First Patients Enrolled in Pivotal HEALEY ALS Trial of Multiple Therapies

The first platform trial for amyotrophic lateral sclerosis (ALS), designed to assess multiple treatment candidates simultaneously with a goal of accelerating the development of ALS therapies, has enrolled its first patients.

The HEALEY ALS Platform Trial (NCT04297683) will start by evaluating UCB’s zilucoplan, Biohaven Pharmaceuticals’ verdiperstat, and Clene Nanomedicine’s CNM-Au8 against a matching placebo. As new investigational products become available, additional regimens will be added to the trial.

HEALEY is being led by specialists at the Healey Center for ALS at Massachusetts General Hospital, and is recruiting adults with sporadic or familial ALS at 54 sites, all part of the Northeast ALS (NEALS) consortium, across the U.S.

“By testing multiple drugs at the same time, this platform trial will dramatically speed our search for effective ALS treatments for everyone living with ALS,” Calaneet Balas, president and CEO of The ALS Association, said in a press release. “The ALS Association is proud to be supporting this effort, and we are grateful to the Healey Center for their leadership.”

Zilucoplan is a small molecule that blocks the C5 protein, a component of the complement system — a set of more than 20 immune proteins — that is abnormally activated in ALS patients. This subcutaneous (under the skin) injection treatment was originally developed by Ra Pharma, which was recently acquired by UCB.

Verdiperstat is an orally administered molecule that reaches the brain and selectively blocks the myeloperoxidase (MPO) enzyme. MPO is believed to increase oxidative stress and inflammation levels in the brain and spinal cord, which are associated with several neurodegenerative diseases, including ALS.

Oxidative stress is an imbalance between the production of potentially harmful free radicals and cells’ ability to detoxify them, which can lead to cellular damage. By suppressing MPO’s activity, verdiperstat is expected to ease these damaging processes and slow disease progression.

“Biohaven continues to advance its novel pipeline across a variety of CNS diseases, and we are so pleased to enroll the first patient in a trial of verdiperstat in ALS. Given the tremendous burden of the disease on people with ALS and their families, more effective treatments are urgently needed,” said Irfan Qureshi, MD, Biohaven’s vice president and verdiperstat’s development lead.

“The HEALEY ALS Platform Trial will allow us to efficiently enroll this trial and determine if verdiperstat has the potential to help people with ALS,” Qureshi added.

Finally, CNM-Au8 is an oral, liquid suspension of gold nanocrystals designed to improve nerve cell survival, function, and communication. It works by supporting these neurons’ bioenergetic cellular reactions, and removing the toxic byproducts of their metabolism.

CNM-Au8 was found to be safe in healthy volunteers, and has shown neuroprotective effects in animal models of ALS and other neurodegenerative diseases. The therapy is currently being evaluated in a Phase 2 trial (NCT04098406) in Australia, with over half of its estimated 42 patients enrolled ahead of schedule.

“We are excited that the HEALEY ALS Platform Trial has begun enrollment of patients, and that the dosing of CNM-Au8, as one of the first three therapies chosen, will begin imminently,” Rob Etherington, president and CEO of Clene, said in a company press release. “This trial will be key in our mission of finding solutions to the progressive neurologic impairment of ALS.”

Those enrolled in HEALEY will be randomly assigned to one of its three treatment regimens. Regimen A (NCT04436497) will investigate subcutaneous zilucoplan, given at daily doses ranging from 0.22 to 0.42 mg/kg; regimen B (NCT04436510) will assess oral verdiperstat, given as 600 mg tablets twice daily; and regimen C (NCT04414345) will study 30 mg or 60 mg daily doses of liquid CNM-Au8.

In each regimen, 160 patients will be randomized in a 3:1 ratio to either the investigative treatment or a placebo, meaning that for every three patients on treatment, one will be given a placebo. Treatment will last 24 weeks.

The main goal of all three regimens is to assess changes in patients’ disease progression using the ALS Functional Rating Scale Revised (ALSFRS-R) score. Secondary measures include respiratory function, muscle strength, and survival.

“I am proud of our collaborators and grateful for the support of this courageous community. We are excited to be at this point and thankful to all teams involved for their invaluable input and support,” said Merit Cudkowicz, MD, MSc, director of the Healey Center and chief of neurology at Mass General.

Two other candidate treatments, Prilenia’s pridopidine and Implicit Bioscience’s IC14 immunotherapy, are expected to be added to the platform trial in the near future. These were among the first five therapies chosen by a group of leading ALS researchers and members of the Healey Center Science Advisory Committee from among 30 applications from 10 countries.

Platform trials have proven successful in the cancer field, and significantly accelerate treatment development by not only allowing simultaneous assessment of multiple therapies, but also by increasing patient access to trials. Costs are also significantly lower and data from placebo groups may be combined, providing stronger results.

“This groundbreaking approach cuts the time to find an effective treatment in half, decreases costs by a third or more, and is supported by our patients, the FDA, ALS clinicians and scientists and our pharma colleagues,” Cudkowicz, lead investigator for  HEALEY, said on the trial’s official website.

“We’re grateful to our supporters and collaborators who have worked tirelessly throughout this pandemic to ensure the trial can begin safely and efficiently,” Cudkowicz added.