Pridopidine

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 .

iStock/ higyou Launched in 2020 to more quickly bring to market an effective medicine for amyotrophic lateral sclerosis, the HEALEY Platform Trial has generated disappointing results for many but also continuing programs from Clene and Prilenia. Clinical wins have been few and far between for the HEALEY ALS Platform Trial . A heterogeneous patient population and delays have posed challenges, with several biotechs discontinuing programs based on underwhelming results. But optimism persists among the trial’s leaders and early participants, with two companies, Clene Nanomedicine and Prilenia Therapeutics, moving their investigational amyotrophic lateral sclerosis (ALS) treatments forward. The first seed for an ALS platform trial was planted when Massachusetts General Hospital’s Merit Cudkowicz read an article on master platform trials by former FDA Principal Deputy Commissioner Janet Woodcock. “I read that one and thought it might be appropriate for ALS,” Cudkowicz told BioSpace . Then, along came Sean Healey, a prominent American businessman who had recently been diagnosed with ALS, with an attractive opportunity. He said, “I might not save myself from this illness, but I want to make a difference. Give me a proposal,” Cudkowicz recalled. So she and her team worked around the clock, ultimately pitching the platform trial, and “[Healey] loved it. He just got it right away, that it was efficient and good for patients.” Healey, in partnership with his global asset management firm, Affiliated Managers Group (AMG), donated $40 million to launch the Sean M. Healey & AMG Center for ALS at Mass General, and set in motion a new chapter in ALS research. Cudkowicz serves as the center’s director. Biopharma quickly jumped on board with the platform trial, with dozens of companies—in addition to Clene and Prilenia, UCB, Biohaven Pharmaceutical and Seelos Therapeutics—vying to be a part of it. Fast forward four years and none of these drugs has hit the trial’s primary endpoints. But Clene CEO Rob Etherington said that doesn’t reflect a failure of the study itself. The HEALEY trial was designed to “fast fail” assets that don’t have utility, he explained, “and it worked in that respect, for a few of the regimens.” Indeed, Cudkowicz noted that Biohaven, which ultimately opted against moving forward with the program, also viewed the trial as a success because “they got a quick answer, a clear answer.” Biohaven did not respond to BioSpace ’s request for comment. But perhaps most notably, Clene and Prilenia showed positive data on secondary endpoints that prompted those companies to progress their candidates, Cudkowicz said. “So, I really actually view that as a success.” The First Five To select the initial round of participants in the trial, Cudkowicz and her team decided to host a competition. She noted that many aspiring platform trials seemed to be stuck at the funding stage and believed a call for proposals would speed up the process. The prize: entry into the Healey ALS Platform Trial, where some costs for the first companies would be covered. The team received 30 proposals from all over the world. Cudkowicz and her colleagues assessed each therapy based on clinical potential, mechanism of action, and diversity of approach. “We did want to pick drugs with different targets for the first five,” Cudkowicz said. Finally, they selected five programs. UBC’s zilucoplan inhibits complement component 5, the dysregulation of which is implicated in ALS, while Biohaven’s verdiperstat blocks the enzyme that reduces oxidative stress and neuroinflammation. Clene’s CNM-Au8, by contrast, is an oral, liquid suspension of gold nanocrystals designed to improve the survival, function, and communication of nerve cells. Prilenia’s pridopidine is also a neuroprotective agent, and Implicit Bioscience’s IC14 is an anti-CD14 monoclonal antibody devised to regulate the pathogenic inflammatory responses to infection and injury. Of these, Clene and Prilenia fared the best. Although both companies’ assets missed their primary endpoints, positive biomarker data and benefit to a subgroup of patients in Prilenia’s case supported moving the programs forward. With Prilenia’s candidate, a subgroup of patients with early-stage ALS who were rapidly declining had “substantially less decline” in ALS Functional Rating Scale-Revised (ALSFRS-R) total score compared to placebo. The company has stated plans to launch a Phase III trial. Meanwhile, Clene has a briefing book in front of the FDA based on HEALEY data and additional biomarker results gleaned from the RESCUE-ALS trial and survival data from ongoing compassionate use protocols. While the agency originally said the data were insufficient to support a new drug application, Clene has since submitted more information, including mechanistic and ALS-specific biomarkers and data on a super-responder group, which Etherington said is now under review. Clene also gathered promising survival and biomarker data from its arm of the HEALEY study. Treatment with CNM-Au8 for up to 133 weeks decreased the risk of death by 49% compared to PRO-ACT database–matched placebo, according to Clene, while also reducing levels of neurofilament light chain (NfL), which is gaining ground as a predictor of clinical outcomes in neurodegenerative diseases. “Without the survival secondary endpoint win and the exploratory endpoint win and the neurofilament biomarker win that HEALEY gave Clene, we’d be in a very different position today,” Etherington said. “We certainly wouldn’t have a briefing book under consideration at the FDA without HEALEY.” The other companies have either shut down their programs or are still determining next steps. Implicit never moved forward to the design phase. UCB’s arm of the trial was stopped early after an interim analysis demonstrated futility, according to a Massachusetts General press release . Meanwhile, Biohaven’s verdiperstat failed to statistically differentiate from placebo, and the drug is no longer listed in the company’s pipeline . Seelos joined after Implicit departed and got mixed results. The company stated in a March press release that while its drug trehalose failed to meet statistical significance in the primary and secondary endpoint in the HEALEY study, it showed a “potential signal of efficacy” in a subgroup of patients not taking Amylyx’s Relyvrio, which was given to some trial participants after its approval in September 2022 . And