Promising Results for Investigational Treatments for Inherited ALS

Two preliminary studies were published simultaneously in the New England Journal of Medicine, both aimed at reducing superoxide dismutase 1 (SOD1) protein levels in people who had amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.

In the first study, a phase I/II trial of intrathecal tofersen, Timothy Miller, MD, PhD, of Washington University in St. Louis, and coauthors treated 48 patients with SOD1-ALS in ascending doses of 20, 40, 60, and 100 mg. Tofersen, an investigational antisense oligonucleotide, binds to SOD1 mRNA, enhancing its degradation and reducing levels of toxic mutant SOD1 protein.

Compared with placebo, the highest doses of tofersen reduced cerebrospinal fluid (CSF) SOD1 concentration from baseline. The reduction from baseline in total CSF SOD1 concentration was 3% in the placebo group and 36% in the group that received 100 mg of tofersen, with reductions in the lower-dose tofersen groups ranging from 1% to 27%.

Patients in the tofersen groups also had greater reduction in neurofilament levels and slower clinical decline on the ALS Functional Rating Scale–Revised.

Lumbar puncture-related adverse effects were seen in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in four and five participants, respectively, who received tofersen. One person who received tofersen died from pulmonary embolus on day 137; one from respiratory failure on day 152. One participant in the placebo group died from respiratory failure on day 52.

“The highest doses of tofersen led to a reduction in SOD1 levels in CSF, indicating target engagement,” Miller and colleagues wrote. “Patients who received tofersen also had reductions in CSF neurofilament levels, which provide indirect evidence of an effect on reducing neurodegeneration.”

“If these findings are confirmed in a phase III trial with longer follow-up, they may lead the way to the first potentially effective disease modifying therapy for a percentage of the ALS population,” noted Orla Hardiman, MD, of Trinity College in Dublin, Ireland, and Leonard van den Berg, MD, PhD, of University Medical Center Utrecht in the Netherlands, in an accompanying editorial.

“In addition, a reduction in neurofilament levels may provide a biomarker for future trials,” they added.

In the second report, Robert Brown, Jr., DPhil, MD, of the University of Massachusetts Medical School in Worcester, and coauthors studied two patients treated with a single intrathecal dose of an adeno-associated viral (AAV) vector containing microRNA shown to degrade SOD1 messenger RNA.

The researchers found no substantial change in CSF SOD1 protein levels, though one patient’s postmortem spinal cord tissue did suggest suppression of SOD1 levels. Clinical efficacy measures were exploratory, and the clinical response in both patients was ambiguous. One developed meningoradiculitis.

“We designed this study to evaluate the safety of the AAV-mediated silencing of mutated genes in two selected patients with ALS. Intrathecal infusion of this viral vector can trigger an adverse inflammatory response, as has been reported in some studies after the intravenous administration of AAV9 in animals,” Brown and colleagues wrote.

“This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS,” they added.

The research led by Brown reflects “the potential for viral-mediated intrathecal microRNA treatment of ALS in patients with SOD1 mutations, but additional work will be required to establish whether biologic and clinical efficacy can be achieved,” the editorialists observed.

“In addition, close attention must be paid to the observation that the viral vector led to meningoradiculitis in the first patient, which prompted the administration of immunosuppressive drugs in the second patient,” they added.

Together, the two studies show a precision-medicine approach to the treatment of neurodegenerative conditions associated with single mutated genes may be within reach, the editorialists pointed out.

“But the studies were not powered to provide evidence of efficacy, and the prediction of rates of progression based on the slope of the functional-status scale, a metric widely used in ALS trials, may not be accurate,” they noted. “The use of improved statistical models that incorporate multiple prognostic factors would be useful in the future.”

Overall ALS incidence is 1 to 3 people per 100,000 (lifetime risk of 1 in 300-1,000) with sporadic and familial forms. Familial forms are estimated to account for 5% to 23% of cases, most autosomal dominant. Multiple genetic causes have been identified, including C9ORF72, TARDBP, and SOD1. “Therapies for other genetic forms of ALS are in early clinical and preclinical phases,” the editorialists noted.

SOD1-associated ALS is autosomal dominant and dominated by lower motor neuron dysfunction; upper motor neuron signs are minimal and frontotemporal dementia is rare. In mouse models of SOD1 ALS, decreasing levels of mutant SOD1 have extended survival.

The present studies “signal a new beginning for ALS therapeutics in which some forms of the disease may become treatable,” Hardiman and van den Berg said. “By starting with subgroups with specific genomic features, investigators are providing new hope for patients at genetic risk for this devastating fatal disease.”

Limitations of these studies include their lack of power to determine efficacy. The treatments also are for SOD1-related ALS (which represents 2% or less of ALS) and generalizability to other forms is uncertain.

Safety and efficacy of tofersen currently are being evaluated in a phase III trial and long-term extension study of patients with SOD1-ALS.

1. In a phase I/II study of patients who had amyotrophic lateral sclerosis (ALS) due to SOD1 mutations, the investigational drug tofersen, an antisense olignucleotide, reduced cerebrospinal fluid SOD1 compared with placebo.

2. In a separate pilot study of microRNA shown to degrade SOD1 messenger RNA delivered in a viral vector to two ALS patients with SOD1 mutations, clinical results outcomes were exploratory and ambiguous.

Paul Smyth, MD, Contributing Writer, BreakingMED

Cat ID: 130

Topic ID: 82,130,730,130,192