It was found in 2009 that toxicity of SOD1 is secondary to a gain of toxic function rather than a loss of enzymatic function of the SOD1 enzyme, thus reducing levels of the mutant protein was predicted to slow progression in SOD1-linked ALS. Tofersen (formerly known as BIIB067), is an antisense oligonucleotide designed for adults with a confirmed superoxide dismutase 1 (SOD1) genetic mutation, a subtype of familial ALS that makes up 2 percent of all ALS cases.
As reducing levels of the mutant protein is predicted to slow progression in SOD1-linked ALS, this antisense oligonucleotide mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA. As there is less SOD1 mRNA, there is less production of the SOD1 protein. This is not without risks in itself, SOD1’s role is to protect against anti-oxidants which are the normal by-product of cellular respiration.
Tofersen was developed in a long time partnership between Biogen and Ionis Pharmaceuticals. With the time doses went from 3mg up to 100mg. They conducted a phase 1-2 ascending-dose trial evaluating Tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of Tofersen or placebo, administered intrathecally for 12 weeks. The results were presented in July 2020.
The results were encouraging, but as for any ALS trial they are anything but stellar. Lumbar puncture-related adverse events were observed in most participants. Among participants who received Tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52.
48 participants received all five planned doses. The technical indicators where better for participants having the higher doses. Patients taking the highest dose of Tofersen saw their ALS Functional Rating Scale score decrease by an average of 1.2 points, while the placebo group saw their score decrease by an average of 5.63 points.
Toby Ferguson the principal investigator acknowledged: “What we saw is a decline in ALS function, breathing and strength that was much greater in the placebo groups than in the treated groups. That said, if I were critical, I could poke holes in any one piece of those data, but we also have the data that SOD1 is being reduced.”
ALS is a difficult field in which drugs that show early promise can turn out to offer no benefit, or pose “unjustified risks” to patients in later studies. Biogen knows this as well as anyone, having seen its last ALS effort, dexpramipexole, fail in phase 3. Since then, the company has switched its focus from drugs with specific mechanisms, like anti-inflammatories, to medicines that target genetic mutations. Biogen strategy is to learn more about the biology of the disease from looking at genetically defined populations (SOD1, C9orf72, ATXN2, XPO1) and then apply those findings to the broader population.
Despite those mixed results and as for other ALS drugs (Nurown, Cu(II)ATSM, Masitinib, AMX0035), there is an online petition for a compassionate access. Nearly 70,000 people have signed this online petition asking Biogen to provide an experimental ALS drug to a patient requesting it under compassionate use, but Biogen disagrees.
At the heart of Biogen’s denial is the question of broader access. The fastest way to get Tofersen to as many patients as possible would be regulatory approval, wrote Biogen chief medical officer, Maha Radhakrishnan, M.D., in a March 17 letter to an ALS patient, Stockman Mauriello that she shared with WCNC. That, of course, requires the completion of clinical trials.
“Providing individual access to Tofersen at this time could jeopardize access to Tofersen for hundreds of SOD1-ALS patients by impeding our ability to complete the study that will determine whether Tofersen is efficacious and safe and to seek subsequent regulatory approvals as quickly as possible,” Radhakrishnan wrote.
It's a moral position, it would not be fair to study participants who were randomized to placebo if Biogen were to offer the drug to patients not participating in the study.
However Biogen will provide early access to Tofersen only after study participants are no longer taking placebo.
“We cannot overlook these patients when considering questions of broader access, and cannot keep them on placebo while at the same time offering Tofersen to those outside of our study,” Sandrock wrote. “Offering Tofersen outside of the study would risk failing to complete the study and risk failing to obtain access for all SOD1-ALS patients".
“These patients agreed to participate in our study acknowledging the risk that they may not receive Tofersen, and with hope that Tofersen could be shown to work and be approved for all patients,” Sandrock wrote.