Emerging tool
In patients with ALS, neurofilament concentrations typically increase as the disease progresses. However, this study documented a reduction in these CSF concentrations. “One interpretation of that could be that there is less neurodegeneration or neuro injury” in patients treated with tofersen, Dr. Ferguson said.
He noted that neurofilament is “an emerging tool” for understanding neurodegeneration. It could also “be another sort of biochemical signal that the molecule is doing something important,” he added.
However, he noted that neurofilament concentration is still an exploratory marker.
Exploratory analyses suggested a possible slowing of functional loss, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R) score and the handheld dynamometry megascore. The latter assesses strength in 16 muscle groups in the arms and legs. The investigators noted that no conclusions can be drawn from these outcomes.
A post hoc analysis showed that among patients with SOD1 mutations associated with a fast-progressing disease course, the slope of clinical decline might have been gentler, and there was a greater decrease in CSF neurofilament concentration compared among those whose disease followed a slower course.
This suggests that “if you pick the right target,” even patients with severe disease can be treated, Dr. Ferguson said.
He acknowledged that in a relatively short study such as this one, it may be easier to see benefits in patients whose disease is progressing rapidly. However, he’s convinced that the treatment “would work for all SOD1 ALS patients, not just fast patients.”
Dr. Ferguson said the study investigators are encouraged by the new data, which “really suggest that we may be developing a meaningful treatment for SOD1 ALS.” However, “it’s still early” in terms of rolling out this therapy for patients with ALS, he said.
The safety and efficacy of tofersen are currently being evaluated in a phase 3, randomized, double-blind, placebo-controlled trial.
Limitations of the current study were the small number of participants, the short duration of treatment and follow-up, the exploratory nature of efficacy outcomes, and the post hoc methods for defining the fast-progressing subgroup.
Although an advantage of tofersen is that it can enter the nucleus of the cell, perhaps boosting effectiveness, a drawback might be that patients need several treatments administered via lumbar puncture. Following three initial doses, the drug is given every month.
An alternative approach might be a viral vector approach.
“Stunning” finding
In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.
The aim of the viral vector therapy is to continually suppress mutant gene activity, said study co-investigator Robert H. Brown, Jr, MD, professor of neurology, University of Massachusetts Medical School, Worcester.
“The virus essentially drops off a piece of DNA, and that DNA keeps making the agent that suppresses the gene,” Dr. Brown said.
He noted that the first patient had a mutation that causes a rapidly developing, “horribly devastating” disease.
Initially, the patient’s right leg, in which movement had been worsening over several weeks, “seemed to get stronger and remain strong for quite a long time. I’ve never seen that in this kind of mutation,” said Dr. Brown.
The patient died of ALS. At autopsy, there was evidence of suppression of SOD1 in the spinal cord. There was some preservation of motor neurons on the right side of the spinal cord, which Dr. Brown called a “stunning” finding.
“We have never seen preservation of motor neurons in an autopsy of a patient with this kind of mutation before,” he said.
Prior to the patient’s death, there were some initial signs of a decrease of SOD1 in CSF. However, the patient developed an inflammatory response in the lining of the CSF known as meningoradiculitis.
“In that setting, the SOD1 level went back up, so we could not say that we produced a significant lasting decrease,” Dr. Brown said.