The Impact of the ENDEAR Trial Regimen
EP: 1.Spinal Muscular Atrophy (SMA) Overview
EP: 2.Typical SMA Presentation Upon Diagnosis
EP: 3.Sebastian's Story: Initial SMA Symptoms and Assessment
EP: 4.Spinal Muscular Atrophy Diagnostic Workup
EP: 5.The Importance of Treating SMA Early
EP: 6.Treatment Barriers: Cost, Location, and Delivery
EP: 7.Treating Children and Spinal Tap Risks
EP: 8.Systemic Effect Prevention: Evaluation & Dose Modification
EP: 9.Life During Therapy: Good Days and Bad Days
EP: 10.Multidisciplinary Management and Educational Support
EP: 11.Family Planning for People With SMA
EP: 12.Centers of Excellence and Future Oral Medication
EP: 13.Psychological Effects of SMA on Children and Adults
EP: 14.The Impact of the ENDEAR Trial Regimen
EP: 15.Ongoing Clinical Trials & Managing Patient Expectations
EP: 16.Adopting Neuromuscular Therapies for SMA
Philippa Cheetham, MBChB, MRCS, MD, FRCS: Now, this drug Spinraza [nusinersen] obviously has made a huge improvement in patient outcomes and yet has relatively recently been on the scene, with FDA approval only in the last few years. You've been specializing in this area for a long time. How dramatic has the improvement been since you've had FDA approval for Spinraza and now that's in your toolbox to treat patients like Sebastian?
Crystal Proud, MD: It's an incredible gift. I am in the new generation of neuromuscular neurologists, where I chose to go into this subspecialty recognizing that I was becoming a hospice doctor. That was essentially what I had chosen. I was there, especially with my infants who had this diagnosis, to support these families through the loss of a child, knowing that there was nothing that I could do to stop that loss.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: We've heard about the weakness in the limbs. Was it the pulmonary complications that resulted in these patients not surviving?
Crystal Proud, MD: Yes, they would eventually, without treatment—because they had none—stop being able to breathe, and ultimately that would lead to their passing. And so I knew that that was the area of subspecialty that I had chosen. But during my fellowship training at Stanford University, we actually treated the first baby girl in the world with this new medication that's now known as Spinraza. I was able to see firsthand some of the excitement that was going along with these new opportunities. And it has been incredible to be able to offer this now as an FDA approved treatment in my clinical practice every single day. It is such an honor and a gift to be able to care for patients like Sebastian and bring hope to them and their families.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: We know that when drugs finally get FDA approved, and we’re all very excited to be able to use them in clinical practice, sometimes that road is long, going through phase 1, phase 2, phase 3 clinical trials. And we know in research settings that these drugs have a huge amount to offer patients. And yet, until we can get FDA approval, obviously many patients are treated in clinical trials if they are lucky enough to be able to be offered the clinical trial. What was the timeframe between being able to offer Spinraza to patients in a clinical trial setting before it was actually given FDA approval and the word was out?
Crystal Proud, MD: It was a few years. And actually, it's FDA approval came in the midst of the pivotal clinical trial that's referred to as ENDEAR. That was a clinical trial that involved babies who were symptomatic, these were weak, what we would categorize as type 1 babies. They had weakness within the first 6 months of life and were not meeting those milestones. And they had to be treated with either placebo, which is where they receive no medication, or with what we now call Spinraza. And then they were followed up over time with these motor scales, looking at the motor scale changes and looking at survival as well.
That trial was actually terminated early because of the success of that medication. At the midpoint where they paused to take a look at the results that had been gleaned from the placebo-controlled trial, they saw that 41% of patients were able to meet these motor milestones that had never been able to be reached before treatment. And so, at that point everyone switched over to an extension of that trial. All those patients were subsequently offered the active drug, and then they continued to be monitored over time.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: So it was obvious early on that the results were beneficial. Were there any initial concerns about the drug in terms of toxicity or safety, that this drug that was going to be injected into the spinal cord area may have dangerous effects?
