Today Biogen announced positive interim results from its phase 1 study using its antisense oligonucleotide (ASO) salanersen (BIIB115/ION306) for the treatment of patients with a rare disease known as spinal muscular atrophy (SMA). The positive outcome dealt with an interim analysis that was done whereby patients received two different doses of this drug, which were 40 mg and 80 mg, respectively. However, these were not just patients who were first given this ASO for their treatment. Instead, the trial itself entailed SMA patients who were previously treated with ZOLGENSMA (onasemnogene abeparvovec-xioi), which is a gene therapy approved by the FDA to treat SMA children under the age of 2 years. It is designed to help such patients be able to sit upright, walk, and stand all on their own.
One thing to immediately point out is that salanersen has the same mechanism of action (MOA) as that of the already approved drug for SMA known as SPINRAZA (nusinersen). This particular gene therapy, though, was approved to treat both pediatric and adult patients with this neuromuscular disorder. In essence, Biogen has taken what has been accomplished with this particular therapy and enhanced salanersen to be more potent than it. One major problem that occurs with patients who have this disorder is neurodegeneration, and thus the goal is to preserve muscle function as much as possible. With that said, the positive data came about from the interim analysis showing that one single dose given to these patients allowed them to slow disease progression.
This was established with a biomarker observed in these SMA patients known as neurofilament light chain (NfL) and the correlation is that elevated levels of it signiffy neuronal damage. Patients who entered the study did so with high baseline levels of NfL and thus had advanced disease. What was remarkable was that despite these patients receiving ZOLGENSMA they were unable to sit up or walk on their own. It is only three months after they were given salanersen that they were able to have an improvement in the functions described. The mode of action was proven with respect to how well this gene therapy did when patients received it. It was noted that there was an NfL reduction of 70% at 6 months, and this effect was able to carry on through the year.
If this was the only piece of evidence, then it wouldn’t have been enough for Biogen to decide that it was a good idea to carry this program forward in phase 3 testing. With that being said, there were other positive efficacy outcomes to point to the fact that the therapy did well even after such SMA patients failed to respond to prior gene therapy. As one example, there is a functional endpoint known as the new World Health Organization (WHO) milestone, and patients were assessed to see if they could achieve important muscle-moving functions. With a subgroup analysis of 8 patients with this disorder who were aged between 2 and 12 and who received 40 mg of salanersen, it was noted that over a 1-year duration, about 50% of them (4 out of 8) were able to achieve muscle movement functions that they could not on their own before, like being able to stand, sit and/or walk.
In terms of safety, there were no issues, and salanersen was well tolerated by the patients who were given one dose of it. The importance of phase 3 is to see if what was achieved in the phase 1 study can yet again be replicated with a larger pool of patients. Thus, this is one cohort that the company is looking to work towards for late-stage clinical development. On top of that, though, there is a plan to also target treatment-naive SMA individuals as well. What this means is to attempt to evaluate the use of this highly potent ASO to go after patients who have not yet been treated with ZOLGENSMA or any other type of therapy. It is worth exploring of course, because maybe such patients could benefit from receiving salanersen as a first-line therapy, but this remains to be seen.
In terms of the mode of action, SPINRAZA aims to fix the genetic mutation that occurs in the SMN1 gene, which is responsible for generating the survival motor neuron (SMN) protein. The point here is that splicing of the SMN2 gene occurs to convert it to a proper working SMN1 protein that patients need to achieve motor function. As I alluded to before, salanersen has the same mode of action as SPINRAZA but with more potency. While this doesn’t guarantee that salanersen will eventually be able to achieve statistical significance in the targeting of SMA patients in phase 3 clinical testing, it at the very least increases the odds for it. Ionis Pharmaceuticals was responsible for the development of this drug, but Biogen licensed the global development, manufacturing, and commercialization rights for it.