An experimental drug for amyotrophic lateral sclerosis missed the main goal of a late-stage clinical trial, marking another setback in attempts to treat the debilitating and deadly disease.
Developed by Biogen and Ionis Pharmaceuticals, the drug, called tofersen, is meant to treat a rare, inherited form of ALS. But results presented Sunday show tofersen wasn't any better than placebo at slowing progression of the disease, as measured by a scale that evaluates how ALS patients breathe, walk and perform other essential and daily activities.
Though the drug failed, Biogen maintains there were also positive findings that justify not yet giving up on it. The company said additional measurements, along with data from a related "extension" study, indicate that treating patients with tofersen early enough led to slower declines in respiratory function, muscle strength and quality of life. Biogen is now engaging with regulators and other stakeholders to discuss next steps.
"I am hopeful and optimistic about tofersen, based on the data we have in hand today," said Tim Miller, the study's principal investigator and a co-director of the ALS Center at the Washington University School of Medicine in St. Louis. Miller has advised and provided clinical research support to Biogen, as well as consulted for Ionis Pharmaceuticals.
Because results on the study's main measure were negative, interpretation of the other results is more complicated and less statistically sound.
But for Miller, one encouraging finding is that tofersen appears to work as intended. The drug was designed to bind to and destroy the genetic instructions for SOD1, a protein that, while normally useful to the body, can progressively damage motor neuron cells when it misfolds. It's estimated that 2% of all ALS cases are caused by mutations in the gene that makes SOD1 protein.
Biogen's study enrolled 108 ALS patients with these mutations and classified their disease as either "slower-" or "faster-progressing." Results showed that after 28 weeks of treatment with tofersen, the amount of SOD1 protein in the cerebrospinal fluid — the liquid surrounding the brain and spinal cord — decreased 26% and 38%, respectively, in these two groups versus participants who were given a placebo.
Tofersen-treated patients also experienced substantial reductions in neurofilament light chain, a protein that provides structure to nerve cells and that signals neurological damage when levels in the blood and cerebrospinal fluid are elevated. Compared to the placebo group, the slow- and fast-progressing patients on tofersen experienced 48% and 67% declines in their plasma neurofilament.
"There's a clear clinical signal here," Miller said.
Still, those effects did not translate into significantly better outcomes for patients in the study. Its main measure looked at fast-progressing patients, using a 48-point questionnaire to assess any changes in the severity of their disease. On that scale, tofersen-treated patients had worsening scores that were only 1.2 points off from those in the placebo group.
Miller acknowledged this result, but argues it could have to do with factors beyond tofersen's effectiveness. The drug may have to be given to patients earlier and for a longer amount of time to see an effect on patients' function, for example.
"I still remain 100% confident that SOD1 is the right target. I think that is what's causing their disease," Miller said.
"It's not that it looks a little bit better on respiratory but not on others," he added. "Across all of the data points, all of the measures we looked at, there's consistency. If this were all noise, I'd expect that to fade away. If this were noise, I'd expect that on some measures tofersen would look better, and on some measures placebo would look better."
Biogen and Ionis investors don't seem as confident, though, as shares in the companies respectively fell 3% and 14%.
Brian Skorney, an analyst at Baird, wrote how his team was "disappointed to see that this strong target engagement did not translate meaningfully to the clinical impact," while Mani Foroohar of SVB Leerink had a similar takeaway.
"While one could point to a signal of target engagement and hints of potential clinical efficacy in this dataset, this is scant silver lining in light of the disappointing top-line outcome and safety profile," Foroohar wrote in his own note to clients.
On safety, Biogen said most side effects in both the main and extension studies have been mild or moderate, with the most common among tofersen-treated participants being procedural pain, headaches, pain in the extremities and fall and back pain.
In the main study, 18% of tofersen-treated patients and 14% of placebo-treated patients experienced a serious adverse event. About 6% of the tofersen group stopped treatment because of an adverse event, compared to no discontinuations in the placebo group. Serious neurologic events were reported in almost 5% of patients who got tofersen in the main and extension studies, including two cases of spinal cord inflammation.
One death was reported in the tofersen-treated group, but it was determined not to be related to tofersen, according to Biogen.
While not zero risk, Miller believes the safety profile of the drug is acceptable.
"Each prescriber will have to make that determination for themselves," he said. "Having said that, if you ask me, as someone who sees ALS patients, I think that the risk-benefit here is okay. There were some events. But I don't see that as a major obstacle."
In addition to the data, Biogen on Sunday announced plans to broaden a previously established expanded access program to allow all eligible ALS patients with SOD1 mutations the opportunity to get tofersen.
Currently, there are only a few medicines approved by the Food and Drug Administration to treat ALS, and each has limitations. The typical life expectancy for patients remains three to five years after diagnosis.
In recent months, the FDA has faced increasing pressure by patient advocacy groups to do more to make new treatments accessible. Amylyx Pharmaceuticals, a Boston-area biotech working on another closely watched ALS drug, recently announced the agency agreed to allow it to submit its drug for approval before conducting an additional late-stage study.
Amylyx's drug, known as AMX0035, succeeded in a late-stage clinical trial last year. Patients who received it scored an average 2.3 points higher on that same 48-point questionnaire, and had slower rates of functional decline, than patients given a placebo. There were also early signs that AMX0035 could offer a survival benefit.