Biogen to Run Phase IV SMA Trial: “I Want to Optimize Their Life.”

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There are currently three approved therapies for Spinal Muscular Atrophy (SMA). They are Biogen’s Spinraza (nusinersen), Genentech’s Evrysdi and Novartis’ Zolgensma (onasemnogene abeparvovec). The three therapies have been revolutionary in treating SMA, a rare, autosomal recessive neuromuscular disease characterized by the degeneration of alpha motor neurons in the spinal cord. This results in progressive muscle weakness and paralysis. SMA type I, the severest form, was almost always fatal by two years of age, with a 50% mortality rate by seven months and a 90% mortality rate by 12 months, although that has changed with the advent of these therapies.

Biogen recently announced plans to initiate a Phase IV clinical trial to determine the benefit of Spinraza in patients who received Zolgensma. The two therapies have markedly different ways of treating the disease.

Zolgensma is a gene therapy that targets the genetic cause of the disease, replacing the function of the missing or nonworking SMN1 gene, which is critical to making the SMN protein. The therapy is a new, working copy of a human SMN gene that is placed inside a viral vector and once in the body, is caught up in the cell’s protein-making machinery to produce the missing protein. The gene does not become part of the child’s DNA.

Spinraza holds an antisense olignonucleotide. Antisense is a non-coding DNA strand of a gene. Oligonucleotides are short single strands of synthetic DNA or RNA. This increases the ability of cells to manufacture functional SMN protein from the SMN2 gene. It acts by binding to the SMN2 messenger RNA (mRNA), allowing the mRNA copied from the SMN2 gene to be full length.

Crystal Proud, a Pediatric Neuromuscular Neurologist at Children’s Hospital of The King’s Daughters in Virginia, and a member of the RESPOND clinical trial steering committee, took time to talk about the upcoming Phase IV clinical trial. At this time, Biogen expects to submit plans for the trial to the U.S. Food and Drug Administration (FDA) in the upcoming months with a goal of beginning enrollment of the RESPOND trial in the first quarter of 2021.

In a long-term trial of Zolgensma, four out of 10 patients were subsequently treated with Spinraza.

“It’s not necessarily that Zolgensma doesn’t work or that it’s not as effective, but in the long-term extension of one of the clinical trials utilizing Zolgensma administration, four of those 10 patients actually chose to pursue treatment with Spinraza,” Proud said. “Within the clinical arena, those of us who administer the gene therapy see room for optimizing clinical response. The gene therapy is not a cure, so those patients may still be symptomatic. The question is, can we optimize that outcome and improve their function, their respiratory function, improve their bulbar function by administration of continued Spinraza.”

Some have written that because Zolgensma is a gene therapy, it is a cure, but Proud is very cautious about that.

“I don’t know that we have anything like a cure in the neuromuscular space. ‘Curative’ is a very lofty term, and so right now within the SMA space we do not have a cure. We have a treatment,” Proud said.

The goal of Proud, physicians in the SMA space and Biogen, is to see if they can optimize the outcome for the patients. Proud notes, “Because ultimately that will impact their quality of life. And those of us who serve these patients know that early intervention is key. And the question is, are we giving them absolutely everything we need to when pursuing that early treatment to let them live a long and healthy life.”

The plan for the RESPOND clinical trial that will be submitted is for a two-year, open-label study to evaluate the efficacy and safety of Spinraza in SMA patients who previously received Zolgensma. Efficacy will be determined by change from baseline on motor function measures, additional clinical outcomes such as swallowing, and caregiver burden. They also plan to utilize neurofilament levels as an exploratory endpoint as a marker of biological disease activity.

Biogen plans to enroll a primary study group of 40 infants who received Zolgensma at six months of age or younger and will be aged nine months or younger at the time of the first dose of Spinraza who have two copies of SMN2, meaning they are likely to develop SMA Type 1. A second study group will enroll 20 children and data will be collected in patients with a broader age range, up to three years old at the time of the first dose of Spinraza.

There will be a screening period, then participants will receive the approved 12 mg dose of Spinraza, which is made up of four loading doses followed by maintenance doses every four months, over the two years the study is expected to run.

Of the trial, Proud says, “The patients will be deemed by the investigator, their clinician, to have had a suboptimal response with potential room for improvement in their clinical symptoms as determined by the primary investigator. That will permit them consideration for enrollment in the clinical trial, in which case they begin treatment with Spinraza and their outcomes will be followed with certain effectiveness scales.”

Proud indicates that, “Right now we have two medications that work on two different mechanisms. These are children that used to pass away at an early age. And now they’re surviving. But surviving isn’t enough. I want to optimize their response. I want to optimize their life. From a doctor’s perspective of someone who cares for these patients, I want to bring them the best medical care I possibly can and so for me that’s what this study means.”

As she notes, “It’s an incredible time and amazing to be able to offer this to patients, because that’s not the conversation I used to have with families. So it’s incredible that we even get to have this conversation today.”