from pridopidine’s extensive development program, Prilenia is pursuing regulatory approval for its investigational medicine, pridopidine, for the treatment of HD and planning to initiate a single pivotal Phase 3 study in ALS. Pridopidine is a potent and selective, orally administered S1R agonist. Prilenia is a private, Netherlands-headquartered company backed by leading life sciences investors. For more information, please visit www.prilenia.com and connect with us on LinkedIn or X (Twitter) . © 2024 Prilenia Therapeutics B.V. For a copy of this release, visit Prilenia’s website at www.prilenia.com .