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 () 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 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 , 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.

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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

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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. Alternatively, several companies approval before the end of the year: On Biogen as part of the companies’ broad are developing myostatin inhibitors, November 11, it announced that the com- strategic partnership around the use which could allow muscle to generate pound met its primary endpoint – change of antisense oligonucleotides to treat more force per action potential, allowing from baseline in an assessment of motor neurological diseases. individuals to do more work without hav- function at year one versus placebo – in The ability to upregulate SMN produc- ing to increase neuronal activity, which a pivotal Phase II/III study. An oral for- tion to stop disease progression, and is depleted in SMA. mulation that could be administered on delineating this new natural course of The most advanced myostatin inhibitor an outpatient basis, it is being tested in disease, opens the door for development is SRK-015 from Scholar Rock Holding pivotal studies enrolling a broad range of of novel supportive treatments, today Corp. Myostatin is a preferential regula- SMA patients from presymptomatic up to focused on therapies that address the de- tor of fast twitch muscle fibers (type II the age of six. Roche also has an ongoing cline in muscle function that SMA causes. muscle, which fatigues easily following study looking at individuals on previous Targeting muscle function is “a very ap- exertion). In SMA, there is a prominent treatments, which include the approved propriate approach now that we believe atrophy and deficit in fast twitch fiber disease modifiers and also olesoxime, a the underlying disease process is under mass and function. “In our view, the neuroprotectant via the acquisition of control,” Day said. He is also optimistic logical hypothesis is that in SMA there Trophos SA, on which Roche stopped there might be ways to increase energy is prominent atrophy of fast twitch fibers development in June 2018. utilization through addressing the meta- and so the idea is to block myostatin to “The way we think about our entry bolic side of muscle function, although address the motor deficit,” said Yung with risdiplam is that there are still quite that work is still early. These strategies Chyung, Scholar Rock’s CMO. a few patients who do not have any treat- are aimed at improving the health, func- Myostatin inhibitors may work best in ment options or access to any treatment tion and longevity of the depleted pool individuals with growth capable muscle, options,” Begelman said. An oral drug of motor neurons in patients with SMA, like younger people in SMA. Notably, in could be advantageous for older patients. as even with disease stabilization, that SMA the skeletal muscle does not appear It also could help Roche compete with pool of motor neurons remains reduced. to have any intrinsic structural defects, at Spinraza, which is an intrathecal therapy Muscle regeneration could also address least in later onset SMA. “That’s impor- and can be challenging to administer in the deficit, but again, research in this tant because we think if you build fiber individuals with scoliosis or spine fusion area is early-stage. mass in an impaired muscle, it is not clear resulting from SMA. Cytokinetics has been developing it will translate into meaningful motor Similarly, Biogen is testing more con- reldesemtiv, a next-generation skeletal functional gains,” Chyung said. venient dosing schedules for Spinraza: muscle compound, in SMA in partnership Scholar Rock’s Phase II trial of SRK- delivering higher doses administered less with Astellas Pharma Inc. It is intended 015 is focused on patients with type 2 frequently could be a benefit for older to slow the rate of calcium release from and 3 disease. Most will have already patients. It also has access to a small the regulatory troponin complex of fast been receiving Spinraza. “It is our belief molecule program aimed at modulating skeletal muscle fibers to improve muscle that a muscle-directed therapy would SMN splicing via a 2019 discovery collab- function and physical performance. In complement any SMN directed therapy oration with Skyhawk Therapeutics Inc. 2018, Cytokinetics announced results irrespective of the way they achieved res- Understanding which patients should from a Phase II study of the compound toration of SMN,” Chyung said, whether get which treatments and when they