the HEALEY trial marches on. In July 2022, Calico Life Sciences signed on to test ABBV-CLS-7262, and Denali Therapeutics announced its participation with DNL343 in December of the same year. Data from these arms of the trial are expected in early 2025. Another company, Australian outfit PharmAust, recently committed to studying its drug monepantel, and Cudkowicz said talks are ongoing with several more companies. Cudkowicz said that no matter what the result of the various arms, “you can learn a lot about [ALS].” Patient- and Business-Centric Platform trials are a fairly new phenomenon, and Cudkowicz shared that she learned a lot from the DIAN Alzheimer’s trial at Washington University. The model offers myriad benefits, including efficiency. While a clinical trial typically takes more than a year to get off the ground, the HEALEY study is a perpetual trial , meaning a new drug regimen can be added in just 30 days. It’s also patient-centric. The use of a shared placebo between all regimens means that more patients receive a potentially efficacious drug. This also means companies have to recruit fewer patients. The fact that some of their costs were covered was a significant benefit for the smaller companies in the HEALEY trial. Prilenia, for example, had six employees at the time it applied to join the trial. “The good news was they paid for the drug, so we didn’t have to raise money for [that],” Hayden told BioSpace . The infrastructure build and support were also partially funded by several foundations, Cudkowicz said. “I’m grateful. Without HEALEY, we would never have done this trial,” Hayden said. “We didn’t have the money.” The companies involved also have access to elite experience in the ALS space. Cudkowicz is widely considered to be the dean of ALS drug development, and both Etherington and Hayden referenced the gravitas associated with the HEALEY trial, which includes 75 research sites. “The advantage of HEALEY is undeniably the fact that you have an easy network of top expert centers . . . so you’re really able to access the top centers in the United States of America,” Etherington told BioSpace . “That is a tremendous advantage for young startup companies to have access to and to be involved with.” Etherington added that acceptance into the trial gave CNM-Au8 credibility “because it really was a testament of others’ stamp of approval that are well respected in the space.” Growing Pains Still, a complex structure with so many moving parts is bound to take time to perfect. Etherington noted that every drug is unique, and “a platform study does not enable an individual drug and its unique aspects of mechanism or side effects or administration to actually make any changes” to the trial’s protocol. For example, each cohort in the HEALEY trial has run for six months. For CNM-Au8, this was too short of a window to prove efficacy, Etherington said. “To have everybody come in and have to fit the framework with no exceptions, that’s a challenge.” Notably, Cudkowicz shared that the team is currently considering amending the protocol based on learnings from the first five regimens. “This includes possibly longer duration of follow up on the randomized controlled trial period to address the possibility that some medications need more time to achieve biological and clinical effects,” she said. Cudkowicz added that a voice app developed by Aural Analytics and used in the first four regimens is “turning out to be a very good digital biomarker. We also did home spirometry (a measure of lung function), which looks pretty much just as good as in clinic.” Another challenge for a trial with multiple centers across the U.S., Etherington said, was an initial delay in receiving data from every center, though Clene is now in possession of the final datasets from the HEALEY trial. Because every regimen starts at a different time, they all finish at different times, slowing down the rate at which results are available. For a company conducting a single study, “all hands are on deck,” Etherington said. By contrast, in a platform trial, “we have to be more ecumenical. We have to share, as it were, the load and the timeline, and we need to recognize that the company’s individual interests need to be subjugated, to some degree, to the whole of the platform study.” Hayden agreed, saying that the HEALEY team was sometimes “overwhelmed” with running what amounts to eight trials, and that there sometimes is “a little frustration in terms of the speed of response, the ability to get statistical analysis done. All of that can be slower than we would like.” Cudkowicz acknowledged that the trial has faced challenges in this regard. “Since the idea of platform trials is efficiency and speed, we want all parts of it to be efficient,” she said. “Some of the structural, operational things that slow down trials in general are still in play in platform trials [and] how trials are started up at academic institutions is still too slow, in my opinion. We have some new initiatives to improve this dramatically for the next several new regimens,” she said in an email. Cudkowicz added that interest in the trial overwhelmed the capacity of some of the trial sites. “There’s high interest in it from the companies, from the patients, but now we’ve gotta do it even faster.” A heterogeneous patient population was another challenge, Hayden said. “The study included essentially everybody with ALS, and that was maybe . . . both positive and negative. The positive was that this gave hope to everybody.” However, ALS has a “very heterogeneous population.” The HEALEY trial included patients with definite, probable and possible ALS, as well as those more than three years out from diagnosis. “We were concerned about that right in the beginning because we knew that all the trials that had been successful in ALS had a different population” that included patients with only definite and probable ALS, and a shorter disease duration, Hayden said. Prilenia ultimately prespecified that it wanted to also study pridopidine in patients with early-stage ALS, diagnosed less than 18 months before the trial’s start, and HEALEY investigators were able to recruit from such a population for the arm of the trial testing the drug. And while pridopidine failed the primary endpoint in the full analysis set, in patients with early ALS, “what we saw is that we had a very wonderful positive effect,” Hayden said. “We delayed progression for the first time ever seen in an ALS trial at eight weeks.”