John Brandsema, MD: When we’re considering the response to treatment when using these 3 targeted treatments we have approved for SMA [spinal muscular atrophy], there are many factors that need to be taken into account.
The first is simply tolerability: Are there any safety factors associated with these treatments? There are some things that we have to monitor for all the treatments related to their safety, but honestly, they’ve very new, and some are still actively in research trial as well. We’re still learning about them, and we’ll likely have other things that we will start to realize as both short-term and long-term concerns in terms of safety that we need to monitor.
In terms of efficacy, this again depends on where you’re starting relative to the trajectory of the disease that the person is experiencing. You can imagine that, in people who have a milder form of SMA, they may start to have symptoms superimposed on normal childhood development. There are clearly issues, but they’re making progress based on any child’s ability to get better at movement as they age.
There has been a point where they plateau because there is no ability for development to keep happening naturally because the disease had gotten to such a severe point. There is then the decline phase. In the most severe form in babies, this is very rapid; there is almost no gain. There’s a quick plateau, but it’s mostly a steep decline where you reach a very minimal level of function quickly in the severe form. In the milder forms, it can be months to years of slow improvement with some symptoms, a very long period of plateau, and then a very slow decline in function. Even in those more severe patients, once they’ve reached a certain level of function, it starts to plateau again and gets much slower in terms of change over time.
When we’re trying to look at the therapeutic response to an intervention, this is a challenge in the clinic. What we’ve seen with nusinersen is that even people who are far into their disease trajectory, who have very minimal function, have meaningful and measurable differences in their function after starting treatment. Whether or not it is stabilization of motor neurons, many of us in the field also believe that there’s a role for SMN protein in nerve signaling, neuromuscular junction integrity, and other aspects of how the lower motor neuron functions.
Whatever is happening, you can see an improvement in some patients. Even if they don’t improve, if they stay the same for a longer period of time than what we could have expected in the natural history based on our understanding of SMA for decades, then that is a therapeutic response because they’re not getting worse the way that you would have expected them to.
An even harder concept to prove to an individual is that, yes, they’re getting a bit worse, but the amount that they got worse is not as much as they would have been if they weren’t taking medication. This is very difficult to prove in a 1-person, n=1 kind of thing. As we look at aggregates of data among the research trials with many dozens or sometimes hundreds of patients with SMA being studied in some of these research trials, we start to understand the difference from what we understand is the natural history.
The key point as you’re trying to use these medications is that it’s not just giving the medication and your SMA is cured, so you can just go home and never have to access the medical system again. These are not cures: These are treatments that make SMA less severe. The patient still needs to stay linked up with an SMA care team who will then carefully evaluate their overall function from many different perspectives: pulmonary function, orthopedic function, nutrition, and all the different aspects of function in addition to the motor function that somebody is displaying. We can measure these things with various skills, but at the end of the day, quality of life is important too. What the patient and their family, their loved ones, and their caregivers are telling them and are telling us is different about them is really important to listen to in terms of whether a treatment is having an effect for the individual and whether it should be continued.
Consultant: Alexion, Audentes, AveXis, Biogen, Cytokinetics, Genentech, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, WaVE
Research support: Alexion, Astellas, AveXis, Biogen, CSL Behring, Cytokinetics, Fibrogen, Genentech, Pfizer, PTC Therapeutics, Sarepta, Summit, WaVE
Speaker: AveXis and Biogen