Novel Agent Safe in ALS, Phase II Study Suggests

Tetramethylpyrazine nitrone was safe for people with amyotrophic lateral sclerosis (ALS), but neither a high nor low daily dose of the drug outperformed placebo for the primary outcome in a phase II trial in China.

At 180 days, changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores were similar with low-dose (mean difference -0.89 points, 95% CI -3.25 to 1.48) and high-dose tetramethylpyrazine nitrone (mean difference -0.20 points, 95% CI -2.48 to 2.07) compared with placebo, reported Dongsheng Fan, MD, PhD, of Peking University Third Hospital in Beijing, and co-authors.

However, there was a slower decline in grip strength with high-dose tetramethylpyrazine nitrone (mean difference 2.46 kg, 95% CI 0.15-4.76), the researchers noted in JAMA Network Open.

In a subset of patients younger than 65 with slower disease progression, high doses of the drug slowed declines in grip strength (mean difference 3.63 kg, 95% CI 0.84-6.41), bulbar scores (mean difference 0.66 points, 95% CI 0.03-1.29), and respiratory scores (mean difference 0.54 points, 95% CI 0.03-1.06).

Adverse events were mostly mild or moderate. No severe treatment-related adverse events or deaths were seen.

“These findings demonstrate that tetramethylpyrazine nitrone is safe and may have potential benefits in slowing the decline in grip strength, although its impact on the primary outcome measure was not statistically significant,” Fan and colleagues wrote.

Currently, three ALS drugs are on the market — riluzole (Rilutek), edaravone (Radicava), and tofersen (Qalsody) — but their clinical benefits are limited, the researchers noted.

“The exact causes of ALS are not fully understood, but research has suggested multiple contributing factors, including oxidative stress, calcium overload, mitochondrial dysfunction, excitotoxicity, protein aggregation, and neuroinflammation,” they observed.

“A nitrone derivative of tetramethylpyrazine, from the Chinese herb Chuanxiong, shows multifunctional neuroprotective effects by reducing calcium overload, improving mitochondrial function, activating autophagy, and providing anti-inflammatory benefits,” they added. “Importantly, tetramethylpyrazine nitrone has been proven to improve motor dysfunction in various neurodegenerative disease animal models, including ALS.”

The trial assessed 155 ALS patients who had disease onset within 2 years, ALSFRS-R scores of at least 2 points on each item, and forced vital capacity of at least 80%. The ALSFRS-R is a 12-subdomain functionality assessment with scores ranging from 0 to 48; lower scores indicate worse function.

The mean age of the cohort was 55, and 74.2% of participants were men. Patients with severe hepatic and kidney impairment were not included in the study. Treatment with riluzole was permitted, but edaravone was contraindicated.

Overall, 51 people were randomized to low-dose tetramethylpyrazine nitrone, 52 to high-dose tetramethylpyrazine nitrone, and 52 to the placebo group. The low-dose group received oral tablets of 600 mg of tetramethylpyrazine nitrone twice daily; the high-dose group received 1,200 mg twice a day.

“In the slower progression subgroup, high-dose tetramethylpyrazine nitrone significantly decreased the decline in ALSFRS-R bulbar subdomain scores,” Fan and colleagues pointed out.

“Additionally, both tetramethylpyrazine nitrone groups showed significant reductions in the decline of ALSFRS-R respiratory subdomain scores, with placebo-adjusted improvements of 76.1% and 85.9%, respectively,” they continued. “These results suggest that tetramethylpyrazine nitrone may delay the deterioration of bulbar and respiratory function, especially in patients experiencing slow progression.”

Additional clinical trials are needed to confirm the effects seen in this study, they added.

“It’s important to publish results of these types of phase II exploratory studies to help field develop better treatments,” noted ALS researcher Merit Cudkowicz, MD, MSc, of Massachusetts General Hospital in Boston, who wasn’t involved with the trial.

“The study was well done — blinded, with good follow-up and retention of participants. The primary goal was safety and this was established, with other goals to look at clinical effects,” she told MedPage Today. “The study selected relatively slow progressing participants and did not see a benefit of the therapeutic intervention during the 180 days.”

A limitation was that the study did not include markers of oxidative stress or neurodegeneration, “so we do not know fully if the drug targets were sufficiently targeted,” Cudkowicz noted. “This is a common challenge for phase II trials in neurodegenerative disorders because of the paucity of those types of biomarkers.”

The trial did not assess serum or cerebrospinal fluid neurofilament light chain, the researchers acknowledged. It also did not evaluate tetramethylpyrazine nitrone in a broader cohort of patients with advanced-stage ALS.

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