Results published for first 4 drugs in HEALEY trial; 2 to be tested further
CNM-Au8, pridopridine now moving toward Phase 3 studies
Four experimental treatments for amyotrophic lateral sclerosis (ALS) have been tested in the HEALEY ALS platform trial and two, CNM-Au8 and pridopidine, have shown promising results and are moving toward Phase 3 testing.
The others, zilucoplan and verdiperstat, failed to show any benefit and are no longer in development. Full data from the four treatment arms has been published in four studies.
The HEALEY ALS trial (NCT04297683) is designed to test multiple treatments at once and compare the results against a pooled placebo group. This lets treatments be tested faster, with fewer participants given the inactive placebo.
The first arms of HEALEY included 161-170 patients, and only about 1 in 4 (40-42 patients) got a placebo. The rest received the experimental treatments. The study is being led by Massachusetts General Hospital (MGH).
“Recent progress in the clinical sciences has fueled a large pipeline of drugs for ALS that are waiting to be tested,” Sabrina Paganoni, MD, PhD, co-director of the Neurological Clinical Research Institute at MGH, said in a press release from the hospital. “For a quickly progressing disease like ALS, trials need to be extraordinarily efficient to bring drugs to patients as rapidly as possible. A platform trial is the perfect approach for doing this.”
Merit Cudkowicz, MD, principal investigator of HEALEY ALS, said the study’s design “has been shown to reduce the time to find an effective treatment by half and decrease costs by a third or more.” The study “unites patients, clinicians, scientists and industry partners,” Cudkowicz said.
Improved survival odds with CNM-Au8
CNM-Au8 is an oral therapy developed by Clene Nanomedicine. It’s designed to boost nerve cells’ energy production, the impairment of which has been implicated in ALS’s development and progression. In HEALEY, patients were given CNM-Au8 at doses of either 30 or 60 mg, or a placebo.
Results from the CNM-Au8 arm of HEALEY were published in JAMA, in a paper titled, “CNM-Au8 in Amyotrophic Lateral Sclerosis The HEALEY ALS Platform Trial.”
The main goal was to see if CNM-Au8 slowed disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R), and survival. The study didn’t meet its goal; no difference was seen in ALSFRS-R decline or survival rates for patients given CNM-Au8 or a placebo after 24 weeks.
Some promising results were seen, however. Exploratory analyses indicated survival odds were significantly better for patients given the lower dose than for those given a placebo. Data also suggested that those given CNM-Au8 tended to be less likely to need interventions like feeding tubes or invasive ventilation.
CNM-Au8 also was associated with reduced markers of nerve damage relative to the placebo, which the U.S. Food and Drug Administration has said may serve as a basis for accelerated approval of the experimental therapy. The therapy was generally safe, with no serious side effects reported. A Phase 3 study that hopes to confirm if CNM-Au8 treatment can extend survival is in the works.
Pridopidine’s effect on speaking ability
Pridopidine, which is being developed by Prilenia Therapeutics, is intended to activate a receptor tied to nerve cell protection. Results from the pridopidine arm of HEALEY also were published in JAMA, in the paper, “Pridopidine in Amyotrophic Lateral Sclerosis The HEALEY ALS Platform Trial.”
Like the CNM-Au8 arm, the main goal with pridopidine was to assess the impact of treatment on disease progression. The study also failed to reach that goal, though some promising data were seen.
Specifically, data suggested pridopidine-treated patients retained better speaking abilities than those given a placebo. Speech is often impacted by ALS and the researchers noted that “the critical importance of speech to ALS patients is well recognized.” Data also suggested a possible slowing of disease progression in a subset of patients with rapidly-progressing disease who started treatment soon after their diagnosis. Based on these data, Prilenia has announced plans for a Phase 3 trial to evaluate the therapy further.
Disappointing results
Results for verdiperstat and zilucoplan were more disappointing. The findings for verdiperstat were published in JAMA Neurology in the paper, “Verdiperstat in Amyotrophic Lateral Sclerosis Results From the Randomized HEALEY ALS Platform Trial,” and the findings for zilucoplan in JAMA Network Open, in the paper, “Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis A Randomized Clinical Trial.”
Both studies failed to show any meaningful effect and the drugs’ development has been discontinued. Three other drugs tested in HEALEY, SLS-005, DNL343, and fosigotifator, also failed to hit their main goals, though some promising trends were seen with fosigotifator and further analyses are ongoing.
“These four papers and the initial few years of the platform trial have shown that when people work together, they can achieve more,” said Suma Babu, who co-led the verdiperstat arm. “An answer for ALS will not come from one source, but from a larger ecosystem that unites the different pieces that are needed to bring change. There is hope, and there are people working hard to cure this complex disease in the best and most efficient way.”
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