Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. Most cases of SMA are due to the SMN1 gene not being present, which results in a deficiency of survival motor neuron (SMN) protein. A lack of the SMN protein leads to progressive muscle weakness with a rapid onset in the most severe forms of the disease.
There are five types of SMA. They are numbered from type 0 to type 4. Classification is based on the severity of the disease and the age of onset. SMA Type 0 is unique because symptoms start in utero, so the infant is born in severe distress with extreme weakness and hypotonia, and often with areflexia. The infants do not survive the neonatal period without intervention and respiratory failure leads to death in one to six months. The symptoms in children with SMA type 1 (SMA1) occur in the first six months of life. SMA1 represents 60% of SMA cases. Symptoms in patients with SMA1 progress rapidly. Muscle weakness leads to difficulty breathing and feeding and the life expectancy is less than two years. Children with SMA2 have an intermediate form of the disease with symptoms appearing before 18 months. Patients are able to sit, but not able to stand and usually survive into adulthood. SMA3 symptoms begin after 18 months and are milder than SMA2. Patients are able to stand, sometimes walk and survive into adulthood. Patients may lose some motor abilities as they age. Patients with SMA4 have an onset of disease in adulthood, are able to stand and walk, and have normal lifespans.
Because research has focused on the most severe forms of SMA the rest of the review will discuss treatment for SMA1. Before the availability of nusinersen and in patients that are not candidates for the drug, treatment consisted of intensive respiratory treatments, nutrition, physical therapy and surgery. Respiratory treatments include use of devices to improve ventilation and secretion clearing, which may include non-invasive and invasive ventilator support. Enteral nutrition is needed to maintain caloric intake. Daily range of motion exercises are used to treat joint contractures and scoliosis. Bracing is used to maintain position and surgical procedures may be used for internal support of the spine. Use of these interventions slow the course of the disease and prolong life.
Nusinersen (Spinraza) is an antisense oligonucleotide treatment for spinal muscular atrophy that was approved by the FDA in 2016. The drug binds to SMN2 pre-mRNA to displace a repressor protein leading to full-length SMN2 mRNA, which leads to a stable, and functional SMN protein. Nusinersen is administered intrathecally, because it does not cross the blood-brain barrier. It is recommended that patients be sedated during administration, therefore the drug is administered in a hospital or surgery center that provides infusion services. Treatment with nusinersen is initiated with a four-dose schedule with the first three doses given at two-week intervals, then the fourth 30 days later. After the initial loading doses, nusinersen is given once every 4 months. Because nusinersen is an antisense oligonucleotide the labeling warns of a risk for thrombocytopenia, coagulation abnormalities, and renal toxicity and recommends platelet count, coagulation testing and quantitative spot urine protein at baseline and before each dose. The WAC for each dose of nusinersen is $125,000. Therefore, the cost of nusinersen in the first year is $750,000, then $375,000 annually for the maintenance dose.
Two pivotal nusinersen trials have been published. Both trials were stopped early after interim analysis demonstrated significant positive efficacy. In the 6-month, 110 patient, Phase III, ENDEAR trial, 51% of patients (37 of 73) that received nusinersen achieved a motor-milestone response as defined by the Hammersmith Infant Neurological Examination compared to none who received placebo in SMA infants with two copies of SMN2 and onset of symptoms at 6 months of age or younger (SMA type 1). Patients in the nusinersen group also had a higher likelihood of event-free survival. In the 15-month, 110 patient, Phase III, CHERISH trial, 57% of patients that received nusinersen had an improvement in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score of at least 3 points compared to 26% that received placebo in patients with late onset SMA (SMA type 2 or 3). The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale of motor function score was 61-62.6. Biogen announced interim results from the Phase II, open-label, NURTURE trial. NURTURE is evaluating nusinersen in 25 presymptomatic infants with SMA. Upon enrollment the infants were 6 weeks or younger, genetically diagnosed with SMA, but had not yet developed symptoms of SMA. At the time of the interim analysis all participants were alive and 14 months or older. No patient required tracheostomy or permanent ventilation and 22 patients were able to able to walk independently or with assistance.
Roche is developing risdiplam, an oral drug that increases the production of SMN by promoting inclusion of exon 7 in SMN2 mRNA. There is no indication on price, but the simplified administration may reduce total cost, when the drug is approved. Roche announced interim data from 17 patient that received the risdiplam dose for the Phase III portion of the the Phase II/III FIREFISH, open label trial, 93% of infants treated with risdiplam for at least 12 months had improved motor function by a median 17.5 points on the CHOP-INTEND scale and 64.5% were able to sit and 52.9% were able to maintain upright head control in patients with Type 1 spinal muscular atrophy. Three patients died but none were felt to be related to treatment.Roche also announced 12-month interim data from the 51 patient, Phase II/III SUNFISH trial; 71% of children age 2 to 11 and 42% of those aged 12-25 years treated with risdiplam improved motor function by at least 3 points on the MFM32 scale in patients with Type 2/3 spinal muscular atrophy. Roche also has trials in patients with SMA type 2/3 (JEWELFISH) and pre-synaptic SMA (RAINBOWFISH). Roche plans to submit an NDA for risdiplam in 2019.
