NUZ-001 slows decline in ALS lung function, Phase 1 trial shows
NUZ-001 expected to enter HEALEY platform trial later this year, Neurizon says
NUZ-001, which was previously known as monepantel, slowed lung function declines by nearly 50% in people with amyotrophic lateral sclerosis (ALS), according to new analyses from a Phase 1 trial.
This slowing of respiratory declines was strongly correlated with slower declines in overall function that were observed in previous analyses.
Developer Neurizon Therapeutics is using the data to finalize its plans for NUZ-001 to enter the HEALEY ALS platform trial (NCT04297683), which it anticipates will occur in the second half of this year.
Still, that’s pending the U.S. Food and Drug Administration (FDA) lifting its clinical hold on the therapy. Regulators issued the hold earlier this year, citing a need for additional animal studies to establish certain pharmacological properties.
“Over the coming months, the Company will continue to work towards finalising participation in the HEALEY trial … which will include completing the two short-term pharmacokinetic studies required to lift the FDA’s clinical hold,” Michael Thurn, PhD, managing director and CEO of Neurizon, said in a company press release. Pharmacokinetics is the study of how a drug moves into, through, and out of the body.
Common oral deworming agent used in veterinary medicine
NUZ-001 is an oral deworming agent commonly used in veterinary medicine. It has an off-target effect of inhibiting mTOR signaling, which is involved in cell growth and the regulation of autophagy, a cellular process by which unneeded or damaged cellular components are broken down.
It’s thought that by blocking mTOR, NUZ-001 could boost autophagy and enhance the clearance of proteins that toxically accumulate and contribute to neurodegeneration in ALS. Pharmaust was developing the treatment as monepantel, but the name was changed to NUZ-001 when Pharmaust changed its own name to Neurizon last year.
The Phase 1 MEND trial (NCT04894240) tested the daily oral therapy in 12 people with ALS, ages 18-75, at sites in Australia. Participants received either a low or high dose for the first 28 days (about a month), with dose escalations possible every month thereafter.
Data showed disease progression, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), was slowed by 39% with the low dose and 58% with the high dose of NUZ-001 compared with a matched group of untreated participants from the PRO-ACT database, one of the largest repositories of clinical trial data for ALS.
After completing MEND, participants continued to receive NUZ-001 via a compassionate use program, and were later able to enter an open-label extension study (NCT06177431), where all are receiving daily NUZ-001 for up to a year.
Slower ALS progression with NUZ-001 in extension study
Data from the extension study similarly showed slower rates of disease progression and extended survival with NUZ-001 compared with the external control group.
In the recent analyses, lung function declines were compared between the 12 MEND trial participants and the external PRO-ACT control group. These were assessed by the Slow Vital Capacity (SVC) test, which measures the maximum volume of air a person can slowly exhale after a deep inhalation.
Results showed SVC declines were slowed by 48% with NUZ-001 compared with the control group. This correlated with the slowing of ALSFRS-R declines that were previously observed.
Based on these data, the company has selected SVC as a key secondary endpoint in the NUZ-001 arm of the HEALEY ALS platform trial, where ALSFRS-R and survival is a primary endpoint.
“We were excited to learn about the strong correlation between reducing the respiratory function decline rate in patients treated with NUZ-001 and overall functional decline as measured by ALSFRS-R,” Thurn said. “Having supporting positive secondary endpoints greatly increases the likelihood of receiving accelerated approval.”
HEALEY is a U.S.-based study designed to test multiple investigational therapies simultaneously against a shared placebo group, with the intention of speeding the clinical development of potential ALS therapies while cutting costs.
Neurizon working on FDA requests for more data
NUZ-001 was selected for the study last summer. In December, Neurizon filed an application with the FDA seeking clearance to conduct clinical studies of NUZ-001 in the U.S. Regulators placed the application on hold the next month.
To address the FDA’s request for more data, Neurizon is working on starting two short-term animal studies, which it expects will take about four months. It’s also awaiting advice from the FDA about these studies.
Meanwhile, HEALEY recently made certain updates to its study protocol. Should NUZ-001 get clearance for clinical testing from the FDA, it will be evaluated under this revised set of rules. Neurizon believes these changes will help enhance the ability to see a clinically meaningful outcome for patients treated with NUZ-001 in the study.
The company is working on finalizing its regimen-specific appendix under the HEALEY master protocol, a document that includes all relevant details related specifically to the NUZ-001 arm. The document will be submitted to the FDA once the clinical hold is lifted.
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