FDA Gives OK to HEALEY ALS Platform Trial Testing Zilucoplan, CNM-Au8, and Verdiperstat

The U.S. Food and Drug Administration (FDA) has authorized the evaluation of the first three candidate therapies for amyotrophic lateral sclerosis (ALS) in the HEALEY ALS Platform Trial.

This trial model, designed to accelerate the development of ALS therapies by assessing multiple treatment candidates simultaneously, is the first of its kind in ALS. It will start by evaluating Ra Pharma’s zilucoplan, Clene Nanomedicine’s CNM-Au8, and Biohaven Pharmaceuticals’ verdiperstat.

The trial, which will be conducted across some 54 U.S. centers, was launched in September at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.

“Obtaining a ‘May Proceed’ notice from the FDA means there are no major issues with the study and the FDA agrees that we can move forward with the first three experimental treatments to be tested,” Sabrina Paganoni, MD, PhD, a co-lead investigator for the HEALEY ALS Platform Trial and a physician researcher at the Healey Center, said in a press release.

“This is a crucial step in providing more access and more options for people with ALS,” she said.

Zilucoplan, administered under the skin (subcutaneously), is a small molecule that blocks a component called the C5 protein that plays a role in the complement system — a part of the immune system that has been shown to be abnormally activated in ALS patients.

In Ra Pharma’s press release, Doug Treco, PhD, president and CEO, said the company’s scientists “look forward” to assessing zilucoplan’s therapeutic potential in ALS. There is “substantial data supporting the role of central and peripheral complement activation” in this disease, Treco said.

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

A Phase 1 clinical trial (NCT02755870) found CNM-Au8 to be safe in 86 healthy volunteers. In preclinical studies, the therapy showed neuroprotective effects while improving the motor function in rodent models of ALS, multiple sclerosis, and Parkinson’s disease.

“We believe Clene’s involvement in this trial has the potential to make a substantial impact in the ALS community,” Rob Etherington, Clene’s president and CEO, said in a separate press release. He anticipates that the trial’s participants will start to receive CNM-Au8 during this year.

The therapy’s safety and effectiveness is currently being evaluated in up to 42 ALS patients enrolled in the Phase 2 RESCUE-ALS study (NCT04098406), which has already dosed its first patient.

Verdiperstat is an orally administered molecule that was shown to reach the brain and selectively block 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 ameliorate these damaging processes and slow disease progression.

“The HEALEY ALS Platform Trial has achieved this key milestone very swiftly, highlighting how it is accelerating drug development for ALS,” Irfan Qureshi, MD, Biohaven’s vice president and development lead for verdiperstat, said in the company’s press release.

“We look forward to rapidly and efficiently studying whether myeloperoxidase inhibition with verdiperstat offers a novel and effective treatment option for people living with ALS,” he said.

In the trial, participants will be randomly assigned to one of three groups: the zilucoplan group, the CNM-Au8 group, or the verdiperstat group.

According to Ra Pharma, the zilucoplan group will include 160 ALS patients who will be randomly selected in a 3:1 ratio to receive daily subcutaneous (under-the-skin) doses of either zilucoplan (0.3 mg/kg) or a placebo, for 24 weeks. After completing the trial, the participants will have the option to enter an open-label extension study in which all patients will be given zilucoplan.

More details on the CNM-Au8 and verdiperstat groups were not yet disclosed.

The trial’s primary goal is to assess changes in patients’ disease progression using the ALS Functional Rating Scale Revised (ALSFRS-R) score. It also will include several promising biomarkers and outcome measures aimed at developing new tools to evaluate the effectiveness of ALS therapies.

Before officially opening enrollment, the trial still needs to be approved by the central Institutional Review Board (IRB) and clinical sites need to be trained on the study’s protocol. In addition, other matters regarding treatment distribution, safety monitoring, and biomarker development still need to be decided.

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

The platform trial will continue to add candidate treatments until safe and successful ALS therapies are found.

This model, already proven successful in the cancer field, accelerates therapies’ development not only by allowing the simultaneous evaluation of several therapy candidates, but also by increasing patients’ access to trials. Testing multiple therapy candidates at the same time also decreases costs by rapidly determining the effectiveness of each treatment. In addition, the results from all patients receiving a placebo in each group can be combined, ultimately leading to stronger data.