Crystal Proud, MD: There were no significant safety signals that I think raised any red flags along the way, although that is something that is obviously very closely paid attention to in any clinical trial. If someone gets a cold, a cough, if they fall down and have a scratch on their knee, that has to be reported to the individuals carrying out the clinical trial. And so those are monitored over time.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: Now obviously you're in a very busy clinical practice and these treatments are ongoing as maintenance. How much paperwork is involved for you to continue to get this drug approved and paid for, for patients? What information do you have to feed back to prove that this is a drug that’s working for patients and the insurance companies should continue to offer it?
Crystal Proud, MD: We have a spreadsheet, and my nurse coordinators and I run this spreadsheet. Once we got above about 15 patients on treatment, it really became an art form. And so, there is a spreadsheet with insurance company information, last authorization, last physical therapy assessment, next to do physical therapy assessment. Some insurance companies will give authorization for a year of treatment.
Some will give 3 months authorization. We have to bring you back to clinic in a timely fashion to be able to reassess you, to give your insurance company a score, knowing also the insurance companies’ process, and some of them take longer to authorize or reauthorize than others. So, it really becomes this artful dance that we do with the spreadsheet.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: When the ENDEAR trial was first developed, were there specific inclusion and exclusion criteria that are now not relevant for you in treating patients? Are you able to treat all SMA [spinal muscular atrophy] patients with Spinraza now?
Crystal Proud, MD: You ask such phenomenal questions. As you are probably very well aware and experienced with, insurance companies these days like to follow inclusion/exclusion criteria to set standards for what they will pay for, for treatment. And in the real world, that's just really not how clinical practice goes. It's constructed very clearly in a clinical trial because we want to follow good form and make sure that the results that we’re demonstrating are truly what's happening.
But in the real world, not everyone meets those inclusion/exclusion criteria. And we have to look at mechanism of action. And that's what I try to impart to these insurance companies that I have vigorous conversations with, I will say, is that the mechanism of action of Sebastian's medication is that it acts on SMN2 [survival motor neuron 2 gene]. And every patient with SMA has SMN2 in their body. So if we look at mechanism of action, it does not matter that he’s not a certain age or of a certain number on a scale. This medication is going to be able to get into his body and act on his SMN2 gene.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: Have you ever had a situation where you provided all the relevant clinical information and you had pushback in trying to get the Spinraza approved?
Crystal Proud, MD: I have, and I actually took 1 insurance company to court because they denied this treatment to a 9-month-old baby girl who would've otherwise passed away, and that was heartbreaking. I was furious and sad all at the same time. Coincidentally, that family ultimately ended up having an opportunity to enroll with a totally new insurance agency. It just happened that dad showed up at clinic and said, "I have open enrollment." I said, “Great, let's switch.”
But it was sad that we had to make that decision. It was sad that she was being denied this treatment that was an emergency by her primary [health insurance]. But thank goodness we had the opportunity to enroll her in dad's insurance, that then had a more appropriate coverage policy that was able to give her the drug. Now I will say that many of the companies that make these drugs also have opportunities for patients whose insurance continue to deny them, and they will offer assistance or sometimes free drug programs, which has been helpful.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: I'm sure you get requests from all over the world to help get these medications to patients who are not necessarily able to get them through insurance. Do patients have options if they are having to self-fund to get support to pay for these drugs if they don't have insurance coverage?
Crystal Proud, MD: If they don't have insurance coverage, they usually fall into a bracket whereby the companies who make the drug are able to help facilitate their treatment. They will actually get free doses of drugs. That is also in the context of trying to help those patients find insurance that works for them and with them.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: So many of the chemotherapy type drugs we give patients, and immunotherapies, we calculate dosage based on milligrams per kilogram of patients’ weight. Does it work like that for patients receiving Spinraza, that you have to calculate the dose based on the weight of the patient, or no?
Crystal Proud, MD: No, interestingly, it doesn't. I am primarily a pediatric doctor by training. And so it is a unique experience for me not to have to do milligrams per kilogram or milligrams per meter squared. It's based on the volume of cerebrospinal fluid. And so everyone, whether you're a day old or 65 years old, as my oldest patient is, you get 12 mg.
Philippa Cheetham, MBChB, MRCS, MD, FRCS: You've talked about ENDEAR comparing placebo to Spinraza, that it was obviously very easy to see the benefit in patients who were doing so well, so much so that the trial was terminated early so that those patients on placebo were able to get the treatment early.
