By Pantelis P. Pavlakis, MD, PhD
Assistant Attending Neurologist, Hospital for Special Surgery, and Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease without available treatments that significantly alter the disease course. Using Medicare databases and pharmacy records, with multiple logistic regression models, researchers studied three candidate drugs (lovastatin, sulfasalazine, and telmisartan) that were identified as possible therapies for ALS and their effects on SOD1G93A transgenic mice. Animal testing showed a delay in disease onset and prolonged survival in mice treated with a mouse-equivalent dose of lovastatin 40 mg, but showed no benefit from the other two candidate drugs.
SOURCE: Kreple CJ, Searles Nielsen S, Schoch KM, et al. Protective effects of lovastatin in a population-based ALS study and mouse model. Ann Neurol 2023;93:881-892.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by relentlessly progressive weakness leading to death within two to five years. So far, available therapies have not been shown to have a meaningful effect in altering the disease trajectory and prolonging survival. Identification of novel drugs usually is based on animal studies, the results of which are translated into human clinical trials. In this study, the authors sought to identify novel candidate treatments for ALS via reverse translation; candidate drugs were identified by population-based studies and then tested for efficacy on animal models of the disease.
Incident cases of motor neuron disease (MND) in 2009 were identified by the Centers for Medicare and Medicaid Services; patients who had Medicare Part D pharmacy services and were age-eligible for Medicare by 2007 were included, as were matched controls. Medication prescriptions from the beginning of 2006 through the end of 2007 were recorded.
Using 24 different logistic regression models, the relative risk of developing MND was estimated, comparing patients who received or did not receive each medication. Medications that were no longer Food and Drug Administration-approved, administered topically, not administered chronically, or previously tested in ALS were excluded. Among the remainder candidate drugs, three drugs were chosen based on the strength of epidemiologic results and possible biological mechanisms of each drug’s efficacy based on the available literature.
After applying inclusion and exclusion criteria, 1,128 incident cases of MND and 56,400 controls were identified. Similar to prior studies, MND was associated with dementia, depression, and smoking and inversely associated with type 2 diabetes and uric acid levels. Among 278 candidate medications, three medications were selected for further testing: lovastatin, sulfasalazine, and telmisartan.
There was an aggregate 7% risk reduction with use of antihyperlipidemic agents, which was not statistically significant. However, the risk reduction tended to increase with increased dose of different antihyperlipidemic agents and was greater with 40 mg of lovastatin daily (28% risk reduction). Risk reduction for MND was greater among patients with ischemic heart disease and/or diabetes treated with 40 mg of lovastatin daily.
SOD1G93A transgenic mice were used for the animal studies. Candidate medications or placebo was administered from day 58 of life by a subcutaneous infusion pump. Animal survival, weight, and gait were tested. On day 100, the animals were euthanized and underwent histopathological studies.
Mice treated with telmisartan (n = 9) and sulfasalazine (n = 7) showed similar latency to onset of paretic gait, degree of weight loss, and survival compared to placebo. Mice treated with lovastatin showed increased median survival (141 vs. 151 days, P = 0.03), delay in onset of paretic gait (126 vs. 130 days, P = 0.006), and delay in onset of weight loss (130 vs. 146 days, P = 0.03). These findings were reproduced when tested in a larger sample of mice. Lovastatin-treated mice had significantly higher staining for choline acetyltransferase-positive motor neurons in the ventral horn of the spinal cord and significantly less staining for misfolded SOD1 compared with mice treated with placebo.
COMMENTARY
The results of this study suggest a benefit of daily use of lovastatin 40 mg, both in terms of risk reduction of developing ALS in a pharmaco-epidemiological study as well as in delay in disease onset and prolonged survival in SOD1G93A transgenic mice treated with an equivalent dose. Apart from its lipid-lowering effects, since elevated low-density lipoprotein has been shown to be a risk factor for ALS, other possible disease mechanisms influenced by lovastatin could be a modulation of neuroinflammation and induction of autophagy with subsequent increased clearance of misfolded SOD1 or other misfolded proteins.
The retrospective design and effects of other possible confounding factors are limitations of this study. These results should be interpreted with caution, since any protective effect of lovastatin may not confer benefit in reducing the disease progression or prolonging survival in ALS patients, which are intriguing questions to be explored further in future studies.
Nevertheless, the reverse translational design of the study is a novel method in rapidly evaluating possible therapeutic agents for diseases such as ALS, where there are no treatments that can significantly alter the disease course.
