Utreloxastat (PTC857), an investigational therapy for people with amyotrophic lateral sclerosis (ALS), was safe, well tolerated, and showed promising drug properties in healthy people, according to an initial Phase 1 study in humans.
Based on these results, the therapy’s developer, PTC Therapeutics, has initiated a Phase 2 study (NCT05349721) to evaluate it in up to 258 adults with ALS, aged 18 to 80 years. Recruiting is ongoing at sites in California, Florida, Kansas and Texas.
The Phase 1 study results were shared in the “First-in-Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15-Lipooxygenase Inhibitor for the Treatment of Amiotrophic Lateral Sclerosis” study, which was published in Clinical Pharmacology in drug development.
Nerve cells that control muscle movement, called motor neurons, are lost in ALS, leading to symptoms of muscle weakness that affect motor function, speech, swallowing, and ultimately breathing.
A central mechanism underlying motor neuron loss is oxidative stress, cellular damage caused by an excess of highly reactive oxygen-containing molecules generated by normal cellular processes. Oxidative stress increases the production of an enzyme called 15-lipoxygenase (15-LO), triggering several processes known to contribute to motor neuron death.
Utreloxastat is designed to block the action of 15-LO, further reducing oxidative stress, preventing motor neuron death, and slowing or preventing disease progression. So far, promising preclinical studies in multiple animal models have supported further evaluation of the therapy in human clinical trials.
PTC has launched a first-in-human clinical study to evaluate the safety, tolerability, and pharmacokinetics (PK) of utreloxastat—how it moves in, through, and out of the body—in healthy participants.
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SAD, MAD and food studies
The Phase 1 process had three parts. Part 1 was a single ascending dose (SAD) study that included 40 people (19 men, 21 women). Participants were randomly divided into four groups of 10 with eight in each group receiving a single dose of utreloxastat (100, 250, 500, or 1,000 mg) and two receiving a placebo.
A medium-fat breakfast was provided prior to dosing, and blood samples were collected before and at several points after exposure.
At all doses, utreloxastat exhibited dose-dependent increases in peak concentrations, which were observed in the blood stream approximately four hours after dosing. Half-life, the time it takes for utreloxastat levels to decrease by half, was constant across all doses, ranging from about 22 to 25 hours.
Part 2 was a multiple ascending dose (MAD) study with 30 people (19 men, 11 women) who were randomly divided into three groups of 10 to receive 14 days of treatment. Participants received utreloxastat at a dose of 250 mg twice daily, 500 mg once daily, 150 mg twice daily/once daily, or a placebo.
After multiple doses, the rate at which utreloxastat entered the bloodstream and the time it took to reach maximum levels were similar to those with the first doses. In the 250 mg twice daily and 500 mg once daily groups, concentrations approached continuous exposure after seven consecutive days of dosing.
Part 3 tested the impact of food on the pharmacological properties of utreloxastat in 12 people after a single dose (500 mg) under fasting, low- and high-fat conditions.
Utreloxastat was absorbed into the bloodstream faster with food, but food did not alter the time to reach peak levels or the elimination of the drug from the body. There were no differences in exposure between male and female participants, regardless of food intake.
After a single dose of up to 1,000 mg and multiple doses for 14 days, no marked safety signals were reported. All side effects were considered mild and resolved by the end of the study. There were no deaths or serious treatment-emergent side effects leading to discontinuation. No abnormal ECG readings were found for cardiac function.
During the MAD study, levels of high-density lipoprotein (HDL) — known as good cholesterol — and total cholesterol followed a dose-dependent decrease after multiple doses of utreloxastat, but those decreases reversed when exposure she broke off. No clinically significant side effects were associated with these observations.
“These PKs [pharmacokinetics] and the safety data indicate that utreloxastat is an appropriate candidate for further development for the treatment of ALS,” the researchers wrote.
The ongoing Phase 2 study, called CARDINALS, will examine whether utreloxastat, given twice daily (250 mg) for 24 weeks (about six months), outperforms a placebo in slowing progression.
The primary goal is to determine functional decline, as assessed by changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary measures include safety, changes in lung function, muscle strength, cognition, and quality of life, as well as time required for respiratory support and survival.
Those who complete CARDINALS can participate in an open-label extension study and continue receiving utreloxastat for 28 weeks (approximately seven months).
