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The SMA Market: Assessing The Unknowns ❚ MARKET ACCESS: When Disease Dynamics Change The SMA Market: Assessing The Unknowns The introductions of Spinraza and Zolgensma in SMA offer new insights into how to address neurodegenerative diseases. But more real-world evidence is needed. BY ALESSIA DEGLINCERTI, FRANK he landmark FDA approval of Novartis AG’s Zolgensma (onasemno- BOROWSKY AND MARK RATNER gene abeparvovec-xioi) in May 2019 shook the biopharma world in several ways including its price ($2.1m per dose) and as important, the very small With the approval of two disease data set on which the FDA primarily based its decision – an ongoing open- modifying agents, some patients label single arm trial of 21 infantile-onset patients with spinal muscular with SMA are becoming healthier Tatrophy (SMA) under two years old. Biogen Inc.’s Spinraza (nusinersen) had already and their medical needs are shifting. been approved in SMA in December 2016. As disease-modifying therapies, these compounds are a rarity in the field of neuro- A new natural course of the disease is muscular diseases of genetic origin. They are also at the core of a fascinating, ongo- emerging, with a larger population of ing real-world case study in how the natural course of a disease can change rapidly. individuals having stabilized disease. How companies’ SMA drug development and market access strategies evolve, both in But the extent of residual issues is not yet known – a picture that will only terms of new disease-modifying agents and supportive therapies that address residual come into focus over time. symptoms, could become a blueprint for other neuromuscular diseases like Duchenne’s Muscular Dystrophy (DMD) or Huntington’s Disease. So what? This evolution is influencing the Changing The Natural Course Of SMA clinical development and implementation of new treatments, leading to greater SMA is a genetic disease caused by an absence of or defect in the SMN1 gene, which opportunity for franchises that include encodes the survival motor neuron (SMN) protein. A back-up gene, SMN2, also produces supportive therapies. SMA could become SMN, although at lower levels (approximately 10-20% of what SMN1 makes) due to a blueprint for development and alternative splicing. Zolgensma is an adeno-associated virus vector-based gene therapy market access for other neurological that delivers a fully functional copy of human SMN gene into the target motor neuron diseases. cells. Spinraza and also Roche’s risdiplam, a small molecule in late-stage clinical trials licensed from PTC Therapeutics Inc., modulate splicing of SMN2 so that it produces levels of full-length SMN protein similar to that of SMN1. 1 | | November 2019 invivo.pharmamedtechbi.com In Vivo invivo.pharmaintelligence.informa.com ❚ MARKET ACCESS: When Disease Dynamics Change Exhibit 1 Disease-Modifying Therapies Are Favorably Shifting The Natural Course of SMA TYPE 1 TYPE 2 TYPE 3 TYPE 4 Severe muscle weakness; Delays in achieving Can stand and walk but Similar symptoms to does not achieve milestones, milestones; some can sit up develops increasingly type 3 (progressive including sitting without assistance whereas limited mobility muscle weakness), others need support but with later onset Symptoms Trouble breathing, coughing Difficulty running, and swallowing General weakness, climbing steps, or difficulty coughing, joint rising from a chair contractures Onset between 0 and 6 Onset between 6 and 18 Onset between 2 and Onset during months with a lifespan months 17 years old adulthood –typically of 2 years after 20 years old Prognosis Life expectancy is ~30 Normal or near-normal Mortality often associated years old, with mortality life span but ~50% Normal life span with pulmonary often due to respiratory become wheelchair complications impairment dependent SOURCE: Bionest Partners SMA falls into four categories based tinib) in chronic myelogenous leukemia. of change will also depend on the level on a combination of age and severity “We don’t have many events like that in of severity of the disease and the degree (see Exhibit 1). The hope is that disease- medicine where suddenly a treatment to which the patient had been affected modifying therapies can lessen the sever- comes along and the degree of change before starting treatment. ity of the disease: type 1s may become is so large that it’s obvious, even with more like type 2s, and similarly up the a small number of patients, that it is The Future Treatment Journey chain to 3s and 4s. something patients should be getting,” In the discussions leading to the ICER Before Spinraza, and now Zolgensma, he said. report, there was back-and-forth between infants with SMA were often unable to “We are inevitably seeing a dramatic Biogen and Novartis over which therapy move by the time they were six months change in the time course of new cases of was getting to all the necessary places to old, needing ventilation and by the time the disease,” added John Day, director