Richard Finkel, MD, Chief of the Division at Nemours Children’s Hospital, Orlando, FL, talks about a new drug to help treat patients with spinal muscular atrophy. This is the first drug of it’s kind to be approved by the FDA.
Interview by Ivanhoe Broadcast News in August 2017.
Tell me a little bit about SMA, what does it stand for?
Dr. Finkel: SMA stands for spinal muscular atrophy, which is a genetically based condition that is one of the most common neuromuscular disorders that we see in infants and children, and it is a devastating disease for these little babies. It comes in different forms of severity, but the most common form over half of the children with SMA have, the most severe type, is called type 1. These are little babies who are born normally, but within the first few months of life start to show weakness, particularly in their legs, and then in the arms, and over time it will affect all the muscles; even their breathing and feeding muscles. There is a consequence, these poor little babies never really have enough strength to roll over or sit, so they do not develop any sort of motor function and because of the difficulties with breathing and feeding. Parents are often challenged with a difficult decision whether to provide supportive care, such as feeding tubes and breathing support at home. With that support, the life expectancy can be extended, but without that support about three quarters of these babies die by two years of age. With the support we are now seeing those babies living longer; but unfortunately, they are not living better. That means they are not acquiring new motor skills, these babies never roll over, they never sit up, they never really acquire any independence in their motor function. This new drug called, Spinraza, has really changed everything for these babies. In addition to these type 1 babies, there is a somewhat milder form of type 2 SMA and these are children who present a little later; usually between six and 18 months of age. They start to show problems, meaning that they were sitting up and they were rolling, but they failed in most cases to stand and they do not ever walk; so they can sit but not walk. What we found is that those children who normally are going to live into their 30’s with good supportive care, with this drug Spinraza they are not only living into the adult years but with this Spinraza treatment they are gaining in motor skills in many cases. There is also a milder form called type 3 SMA and this is where children not only sit, but also do develop walking. Unfortunately because it is a progressive disease many of the children will lose the ability to walk by age 10 years or so, and there is a rare form that we see in adults that is called type 4 SMA, where people that are affected can develop some weakness in the adult years. So we look at SMA on a spectrum from a little baby shortly after their birth to somewhat older infants, the type 2, to then the children who are the walkers, they are type 3 and then into the adults; so it really is a long spectrum. What we have learned through the clinical trials in Spinraza is that definitely the drug improves both survival and the ability to improve in their motor functions for those severe type 1 babies. We were able to identify significant benefit in the children who are a little bit older with type 2 diseases. We have not really yet looked at the type 3 children and the type 4 for adults, but because this drug should work the same way whether you have type 1, type 2, type 3 or type 4. The FDA when they approved this drug in December of 2016, they gave it a very broad indication for all patients with SMA from newborns all the way through adult years. It is only more recently that we are starting to give the drug to these other patients, older children with type 1, even adults with type 4.
What does Spinraza do exactly for these patients?
Dr. Finkel: Spinraza is what you might call a designer drug. This is because we understand the genetic bases of SMA and it is a little bit complicated, but the basic problem with all patients with SMA is they have a genetic flaw in a piece of DNA, called the SMN1 gene. They are missing the SMN1 gene; there is a change in it, what we call a mutation, and because of this, patients with SMA are dependent on what we call a backup gene, called SMN2. Normally if you have SMN1 you really do not have to worry about what your SMN2 is doing, you do not need it. But if you are missing SMN1 then it is critical and you are totally depended on this backup gene. What Spinraza does is it improves the function of the SMN2 gene, because these two genes, SMN1 and SMN2 are not identical. There is a little bit of a difference and unfortunately the SMN2 gene does not produce as much of the protein that is necessary for these nerve cells to function as the normal SMN1 gene. So what Spinraza does is it works on this SMN2 gene to try to increase the amount of protein that is made and try to restore function; and that is exactly what the drug does. Some of the clinical trials were able to demonstrate that little babies, with type 1 SMA treated with Spinraza did exactly the same as the mice who were treated in the laboratory; that the drug does increase the amount of the protein that is deficient in these babies and it does it in the nerve cells, which is really the critical area. Because when we talk about spinal muscular atrophy the way that the name came to be for this condition is it’s nerve cells that live in the spinal cord that are primarily affected in SMA, that is why you have the word spinal; it is nerve cells in the spinal cord. When those nerve cells are not working effectively it leads to muscle atrophy and that atrophy causes weakness, so spinal muscle atrophy or SMA. The challenge here with Spinraza is that the drug has to be given into the spinal fluid. You cannot give it by mouth; you cannot even give it intravenously. It does not get to the nerve cells unless you do a spinal tap and you have to put the medicine, the Spinraza, into the spinal fluid and it has to mix in the spinal fluid and go all the way from down near the tail bone, down in the hip area, it has to move all the way up into the brain so that it can get absorbed into the nerve cells of the spinal cord and the brain, because that really is the target. These clinical trials are able to demonstrate that the drug does actually get all the way through the spinal cord and into the brain area when it is given by spinal tap. We were not sure how well this drug was going to work when we started, and we were concerned how well are these fragile little babies going to be able to handle repeated spinal taps, because the drug has to be given multiple times. In fact, there are four spinal taps and four administrations of the drug in the first two months; that is a lot for a little baby. Then after that the drug is given every four months in what is called a maintenance schedule, so what we were able to identify is that these little babies actually did very well with the spinal taps and the administration of the drug; and we were able to observe that the drug seem to be safe and well tolerated. There do not seem to be much in a way of side effects from Spinraza and of course, we need to monitor for that going forward. So far it seems to be a very safe drug; and the procedure seems to be well tolerated, even the little babies, the older children we do under sedation. They go to special part of the hospital, they get sedated and then a special doctor, usually a radiologist, will then do the spinal tap while the child is sedated and administrator the drug that way. With these clinical trials we have been able to not only identify that the drug is safe and the procedure is well tolerated, but we can see that survival has improved in those type 1 babies and also that their motor function has improved. By motor function I am talking about significant changes, some of these babies are not only rolling over, but many are now sitting and that progress seems to continue to improve over time; so as they continue to get the drug treatment we are seeing continued improvement; which is obviously very rewarding.