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should receive them is critical. Assuring treating physician, as opposed to say costs as much as Spinraza year after year that the best subpopulation is enrolled to type 1 babies who immediately start to to be cost effective,” Rind said.) be better able to demonstrate benefit will have problems,” Begelman said. Still, the high price of these drugs has also be a priority. Real-world evidence Disease stabilization should lead to an prompted discussion of new payment (RWE) will show longitudinally how pa- increase in the number of people living models, especially with scant RWE. In tients change over time. But in SMA, those with what becomes a chronic disorder, the case of Zolgensma, payers have em- data are limited. That’s a challenge, Jordan who will have to deal with the conse- braced an outcomes-based model, but said, when it comes to doing clinical trials. quences of adjusting to and managing have shown little interest in the install- “What are the appropriate endpoints for their various symptoms. Increased aware- ment plan model proffered at the time ambulatory patients and non-ambulatory ness could mean more older individuals of approval. patients when we don’t know the natural living with milder forms of SMA will seek “In many cases, ICER feels outcomes- history,” he posed, in particular if patients (or return to) treatment. Conversely, in based contracts don’t accomplish very have been treated with the new SMN- some cases, older adults given a clinical much,” Rind said. “If you have a PCSK9 directed therapies. “That will complicate diagnosis of SMA without genetic testing inhibitor, for example, and you say if clinical trial design.” are now getting tested and found not to somebody has a myocardial infarction Assessing outcomes becomes com- have SMA, Day said. or a stroke within the given timeframe, plicated when layering in a therapy Indeed, assessing SMA in adults with- we’ll give back money, it’s basically like where you don’t know when a patient is out a genetic diagnosis can be tricky. In a discount,” based on the likelihood stabilized according to a short-term end- studies done at key medical schools eval- the event will occur, he explained. “You point measure like the Six Minute Walk, uating the effect of Spinraza in adults, might as well just give that discount to especially as children grow. “The ques- patients reported a perceived benefit in people.” However, with a $2.1 million tions are: When does a patient become stamina and more ability to do things, one-shot therapy where you are basing stable following treatment with these said Bennett, but the clinical measures the value of that price on the expecta- new SMN-directed therapies? And what being used did not capture those. “The tion of sustained benefit over decades, is the new natural history of the disease?” challenge is to develop new metrics for an outcomes-based contract potentially Jordan said. adult patients,” he said. makes more sense, he said. “If you’ve Engaging with patients, advocates, It is unclear whether the evolution in paid with the expectation of long-term regulators and health technology assess- SMA care will signal a move away from benefit and over time it’s shown that’s ment groups can help to direct clinical Centers of Excellence into secondary not true, you’ve way overpaid.” trial strategy and study design given this and tertiary medical practices as the The thornier question is what to do evolving natural history – identifying the disease stabilizes. “We are a little bit when new therapies come along. To date, best outcomes measures important to anxious about that,” Day said: Especially no studies have been done using two patients regardless of the natural history, for the newly diagnosed patients, the SMN splicing modifiers, leaving open then conducting a study that allows you concern is that they will likely still need questions of the overall value to a patient to look at a patient and make sure you other services such as physical therapy, of combining them, and how that would are seeing the benefit associated with a pulmonology, respiratory therapy or be looked at by a payer in terms of cost. supportive therapy rather than another occupational therapy, because of some “That is one of the challenges today,” therapy they may be on or have been degree of physical disability. “We want Begelman said. treated with historically. to make sure those are being addressed If a new disease-modifying drug like and attended to, and consequently we risdiplam comes along that’s intended to Market Access Considerations are working hard to coordinate with the be used in place of or on top of another Optimizing clinical design will help local providers and pediatricians, at least one, it would have to be used before loss determine the range of access to patient for the pediatric side of the equation, to of function occurs, Rind suggested. For populations for both disease-modifying make sure all of the chronic care needs add-ons like muscle-directed therapies, and supportive treatments. Establishing are being attended to.” in principle there is no reason why they the duration of response of a disease- Newborn screening for SMA is gradu- could not be started in tandem with a modifying treatment and the benefit of ally spreading throughout the US, with disease-modifying treatment. But payers sustained treatment will also help define the promise that all newborns will may require proof of disease stabiliza- the extent of access to certain SMA popula- have it in a few years. So, access for tion first. tions. Eventually, guidelines will emerge. presymptomatic and infantile-onset It is likely that a large number of SMA patients is virtually assured. Re- Building a Neurodegenerative SMA patients are untreated today. imbursement is also a given for these Disease Franchise Those with less severe forms of the dis- patients. ICER found both Spinraza and Three large biopharmas – Novartis, Bio- ease may not have enrolled in clinical Zolgensma clinically effective, and in gen and Roche – are aiming to establish trials or may go undiagnosed for some the case of Zolgensma, cost-effective as disease-modifying SMA franchises (see time because of a delayed manifesta- well. (The group thought Spinraza was Exhibit 2). Biogen and Roche are also tion. “SMA is not top of mind for a local overpriced: “It’s very hard for a drug that developing therapies to address muscle