of alter production of SMN, as the drugs tar- they were two, a feeding tube. They often the neuromuscular disorders program at get different loci in the body. The question did not live past two years old – or with the Stanford Neuroscience Health Center. points to unknowns around how these rigorous intervention, maybe to five But for prevalent cases already in exis- drugs will change the natural course of years old. “Now, we have kids that are tence, it is more of a leveling out of the the disease: over what period of time are walking sometimes, and certainly not disease course so that individuals with the effects sustainable, and for which ending up on ventilators, who are speak- SMA are no longer progressing. patients? (With Gleevec, for example, ing and able to feed themselves,” said “These are amazingly effective treat- its effects ultimately proved not to be as David Rind, chief medical officer of the ments but they can’t significantly reverse durable as originally hoped.) “We don’t the Institute for Clinical and Economic profound disability,” Day said. “We really know what the long term looks Review (ICER), whose amended Final are increasing life span but in a sense like for these kids with either therapy,” Evidence Report from May 2019 found increasing the morbidity associated Rind said. that Zolgensma can be reasonably con- with the disease because very few of New morbidities may also emerge, al- sidered cost-effective even at its $2.1m these children will be actually physi- though presently there is no concrete evi- price. “That’s an enormous change.” cally normal or typical.” After treatment, dence of this. That is because even with What happened with Zolgensma was already-symptomatic patients will have a static disease process, as a child ma- also unusual, Rind said – to have Phase some residual degree of motor neuron tures, the growth in body weight, height I trial results results so dramatic that it loss and attendant weakness and fatigue. and bone length increase the strain on was obvious the drug worked. The only The earliest onset features are proximal muscles. “As you get taller there may very other treatments Rind could recall having weakness in the lower extremities. “That well be a functional decline even though that level of dramatic effect were protease will continue to be a fairly common ele- there is no ongoing disease process,” Day inhibitors in HIV (the triple therapy) and, ment, depending on the age and stage said, not unlike a post-polio syndrome. to some extent, Novartis’s Gleevec (ima- of development,” he said. The degree “The challenge we and others will face 2 | | November 2019 invivo.pharmamedtechbi.com In Vivo invivo.pharmaintelligence.informa.com ❚ MARKET ACCESS: When Disease Dynamics Change in this field is what is the new natural in SMA that showed increases in the through gene therapy or a small molecule history of the disease,” offered Scott Jor- Six Minute Walk as well as a measure of or antisense drug. dan, senior vice president, new product respiratory muscle strength, but failed Taken together, the availability of planning and commercial development, to demonstrate differences as compared disease-modifying agents with different at Cytokinetics Inc. “With these new with placebo across several other assess- mechanisms that target different cell SMN-directed therapies, I think we are ments commonly used in SMA. “We are populations, the expectation of residual looking at a change from an approach of evaluating the best way to move forward disease for patients already showing characterizing patients based on their with reldesemtiv,” Jordan said. symptoms and the promise of muscle- genotype to one centered based on their According to Day, if reldesemtiv directed supportive therapy suggest that phenotype,” he said, perhaps measured increases muscle efficiency or force sequencing of treatments and establish- by meeting milestones over time instead production by 20% or 25%, it could be a ing the benefit of combination therapies of looking at the number of functional very valuable addition to any of the SMN for different sub-populations will be im- copies of SMN2, age of disease onset, or upregulating treatments. Increasing the portant future considerations. “One drug assessments based on the ability to sit efficiency of muscle force production for one patient is probably not the wave without support, stand or walk. means it would take less effort and energy of the future,” said Susan Begelman, vice “It remains to be seen what the new utilization to generate the required force, president, rare disease and neuroscience disease is,” added C. Frank Bennett, which should improve stamina. medical unit, US medical affairs at the senior vice president, research, at Ionis Cytokinetics’s approach is based on Genentech Inc. unit of Roche. Pharmaceuticals Inc., which discov- modulating the biology of muscle con- Roche plans to submit risdiplam for ered Spinraza and licensed the asset to traction.

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