The FDA approved onasemnogene abeparvovec (Zolgensma, Novartis) on 5/24/2019 for the treatment of patients under the age of two with bi-allelic mutations in the SMN1 gene. This would include babies with Type 1, 2 or 3 spinal muscular atrophy (SMA). Because the drug crosses the blood-brain barrier, it is administered as a one-time intravenous infusion. Onasemnogene abeparvovec prevents further muscle degeneration by providing a copy of the human SMN gene, allowing sustained SMN protein expression. Onasemnogene abeparvovec is a nonreplicating adenovirus (scAAV9) vector containing complementary DNA encoding the normal SMN. If long term data shows the effect of the therapy declines over time, it is likely that onasemnogene abeparvovec could not be repeated, because the patient would develop antibodies to it. The drug was approved with a black box warning regarding acute serious liver injury. Onasemnogene abeparvovec will initially be available at 60 medical centers. The sites will send blood for genetic manipulation to Novartis, who will then deliver the re-engineered treatment to the center.
In a 20-month, 15 patient, Phase I trial, treatment with onasemnogene abeparvovec resulted in all patients being alive compared to 8% of a historical control group of patients with SMA Type 1. At 3-months there was a 15.4-point improvement in the CHOP INTEND score in patients treated with onasemnogene abeparvovec compared to a decline in the historical control. Novartis announced that 10 patients enrolled in a long-term follow-up of the Phase I START trial had maintained the motor function and milestones gained during the trial at a mean 3.7 years follow-up. Novartis announced interim data from 22 patients in the Phase III, STR1VE trial, where treatment with onasemnogene abeparvovec resulted in a 14.3 point improvement in the CHOP INTEND score at five months in patients with SMA type 1 with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations. One patient died from respiratory failure, which was deemed to be unrelated to treatment. The Phase III STR1VE is estimated to be completed in 2020. A second Phase III trial is being conducted in Europe called STR1VE-EU. Results are not currently available, but one death has occurred in the trial. A preliminary examination suggested the death was due to severe respiratory infection followed by neurological complications, which was deemed possibly related to treatment. Novartis announced interim data from 19 patients in the Phase I, STRONG trial, where a single intrathecal injection of onasemnogene abeparvovec improved the HFMSE score by a mean 4.2 points at a mean average follow-up of 6.5 months post-treatment in patients with SMA type 2 with three copies of the SMN2 gene. Novartis also announced interim data from 18 patients in the Phase I, SPRINT trial, where a single intrathecal injection of onasemnogene abeparvovec improved the HFMSE score by a mean 8.9 points at a mean average follow-up of one months post-treatment in in pre-symptomatic patients with SMA and two or three copies of SMN2 who are ≤6 weeks of age.
Both onasemnogene abeparvovec and nusinersen may offer more benefit if used earlier or in presymptomatic patients. All three drugs are being evaluated in presymptomatic patients: nusinersen in the NURTURE trial, onasemnogene abeparvovec in the SPRINT trial and risdiplam in RAINBOWFISH. Long term trials of all three drugs are also needed as the effects of chronic administration are not known.
The Institute for Clinical and Economic Review or ICER reviewed nusinersen and onasemnogene abeparvovec for the treatment of Spinal Muscular Atophy and developed a cost effectiveness review that was finalized in April 2019. ICER used WAC for nusinersen to calculate a quality-adjusted life year (QALY) of $1.1 million as compared to best supportive care for SMA patients. ICER estimated that nusinersen would need to cost between $72,000 and $130,000 for the first year of treatment, with a maintenance cost $36,000 to $65,000 per year to be within the cost-effectiveness thresholds of $100,000-$150,000 per QALY. In calculating the cost based on the additional number of years a person lives due to a treatment, which is referred to as the life-year gained (LYG), ICER estimated that nusinersen should cost $83,000 to $145,000 in year one, and $41,000 to $72,000 for maintenance therapy to be in a range of $100,000-$150,000 per LYG. ICER released an addendum to the SMA review after the approval of onasemnogene abeparvovec based on additional clinical data. ICER estimated the drug cost at $1.1 to $1.9 million compared to best supportive care to reach cost effective QALY thresholds and $1.2 million to $2.1 million to be cost effective as the LYG threshold.
Novartis priced onasemnogene abeparvovec at $2.125 million per dose with the total price paid over five annual installments of $425,000 The price is lower than the $4-5 million cost to treat an SMA patient for 10 years and similar to the higher ICER estimates. AveXism said that if ICER had compared onasemnogene abeparvovec to nusinersen, instead of best supportive care, the drug would have been found to be cost effective up to $5 million. Novartis may agree to a performance-based agreement on pricing for onasemnogene abeparvovec as it has for tisagenlecleucel, where Novartis is only reimbursed for patients for whom the drug works.
Onasemnogene abeparvovec has the potential to replace nusinersen as the treatment of choice, even at a seven-figure price. An indirect comparison of the two drugs based on the 15 patient Phase I onasemnogene abeparvovec trial and the 73 patients that received nusinersen in the ENDEAR trial suggested an advantage of onasemnogene abeparvovec over nusinersen. However, with such a small patient population, a definitive conclusion should not be made. Nusinersen could eventually have competition from risdiplam. Assuming Roche submits an NDA for risdiplam in late 2019, the drug could be available in 2020.
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