AAN 2023: ALS treatments ID’d in HEALEY head toward Phase 3 tests

Testing has been ruled out for two other potential medications

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A graphic of the American Academy of Neurology (AAN) 2023 Annual Meeting.

It’s been nearly three years since the HEALEY platform clinical trial started and, so far, two promising experimental treatments for amyotrophic lateral sclerosis (ALS) have been identified.

Both potential medications — CNM-Au8 and pridopidine — are headed toward Phase 3 clinical testing, while testing has been ruled out for two others.

“Since we launched in the summer of 2020, we’ve had two no-go decisions and moved two drugs to Phase 3 testing,” said Sabrina Paganoni, MD, PhD, a physician-scientist at Massachusetts General Hospital (MGH) and the trial’s co-lead investigator.

Paganoni discussed the findings at this week’s American Academy of Neurology (AAN) 2023 Annual Meeting in the oral presentation, “Results from the First Four Regimens of the HEALEY ALS Platform Trial.”

The HEALEY platform trial (NCT04297683), led by the Sean M. Healey & AMG Center for ALS at MGH, intends to test multiple potential ALS therapies at once, an approach that may help reduce the cost and time associated with drug development.

“A platform trial is a novel approach to trial design. The goal of platform trials is to develop new drugs faster and more efficiently, and we do so by using a common infrastructure or platform,” Paganoni said, noting the platform approach hasn’t been tried before in ALS, but has led to “savings across the board,” including in time, money, and patient resources in cancer studies.

“This is the perfect time for a platform trial in ALS, because like never before we have a very robust and growing drug pipeline and companies are looking for ways to develop their drugs most efficiently,” Paganoni said.

HEALEY encountered obstacles soon after its launch that arose from the COVID-19 pandemic. “As you can imagine, this was challenging because this was at the very beginning of the pandemic, but COVID did not stop ALS trials,” Paganoni said. “In fact, we continued to grow and experienced great enrollment rates.”

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Participation in HEALEY trial

Enrollment has been completed for five potential therapies, including zilucoplan, verdiperstat, CNM-Au8, pridopidine, and SLS-005. The sixth trial arm testing ABBV-CLS-7262 started enrolling last month and the DNL343 arm is expected to begin later this year.

Patients enrolling in the trial don’t choose which treatment arm they’ll enter. They’re randomly assigned to one of the arms that’s enrolling at the time they join.

“When we started the trial, people asked us: ‘Will patients want to enroll in a new type of trial, a platform trial, where they cannot choose the drug they are assigned to?’ And the answer to that is a resounding yes. Patients are eager to learn about and participate in innovative research,” Paganoni said, adding trial sites have also been eager to join. More than 70 clinics across the U.S. are participating in HEALEY.

Paganoni’s presentation covered data from the first four treatment arms, testing the experimental therapies zilucoplan, verdiperstat, CNM-Au8, and pridopidine, respectively.

In each treatment arm, most participants were given the investigational drug while a few were given a placebo. Because each treatment arm uses the same eligibility criteria, data from patients given each treatment can be compared with data from those given a placebo across all arms of the study.

The main goal of each treatment arm is to compare the effect on survival and disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R), after six months.

Researchers also regularly carried out interim analyses to test for futility — in other words, statistical tests based on available data to check if there was a reasonable likelihood the therapy may provide a benefit for patients.

Disappointment with zilucoplan, verdiperstat

The first treatment arm for zilucoplan ended early after futility analyses showed it was unlikely to be beneficial.

“While this was disappointing, it actually in a way met the goals of the trial, which is really to screen out drugs rapidly. So we were able to end this regimen early, saving months of operational activities,” Paganoni said.

Data from the second arm showed verdiperstat failed to significantly slow ALS progression and that arm has also been discontinued.

Findings from the third and fourth trial arms have been more promising, however.

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CNM0Au8, pridopidine move toward Phase 3 testing

Data from the third arm suggested CNM-Au8, at a daily dosage of 30 mg, significantly reduced the risk of death and the combined risk of death or permanent assisted ventilation by more than 90%. Recent analyses also suggested CNM-Au8 delayed clinical worsening. The treatment is designed to boost energy production in the nervous system.

Long-term data from a separate Phase 2 trial, RESCUE-ALS (NCT04098406) and its open-label extension (NCT05299658), indicated early CNM-Au8 treatment may slow disease progression and reduce the risk of death. Findings from early clinical trials of CNM-Au8 in multiple sclerosis (MS) have also been promising.

“With this growing body of evidence, we are increasingly confident that CNM-Au8 has an effect across neurodegenerative diseases, such as ALS and MS, providing a potential treatment option with a novel and complementary mechanism of action for the patient community,” Rob Etherington, president and CEO of CNM-Au8’s developer Clene Nanomedicine, said in a company press release.

In the fourth arm, pridopidine failed to show an effect on ALSFRS-R scores or survival outcomes in the overall group, but promising trends were seen for patients with early, rapidly progressing disease.

Pridopidine also significantly improved objective measures of speech function in a pre-specified analysis.

“This was of great interest to us because of the mechanism of action of pridopidine,” Paganoni said, noting the therapy is thought to act on a type of protein involved in regulating mouth and throat functions.

Pridopidine’s developer Prilenia Therapeutics recently announced positive data from a Phase 3 study testing pridopidine in Huntington’s disease (HD).

“Pridopidine showed encouraging results for the potential treatment of ALS that deserve further exploration,” Merit Cudkowicz, MD, the HEALEY trial lead investigator, said in a press release from Prilenia.

“The impact of pridopidine on rater-independent speech measures was especially notable … Speech is a highly clinically relevant endpoint in ALS studies and more than 80 percent of ALS patients become speech impaired, which significantly impacts their quality of life,” said Cudkowicz, the director of the Healey & AMG Center and chief of the department of neurology at MGH.

The CNM-Au8 and pridopidine arms are still collecting more long-term data. Clene is working to launch a Phase 3 study of CNM-Au8 and Prilenia is exploring Phase 3 ALS testing of pridopidine.

“Clene now awaits important new biomarker data from both the double-blind and open label periods of the HEALEY ALS Platform Trial … These data will help determine our regulatory filing strategy,” Etherington said. “In parallel, Clene plans to meet with the FDA in an end of Phase 2 meeting during the third quarter of 2023 to discuss the regulatory path forward for CNM-Au8 in ALS.”