For 25 years, researchers have explored an idea that, by regulating certain genes, they could treat one of the world's most debilitating neurological diseases. That work has led to encouraging data, with the latest coming Wednesday from two studies published in the New England Journal of Medicine.
"It's a really exciting time for the field," said Orla Hardiman, clinical professor of neurology at Trinity College in Dublin and co-author to a NEJM editorial published alongside the studies.
Previously, scientists discovered the risk of developing amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is higher if a select group of genes mutate. The newly published studies each tested an experimental drug meant to silence one such gene, called SOD1, that encodes an eponymous protein. While both studies were designed to evaluate safety, researchers also looked at protein levels to see if the drugs were working as intended.
One of these drugs uses a virus to deliver a small strip of genetic material into patients' spinal areas. In theory, the material would block the gene from making its protein, but results from two patients showed that neither had a substantial change in protein levels in their cerebrospinal fluid.
However, after one of the patients died, an autopsy showed SOD1 protein levels in his spinal cord tissue were lower than in untreated patients with the same form of ALS. The study investigators concluded that additional trials with a larger number of patients are necessary to better understand the drug's effects.
The other study had more clearly positive results. It tested four doses of Biogen's tofersen against placebo, and found lower SOD1 protein levels in the cerebrospinal fluid of patients who received the drug. Compared to those in the placebo group, protein concentrations were about 20 to 25 percentage points lower for patients given the two middle tofersen doses and 33 percentage points lower for patients on the highest, 100 mg dose.
Biogen, which announced summary data from the trial last year, has since moved the high dose into a larger, efficacy-focused trial that aims to recruit around 100 patients. Enrollment has been "reasonable," albeit with slight delays due to the coronavirus pandemic, according to Toby Ferguson, head of the company's neuromuscular development unit.
Though tofersen will likely need positive late-stage results to support an approval, the currently available data offer a confidence boost for Biogen. Like other ALS drug hunters, the biotech has hit setbacks — the most damaging of which came in 2013 when its small molecule medicine dexpramipexole failed a Phase 3 study.
"It's not fully shown to work yet, but at least the biology seems to be going in the right way," Ferguson said of tofersen. "It fundamentally says to me that if we pick the right targets, ALS can be a treatable disease. And we need to push forward both with genetic targets and appropriate targets for the broader population."
The tofersen study may also fuel optimism in the broader ALS research community. While two drugs are approved for ALS, there remains an urgent demand for more treatments. Most patients live just three to five years after they're diagnosed, according to the Centers for Disease Control and Prevention.
Following decades of research, genetic medicine has, in recent years, proven itself to be a valuable weapon against hard-to-treat neurological conditions. In 2016, for example, Biogen's drug Spinraza became the first ever approved treatment for spinal muscular atrophy, a rare and often life-threatening condition that impairs muscle growth. Spinraza, like tofersen, is a type of gene-silencing medicine called antisense oligonucleotides, or ASOs.
Sarepta Therapeutics also has two ASO products approved for a different muscular disorder, and research on other gene-based treatments is advancing for difficult neurological diseases like Huntington's and Rett syndrome.
In ALS, several companies are working on genetic medicines. Novartis and Voyager Therapeutics each have plans for a SOD1-targeting ALS gene therapy, while MeiraGTx and the partners Pfizer and Sangamo Therapeutics are developing gene therapies not specific to SOD1.
With tofersen, though, Biogen holds a leading and potentially tone-setting position.
As the drug progresses through late-stage testing, Hardiman said it would be "fantastic" if the drug demonstrates not just reductions in SOD1 protein levels, but also the ability to slow or stabilize the disease. Biogen's smaller study hinted that tofersen's effect on SOD1 protein levels might translate to slower functional declines, but the data aren't proof it actually does.
"If we can show that gene-silencing in SOD1 is effective, it opens the way for other gene-silencing approaches in other genetic forms of ALS," she said, pointing to several other mutations associated with ALS.
"We are in a new era now where we have a much better understanding of genomic regulation, and we're getting to a place where it's really possible to modulate these pathways in a way that's genuinely therapeutic," Hardiman added.
ALS drug research also extends beyond genes, since estimates hold that only 5% to 10% of cases are inherited — and, within that fraction, SOD1 mutations account for 15% to 20% of cases.
Currently, the Sean M. Healey & AMG Center for ALS Research is running a first-of-its-kind platform trial to test five experimental therapies, including ones from Biohaven Pharmaceutical and Cambridge, Massachusetts-based Ra Pharmaceuticals, now owned by Belgium's UCB.
Privately held Amylyx Pharmaceuticals, meanwhile, is working separately with the Healey Center. The company said in December its experimental treatment slowed ALS progression in a mid-stage study, although no actual data was released.
Alexion Pharmaceuticals, a large rare disease drugmaker, also recently began exploring whether one of its approved therapies could work in ALS too.