SMA Therapy Innovation, Addressing Weakness Before It Occurs Are Key to Improving Outcomes

There is currently no complete cure for the genetic disorder spinal muscular atrophy (SMA) which effects approximately 1 in 10,000 people, according to the Centers for Disease Control & Prevention; however, recent research and therapy options have made strides in managing symptoms and preventing associated complications.

In an interview with First Report Managed Care, Jennifer Kwon, MD MPH, director, professor of child neurology, department of neurology, University of Wisconsin School of Medicine and Public Health, offers insight on the current treatment landscape for spinal muscular atrophy and sheds light on the burden these patients face. 

Please introduce yourself and tell us a bit about your background.

I'm Jennifer Kwon. I'm a professor of Neurology at the University of Wisconsin (UW) School of Medicine and Public Health. I am an academic child neurologist, and I've been interested in neurogenetics and neuromuscular disease my entire career. I am currently the director of the pediatric neuromuscular program.

In recent years, I have been interested in newborn screening policy as  a way to help prevent treatable neurologic disorders in  infants,  This has coincided nicely with my work at the UW neuromuscular program, not only because of our role in spinal muscular atrophy (SMA) newborn screening, but also the care of children with SMA who were diagnosed before newborn screening came into effect.

Can you describe the current treatment landscape for SMA? What makes it challenging?

The current treatment landscape for SMA is exciting because among the serious inherited neurologic disorders; this disease  has unique genetic mechanisms that pharmaceutical companies could go after for treatment. SMA is a disorder of severe weakness in children, and the weakness comes from the ongoing loss of lower motor neurons.  While upper motor neurons are needed to take signaling from the brain to the spinal cord, it is the lower motor neurons that take motor signaling from the spinal cord out to the muscle. The signals that go from the brain to the spinal cord are fine—these children have normally developing brains—but they cannot get messages to the muscle because of the ongoing loss of lower motor neurons due to a lack of survival motor neuron (SMN) protein.

Pharmaceutical companies have been clever about understanding the genetics of deficient SMN protein and finding ways of boosting SMN protein. This allows the lower motor neuron to survive for the lifetime just like it is supposed to. When children are treated early enough with these drugs—before their lower motor neurons have a chance to be damaged and then atrophy and die—they can have fairly normal motor function and that is what has been really exciting about the treatment landscape for SMA recently.

Unfortunately for children who are already weak, these drugs do not reverse their weakness, but they will prevent further ongoing weakness. SMA is a progressive disease so these drugs can help prevent ongoing loss of lower and motor neurons. It's a complicated landscape because there are now three treatments available to children with SMA.

One treatment that is available to all individuals with SMA is nusinersen, which is an intrathecal medication that when dosed routinely can result in greater levels of SMN protein and therefore the lower motor neurons can survive. The second drug that can be given to all patients with SMA is an oral medication called risdiplam. It also acts to increase the amount of SMN protein that a patient with SMA sees. The third treatment is gene therapy, which is given as a one-time intravenous infusion.

Again, if patients are treated when they have a fair number of still surviving lower motor neurons, they can maintain strength and actually gain strength through therapy. What happens in our muscles is, even if you've missed some lower motor neurons and you have some areas of weakness, the areas of muscle that are supplied by healthy lower motor neurons can actually get stronger. And so patients with SMA for the first time can really make motor gains that we never used to see before.

There are three different delivery mechanisms. One is a daily oral medication. One is an intrathecal medication that's given every few months, but both of those can be expensive which can present problems when it is a lifetime medication. There is gene therapy, which is a one-time intravenous dose that can only be given to children under the age of 2 years in the United States.

What are some of the significant findings from your recent SMA and risdiplam research?

It has been a great opportunity to work with the pharmaceutical companies that are designing and researching these new drugs. Our site at the University of Wisconsin was part of the early gene therapy trials and we were able to see, even before the drug became commercially available, the promise of these drugs as treatment for children with both largely presymptomatic and symptomatic SMA.

Likewise, we were able to see how useful an oral drug is, especially in the time of COVID when children could not come to a hospital for a lumbar puncture, for an intrathecal infusion. Having an oral option that they could just simply get delivered to their house was so convenient.

Something I'm seeing in the research landscape for SMA is that many pharmaceutical companies are targeting SMA for less specific drugs that are designed to improve strength in various ways. When you think about all of the different pediatric neuromuscular disorders that could benefit from these drugs, you might say, "Well, why SMA?" but I think it's for the same reason that these highly effective drugs were designed in the first place. SMA is genetically homogeneous. All children have the same primary genetic defect. There is some variability in how much strength they have, but there is a lot of excitement in adding on new medications that may help with muscle bulk, for example, onto a patient who has already treated with disease modifying treatment. I think of these more symptomatic treatments as sort of secondary treatments. They are not attacking the primary genetic problem, but they are still extremely helpful to our patients.

What is something that you would like payers or formulary decision-makers to better understand about the burden of SMA?

In the past 2 years, I've been able to do something that I never thought that I would be able to do with children with SMA, which is prevent them from ever becoming significantly weak or even weak at all.

I spent the first 20 years of my career knowing that I would see, with a certain regularity, children with SMA who would either die in their first 2 years of life or who would be left extremely weak for the remainder of their lives. They would survive, but they would survive because they are smart kids who are good planners and could figure out how to carefully negotiate the world when they have little strength to maneuver their wheelchair and get themselves around. In the last few years or treating SMA, what I have found is that I just do not want to see weakness anymore. As a clinician, I want to say to payers, "There is this idea that some children are not as weak as early as other children, so we can treat them later.”  My question is “Why wait?.  Let’s treat these children early to give them the best chance at a normal life.” 

The problem with waiting for weakness to occur is that the loss of lower motor neurons is permanent. If we are going to invest in expensive medications, let's invest when we are going to get the best return, which is early.  Before treatments, some children with SMA, even though severely weak, were able to grow up and make a difference in the world. If they could have normal strength from early on, I feel like that is a gift for all of us. That is a boon for society. Let's not quibble about when they are going to be weak or how much weakness they have. If we have established a diagnosis and we know they are going to have a disorder that is going to result in weakness, then we should treat them as soon as we find the diagnosis.

Is there anything that I haven't asked you about or anything that you'd like to add?

As a clinician who also cares for children who don't have highly effective treatments to help them, I would hope that their care is not impacted when others are getting these very expensive treatments.  I know that my team and I have been able to successfully treat all the children with SMA that we have wanted to treat. However, at the end of the day, I do not really understand the long-term impact to an insurer, when they authorize payment of a medication.  I do not think payers are the enemy.  But I do think that our medical system forces us to work against each other.  I do wonder if our efforts to give our SMA patients truly effective treatments may make it harder to provide reasonable and sustainable care for all.

At the end of the day, we all want health care for children. I hate it when I can get one patient the drug on time and then the very next patient I see, I feel totally helpless and frustrated because I cannot get a wheelchair modification performed because of insurance policy restrictions.