High-Dose Nusinersen Trial Paves the Way for More Individualized Treatment of SMA

Richard Finkel, MD

Biogen recently announced that the first patient has been treated in the DEVOTE global clinical study (NCT04089566). The study will use the well-established safety profile and proven efficacy of nusinersen (Spinraza; Biogen) in a broad range of patients with spinal muscular atrophy (SMA) while exploring a higher maintenance dose of 28 mg.

Approved in 2016, nusinersen currently stands alone as the only treatment for both pediatric and adult patients with SMA as Biogen continues to invest in its clinical development. Since its FDA approval, the drug has treated over 10,000 patients with SMA.

To find out more about how this trial can once again alter the landscape of SMA treatments, NeurologyLive talked to Richard Finkel, MD, director of Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis Tennessee, and principal investigator of the DEVOTE study. He shares his insight on the finer details of the study, why Biogen chose to assess an increased dose, and the impact successful results can have on patients with SMA.

NeurologyLive: What are the details of the new phase 2/3 trial of nusinersen?

Richard Finkel, MD: Nusinersen was approved by the FDA over 3 years ago ,and subsequently by EMA (European Medicines Agency), under the commercial name Spinraza. Since then, over 10,000 patients have been treated worldwide with this drug.

The approved label is for a fixed dose and a fixed schedule of administration, which has proven to be beneficial for the majority of patients. This study is attempting to optimize the dosing. While we currently have a dose that works, we don’t know if it is the optimal dose for each individual patient. That is the main objective of the study. It is designed to capture 2 different particular objects. The first is to see whether there can be a higher loading dose administered, which in turn, would reduce the number of loading doses that are administered. The current schedule calls for 4 loading doses within the first 2 months of initiating treatment. Each of those is a 12-mg dose, spaced out over those 2 months. This new study will first look at a higher dose of 28 mg and give 3 loading doses instead of 4. If proven safe, the next stage would be to look at a 50 mg loading dose and see whether that could be administered on 2 occasions. The second part of the DEVOTE study is to see whether the maintenance doses, which currently are 12 mg given every 4 months, can be more effective and safer at a 28-mg schedule, again, given every 4 months.

What influenced the decision to settle with a new 28-mg maintenance dose?

Biogen did quite a bit of preclinical work, going back to animal testing to try to look at what doses will achieve a certain concentration of the drug in spinal fluid at different time points. By using pharmacokinetic-pharmacodynamic modeling, we were able to put together information from the preclinical testing as well as information that we've learned from treating patients with Spinraza and say, “How do we model the drug to be able to identify with what we think is an optimal dose?” This decision ultimately came back to the idea of trying to optimize the response for each individual patient as much as possible.

Do you anticipate efficacy levels to be similar to what has shown in previous studies?

Speaking personally, based on working with these patients and seeing how some patients seem to respond to a greater degree than others, it is my realistic hope that with this increased dosing schedule, we will see an enhanced response. In other words, in my experience, all patients are responding to this drug, but there's variability. In some situations, we can associate the drug level with the clinical response. This study gives us an opportunity to increase the dose to confirm that we’ve achieved higher spinal fluid drug levels at the trough concentration point. Additionally, we want to see the drug demonstrate an improved clinical response over that, which we’ve already experienced at the standard 12-mg schedule.

If the trial is successful, what impact can it have on the treatment landscape for the SMA community?

I would categorize the landscape right now as rather fruitful because we have 2 and hopefully, a third choice of a therapeutic for this deadly disease. For most of the neurologic diseases that I deal with in children, there is no specific treatment, only supportive care. To me, this is a wonderful time to be in the field of treating children with SMA.

What we’ve learned already from the standard dose of Spinraza is that it is a very safe drug. These children, even babies tolerate the repeated lumbar puncture procedures very well. We have a very strong safety profile over many patient years of experience with the drug and we know the drug works. Additionally, we know that you can use this drug to treat—under current FDA labeling—any patient from presymptomatic newborn through adulthood. This also includes the most severely affected type 1 SMA, to the more modestly affected type 3 or type 4 patient.

Spinraza has this very broad label with a great safety profile, but we’re still trying to learn how these different populations of SMA respond to the drug. With that, there’s a huge opportunity to learn more about Spinraza in patients living with SMA and in the presymptomatic population. Another marketed drug, Zolgensma (onasemnogene abeparvovec; AveXis), has shown great promise but is currently label-limited to patients under 2 years of age. Though that label may expand over time, there’s a very limited population of patients that are eligible to receive this SMA gene replacement therapy. We’ll have to wait and see about risdiplam (Roche), which has been studied in a broad age range and population of patients with SMA 1 and 2, and non-ambulant type 3. That may offer a third choice for the clinician.

Even with all these options, it is fair to say that at this point in time, the clinician has the most data at their fingertips on Spinraza. If you’re sitting down with a parent or a patient and you’re trying to make a data-driven decision, you have the most information at the end on Spinraza. I think that’s very powerful. If Spinraza shows good safety and enhanced efficacy at this higher dosage, then the clinician will be able to discuss the potential extended role that it can play. Beyond that, I cannot predict the future, but there’s still a very important role for Spinraza in the treatment of patients with SMA, even with the other 2 drugs mentioned.

What impact can the increased momentum in treatments for SMA do for the future of the community?

It's a deadly horrible disease, particularly for the majority of patients who are destined to have Type 1 SMA. I think it's fair to say that both the clinician and the patient and their parents are eager to learn about the different drugs and because they're likely not going to be able to get all 3 drugs. You have to make a choice as to which drug you think is the right one, the best one for that particular patient or for a parent’s child. To me, there's a sense of chaos here because there's so many moving parts. But it's chaos in a good way, because it's creating so many opportunities. It will take us, I think the next decade, really to sort this all out and answer these questions effectively.

Any additional comments on the study?

The 1 question that I'm commonly asked in the clinic is for patients that are currently being treated on the 12-mg dosing schedule is “When will they be able to move to the new higher dosage?” I've had to explain to them that this is a new study, it has to go through these 3 different parts. We have to identify the safety first, and then look at whether there's enhanced efficacy. If proven effective, there will be an opportunity to move patients over to this higher dosage and due course.

In fact, 1 of the 3 parts of the study is to take both children and adults who have been treated with Spinraza for over 1 year and look at a transition from the 12-mg to the higher 28-mg maintenance schedule. For the 10,000 patients currently being treated with Spinraza, they're eager to know, “Is this higher dose going to offer me, or my child, a chance to improve yet get more than what I'm already seeing from the drug?”

Transcript edited for clarity.