There has never been anything like this before?
Dr. Finkel: This is the first drug that has ever been shown to have any significant benefit for SMA and it is the first drug that has been approved by the FDA for use in the US, but also it has been approved for use in Europe and other countries.
If a viewer had a child with SMA, they could go and talk to their doctor about getting the same kind of treatment?
Dr. Finkel: Yes, I think the hope is for the word to get out to neurologists who would be caring for these babies to say that SMA is now a treatable disease. Up until this drug came along, unfortunately, we were often faced with the unfortunate situation of telling parents that their beautiful little baby has this fatal condition. Take your baby home, make him or her comfortable, make a decision whether you want a prolonged life with a feeding tube or breathing support, but we really do not have anything to offer to make the situation better. So when you talk about the quality of life and the ethics of how to treat these little babies it was very difficult. Now we have a drug that has a meaningful difference. I think it is important also to remember that Spinraza is not a cure. While it improves children from what was literally a death sentence before, to now a situation where many of these babies are living longer and they are certainly living better; they are not normal. The exception to this is maybe if we treat these babies very, very early and that means doing screening for this genetic condition in babies right at the time of birth, and if we can identify them even before they have started to show any weakness. Because you remember I said that they are born normal and usually these type 1 babies do not present until maybe two months of age or so. So we have a little bit of a window of time and if we could identify these babies, and if we can start the treatment before they become systematic, what we call pre-systematic we are finding remarkable results. Spinraza when treated in little babies even one week old, those babies are developing normally so far and in that case maybe we are dealing with a cure. It is a little early to be able to say that with any certainly, but the early results are very, very promising.
Tell me a little bit about Asher and his progress?
Dr. Finkel: Asher is a wonderful little boy and he has been special from the start. I first meet him when he was about six months old and he was already at that point of being on the stronger end of the scale for a type 1 baby; he was weak. He was clearly having problems, but if you look at the whole spectrum of babies with type 1; he was at the stronger end. Fortunately, we were able to enroll him in the clinical trial and he has been getting treatments since about six to seven months of age, and he has done remarkably well. By remarkably well, he has never needed any feeding support, which is in of itself remarkable. We admitted him to the hospital once for a cold; just because I think I was a little nervous and wanted to make sure we were watching him carefully. But he has never really needed any breathing support, also remarkable for a type 1 baby and he has made an incredible improvement in his motor functions. Not only is he rolling over and sitting by himself, but also he can get himself up and he is now weight bearing and starting to walk a little bit with a walker. What we are seeing is a little boy who genetically was destined to be a type 1 baby who never sat, never walked; and with this drug Spinraza is a type 2, meaning he can sit and on the verge of being a type 3; meaning a walker. In that regard, I think we can truly say that Spinraza has been transformative for Asher and being able to see his continued improvement.
What is the norm that parents can expect with this treatment?
Dr. Finkel: Asher has responded better, what we are learning from the different clinical trials and since the drug has been approved about eight months ago, is that the earlier we start treatment the better the response. That is a general concept, not true for every little baby, but I think what we are hoping to achieve is a situation where babies are diagnosed early after they start to show weakness. Neurologists understand that there is an urgency here to get them on this drug as soon as possible, because those babies overall are going to respond better than the children who were started later. All children respond to some degree, but we are trying to see what is the optimal response, we want to get them started early after diagnosis.
Is there anything else that I left out that you would like to add?