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Exhibit 2 Overview Of The SMA Pipeline

COMPANY PRODUCT/PROGRAM STATUS

Biogen Spinraza (IV infusion SMN2 upregulator) Approved 2016

Novartis (AveXix) Zolgensma (SMN gene therapy) Approved 2019

Roche/Chugai/PTC Therapeutics Risdiplam (oral SMN2 upregulator) Phase III, filing expected 2019

Scholar Rock SRK-015 (myostatin inhibitor monoclonal antibody) Phase II

Astellas/Cytokinetics Reldesemtiv (oral fast skeletal troponin activator) Phase II

Catalyst/Jazz Pharmaceuticals Firdapse (oral potassium channel blocker) Phase II

Novartis Branaplam (oral SMN2 upregulator) Phase I/II

Biogen/AliveGen BIIB110 (Activin receptor IIA/B antagonist protein) Phase I

SOURCE: Biomedtracker

atrophy, suggesting a portfolio strategy. including multiple sclerosis, Alzheimer’s The nature of SMA made it a good start- Roche is planning a Phase III study of Disease, and DMD. A myostatin inhibitor ing point for drug development, which the anti-myostatin adnectin candidate or reldesemtiv might have a beneficial the Neurogenetics Branch of the National RG6206 (BMS-986089) in a different indi- effect in several. Institute of Neurological Disorders and cation, DMD, while Biogen has licensed The fact that Spinraza and Zolgensma Stroke recognized in the 1990s when it recombinant proteins from AliveGen USA are significant revenue-generating drugs identified SMA as an appropriate target Inc. that inhibit myostatin by interfering with obtainable reimbursement also pro- to develop novel treatments because of with the activin receptor. vides a benchmark for future clinical and the disease’s almost idealized clinical To compete, companies developing cost-effectiveness assessments in other features. SMA affects motor neurons but novel SMA drug candidates must address diseases, and with Spinraza, shows that not a lot else. It does not alter cerebral the key questions around how to design ef- companies should also have a broad- function: as opposed to most infants with ficient trials to optimize treatment timing based plan for evidence development weakness, children with SMA are alert and effect and whether alternative routes – an even more important consideration and awake and fully interactive – they of administration offer advantages. in other neuromuscular diseases, with have a fairly isolated muscle weakness In the hundreds of ultra-rare neurode- multi-factorial causes and symptomology due to the motor neuron loss. Plus, it is generative diseases, being able to show a compared to SMA. a recessive disorder with a back-up gene large effect size in a small patient popu- Had the Spinraza data been only pretty that makes the identical same protein, lation is a necessity. With Spinraza, for good rather than great, Biogen’s research providing two ideal targets to try to cor- example, after 20 patients, Ionis knew plan for it, where they did multiple rect genetically. the drug was working. “We are counting randomized trials looking at different Technologies altering genes have ma- on a large effect size to make our strategy groups, might have been a saving grace. tured and companies now have multiple work for rare diseases where it is difficult “I think it should be a model for look- gene-targeting platforms to choose from. to find homogeneous patients for clini- ing at diseases and new treatments for “I think the thought all along was SMA cal trials,” Bennett said. And to be able diseases,” Rind said. Contrast that with would allow us to move this methodology to demonstrate efficacy in a relatively the studies of Sarepta Therapeutics Inc.’s into other neurodegenerative and neuro- short amount of time, as was also the Exondys51 () in DMD, another muscular diseases,” said Day. case with Spinraza. neuromuscular disease in children. ICER IV124372 The evolution of SMA treatment could panned that drug in a recent review of become the blueprint for developing DMD drugs. “I can’t tell from the data we About The Authors disease-modifying and supportive have now if Exondys51 works or doesn’t Alessia Deglincerti (adeglincerti@bionest. therapies in other neuromuscular and work,” Rind said. “They didn’t do a com) is a senior consultant and Frank neurodegenerative diseases and in the trial that looked like what Biogen did. If Borowsky ([email protected]) a case of the latter, potentially applying Sarepta had done what Biogen did, we consultant with Bionest Partners based them across indications. Fatigue, for ex- would certainly know by now whether it in New York. Mark Ratner (mlratner@veri- ample, is common across many disorders is helping patients.” zon.net) is a contributing editor to In Vivo.

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