Tamoxifen Shows Modest Effects in ALS Patients, Phase 1/2 Trial Finds

A cancer treatment called tamoxifen, which previously showed promise in preclinical studies for the treatment of amyotrophic lateral sclerosis (ALS), provides only modest and short-lasting benefits to patients with the disease, a small Phase 1/2 clinical trial has found.

According to the study’s researchers, larger studies and longer observation periods are needed to fully address the effects of tamoxifen in these patients.

The study, “Tamoxifen for amyotrophic lateral sclerosis: A randomized double-blind clinical trial,” was published in the journal Medicine.

Tamoxifen, sold under the brand names Nolvadex and Soltamox, is an approved therapy used to prevent breast cancer, but research has suggested it  also may have neuroprotective effects, controlling multiple processes that are defective in ALS. One such mechanism is autophagy, which cells use to eliminate toxic or unneeded components, including the protein clumps that cause damage to nerve cells in ALS.

In animal studies, tamoxifen was able to slow ALS worsening by activating this cleaning pathway, and was found to be the best among several compounds at preserving nerve cells.

That led to a Phase 1/2 trial (NCT02166944) at Taipei Medical University Shuang Ho Hospital in Taiwan, testing tamoxifen as a potential add-on treatment for ALS.

The trial enrolled 18 patients, ages 20–65 years, who could still breathe independently and had no mutations in the FUS or SOD1 genes. They were randomly assigned 20 mg tamoxifen or a placebo, while continuing to receive their standard Rilutek (riluzole) treatment.

Participants were assessed at one, three, six, and 12 months after entering the trial. The main goal was to determine if adding tamoxifen to the standard care could extend the time patients lived without needing mechanical ventilation.

Secondary measures included differences in the decline in ability to perform daily functions — assessed via revised ALS functional rating scale (ALSFRS-R) scores — and in lung function, measured through forced vital capacity (FVC).

Over the one year of treatment, six patients withdrew from the trial, including one woman in the tamoxifen group who experienced progression of an ovarian cyst, and five patients — one on tamoxifen, four on placebo — who perceived a subjective progression in their ALS symptoms.

Of those who remained, one patient on placebo became dependent on mechanical ventilation, another on placebo died, and one on tamoxifen died 11 months after enrollment due to disease progression. While this suggested a benefit from tamoxifen, the results did not reach statistical significance — likely due to the small number of patients included in the analysis.

The decline in ALSFRS-R scores was lower among those on tamoxifen for the first three visits — at months one, three, and six – compared to patients on placebo. This effect, however, appeared to be temporary, and no differences were observed at the one-year visit.

Lung function declines were similar between tamoxifen and placebo-treated patients across the entire study.

“Despite the compelling positive report in the transgenic TDP-43 overexpression animal model, the results of the present clinical trial showed only modest and transient beneficial effects in the tamoxifen group compared with the placebo group,” the researchers wrote.

They caution, however, that the trial included a small patient sample and followed participants for a very short period before starting the therapy, which prevented them from examining the effects of tamoxifen on the rate of disease progression.

The study’s results also may have been influenced by those who stopped treatment and by not being able to conduct follow-up assessments on those who died or required mechanical ventilation between screening and enrollment.

Researchers further suggest the possibility that treatment with tamoxifen took place at a disease stage when most neurons have been lost, and that activating autophagy at that time may not bring meaningful benefits to patients

Additional trials are now warranted to address these questions.