Dr. Finkel: My final few points are that we still have a lot to learn about Spinraza, because the clinical trials study is sort of a narrow population, a small slice of the SMA group. They were type 1 infants and they had to be diagnosed and treated before seven months of age. So what about the type 1 infant who is two years old or eight years old? How are they going to respond to Spinraza? We do not know that yet but that is the type of thing we are going to be learning. What about the type 2 patient; because those patients were typically about two to 12 years of age. What about the 20 year old, and what about the type 3 patient; the adults who are walking, the type 4? Are they going to respond and what can we expect? We do not know that yet, so now that the drug has been approved we hope to learn from our experience in the full range of the SMA population; from the little babies straight through adults. I think also what we need to learn is this Spinraza in and of itself, and as wonderful as it is, is it significant to get the best response alone or are there some other drugs in development, maybe in combination with Spinraza, which might provide an even a higher level of response? Much like other conditions you might look at. Cancer as an example, where chemotherapy is often a combination of different medicines; SMA may end up similar. It is going to start with Spinraza, but maybe over time we are going to mix in other medicines that have different targets and they are going to work together to get an even more robust response for these.
What happens to the other quarter of babies who survive past the age of two without supportive care?
Dr. Finkel: In the past there was about a quarter of the patients who would survive more than 18 years, sometimes several years and would not need extensive support. There has always been that small group that the typical patient with type 1 SMA, unfortunately, would falter and many did not make it to their first birthday, let alone to age two.
Would an SMA patient have to take this drug for the rest of their lives?
Dr. Finkel: Until something better comes along, yes. This drug is going to be necessary to sustain these nerve cells in the spinal cord. These nerve cells without the constant protein that is deficient, without having that replenished by Spinraza, those cells would go back and start to wither away, unfortunately, so we do think that they are going to need a continued supply of the medication. The good news is that once the drug is delivered into the spinal fluid it has a fairly long duration of around four months, so it is not something that has to be done, say weekly. Over time the different pharmaceutical companies are going to try to work on, shall we say version 2. Is there some way to improve the strength of the drug and maybe make it so we do not have to give it as frequently, but at the moment, yes we are thinking that Spinraza needs to be given as a lifelong treatment.
Do you know of any clinical trials going on right now that are working towards a version 2 as you said?
Dr. Finkel: The current studies include what is called a long-term extension, this is the same drug Spinraza and it is going to be given every four months as needed and the company, BioGen that is sponsoring this, has agreed to do this for another five years up until 2022. We should have much more experience at that point. We do know that some companies are working on the next version of the drug. I do not have specifics to know where that stands, but I expect that like most medical conditions once you find that something works you are going to try and say, can we make it work better? There are other drug companies, which are taking different approaches. There are two pharmaceutics companies looking at drugs that you would take by mouth that function similarly to the Nusinersen or Spinraza. The advantage there is that obviously you are given something oral and you do not have to go through the repeated spinal taps, but will it work as well we do not know that yet, that is still in the early phase testing; but some of those early results as also very promising.
What is the cost of the drug?
Dr. Finkel: The cost is huge it is around $125,000 per dose. That means for a child who is getting the six doses in the first year, that is about $750,000. Then each year after that it is three doses every year that is $375,000 and we are concerned about that because we do not want the price to be an obstacle to getting drug to these patients, but we also recognize that the drug company has a large cost to develop drugs and the populations of SMA patients is fairly small. It is estimated that 20,000 patients or so are living in the United States with SMA. That is from type 1 up to type 4, and probably a similar number in Europe; so far somewhere around let’s say 40,000 patients which is not a huge number. The pharmaceutical companies obviously have to try to figure out a cost structure that works for them to help develop these drugs, so we are concerned um about the cost. Fortunately the company BioGen is trying to make the drug available to patients while we are waiting for insurance authorizations when necessary, but I am also pleased to see that the insurers including most of the state Medicaid’s have reviewed this and have a policy now about which patients they will except for treatment. Because of the cost I think they are setting up some guidelines to say, in order to be eligible for the treatment let say in the state of Florida where I work and to be covered by the state Medicaid you need to have the following criteria met. They are in my mind reasonable, I think most others states are having similar struggles to try to come to an understanding as to which patients are really going to benefit from this expensive drug, how do we get this drug to them as quickly as possible. Particularly those who have just recently been diagnosed, the type 1 and the type 2 children with SMA really do need to be started on drugs as quickly as possible after diagnosis in my opinion.
Okay, so currently at the moment it is covered by insurance?
Finkel: It is covered by most insurances but there is a process because we are only about a full seven months out since the drug was approved. It has been a learning curve for us and for hospitals, how to deal with an expensive drug, because it is administered in a hospital or a clinic setting because you have to have the spinal tap done. I think each of the insurance companies in the United States is taking some time to think through and develop a policy as to which patients they are going to provide this treatment for, and in what setting. What would be necessary to demonstrate that the particular patient is responding to the drug so that they can authorize and continue treatment going forward.
END OF INTERVIEW
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