Declines in motor function seen in SBMA despite long-term leuprorelin
But slower disease progression seen for patients with less initial disability
Despite treatment with leuprorelin over three years, all spinal and bulbar muscular atrophy (SBMA) patients in a study in Korea continued to experience declines in motor function, a new study found.
However, those individuals with less disability at the start of treatment experienced slower disease progression, “indicating a more favorable prognosis,” according to the researchers.
Additionally, data showed that patients who consistently stayed on the therapy — which is widely used to treat certain hormone-related conditions and cancers — for the entire three years saw slower functional declines than those who stopped treatment early.
“Randomized controlled trials are imperative to validate our findings and provide deeper insights into the optimal treatment strategies for individual SBMA patients,” the researchers concluded.
The study, “Efficacy of leuprorelin in spinal and bulbar muscular atrophy: a 3-year observational study,” was published in Neurological Sciences.
Leuprorelin typically used to treat breast, prostate cancers
Also known as Kennedy’s disease, SBMA is a rare adult-onset type of spinal muscular atrophy (SMA) characterized by weakness and wasting in the muscles of the face, mouth, and throat — the bulbar muscles — as well as the limbs.
It is caused by mutations in the AR gene that lead to the production of an unusually large androgen receptor protein, called an AR protein, that has an abnormal structure and accumulates in cells. It’s not exactly known how, but this is associated with damage to the specialized nerve cells needed for muscle control.
ARs are involved in mediating the effects of male sex hormones (androgens), such as testosterone. It has been suggested that testosterone-associated toxicity may be involved in SBMA, and thus, approaches to reduce testosterone production have been proposed as a possible treatment strategy.
Leuprorelin is a medication that mimics the activity of a hormone called gonadotropin-releasing hormone. While this initially boosts testosterone production, over time, the receptor proteins on which leuprorelin acts become desensitized, and testosterone is reduced. Commonly used to treat conditions such as breast and prostate cancers, the medication also is approved in Japan for the treatment of SBMA.
Preclinical studies showed that leuprorelin improved motor function and lowered levels of the abnormal form of AR in a mouse model of SBMA. Importantly, however, such benefits have not been as pronounced in clinical trials involving SBMA patients, according to the researchers.
In this observational study, conducted at a single center in Korea between January 2018 and December 2022, scientists aimed to examine the long-term effects of leuprorelin treatment on motor function among SBMA patients.
A total of 48 adults with SBMA, ages 30-75, were started on leuprorelin, administered via subcutaneous or under-the-skin injections once every 12 weeks, or about once every three months. Among them, 39 completed three years of treatment; nine discontinued treatment earlier than the three-year mark.
Consistent with its known mechanism, testosterone and related hormones were significantly decreased after three years of treatment.
Patients who stuck with treatment had better results than those who quit
The study’s main goal was to evaluate the therapy’s effects on functional disability, as assessed by scores on the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). Ranging from 0 to 56, lower scores on this measure reflect more significant impairment.
The results showed that SBMAFRS scores significantly decreased from a mean of 41.72 at the start of treatment, known as baseline, to 36.74 after three years of leuprorelin. These declines were similarly observed across all of the SBMAFRS subdomains, or assessment areas, including those related to upper extremity, trunk, lower extremity, respiratory, and bulbar function.
Patients also experienced significant worsening in a measure of functional disability normally used for amyotrophic lateral sclerosis patients, as well as reductions in exercise capacity over three years.
The researchers concluded, therefore, that reductions in testosterone levels with leuprorelin “might not necessarily lead to direct enhancements in functional outcomes for patients.”
Still, patients who completed three years of treatment were found to experience slower declines in SBMAFRS scores than did those who stopped treatment early — indicating a possible therapeutic benefit of long-term treatment, according to the team.
“The disparity in results between the leuprorelin and early-discontinuation groups underscores the importance of consistent treatment adherence,” the researchers wrote.
Moreover, despite general declines in function, patients in the leuprorelin group with higher baseline SBMAFRS scores — of at least a 42 — saw slower functional declines than did patients with baseline scores of 41 or lower.
Patients with a higher overall SBMAFRS score [indicating less functional disability] may respond more favorably to leuprorelin treatment than would those with lower scores.
At a cut-off of 41.5, baseline SBMAFRS scores were found to have a moderate ability to predict SBMA prognosis.
“Patients with a higher overall SBMAFRS score may respond more favorably to leuprorelin treatment than would those with lower scores,” the researchers wrote, noting that SBMAFRS “may be a valuable tool for stratifying patients and personalizing therapeutic interventions.”
Because less-affected patients seemed to respond better to the therapy, the findings also emphasize the importance of early diagnosis and treatment in SBMA, according to the scientists.
No significant adverse events related to leuprorelin were observed over three years of treatment. The nine people who stopped treatment early did so due to disease progression not related to side effects. The most common side effects included hot flush (42%) and impotence (38%).
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