Overcoming Barriers in Spinal Muscular Atrophy Treatment, Research

In a recent interview with First Report Managed Care, Lucia Chehade, BSc, MD/PhD Candidate, Cellular and Molecular Medicine, University of Ottawa, Canada, outlines available therapy options for spinal muscular atrophy (SMA) and sheds light on the challenges related to overall knowledge of the disorder and its associated costs.

Please introduce yourself and tell us a bit about your background.

My name is Lucia Chehade and I am an MD/PhD Candidate in the faculty of medicine at the University of Ottawa. I am currently completing my PhD studies in Cellular and Molecular Medicine under the supervision of Rashmi Kothary, PhD, at the Ottawa Hospital Research Institute in the Regenerative Medicine Program.

In Dr Kothary’s laboratory, we address the pathogenesis of the human disease SMA. We study peripheral organ involvement to better guide therapeutic intervention when considering clinical care management for SMA patients.

Can you describe the current therapy landscape for spinal muscular atrophy and what makes it challenging? What burden do these challenges and gaps have on patients and their families?

In terms of the current treatment landscape, there are 3 therapies for SMA including nusinersen, onasemnogene abeparvovec, and risdiplam. Nusinersen was the first of the 3 to have received approval from the US Food & Drug Administration (FDA) in 2016 for all ages and types of SMA for both pediatric and adult patients. It is an antisense oligonucleotide that targets SMN2 mRNA splicing resulting in more full-length functional SMN protein. The treatment is delivered into the spinal cord via intrathecal injection and involves several loading and maintenance doses throughout the lifespan of the patient.

In 2019, onasemnogene became the second treatment approved for SMA. It is a gene therapy replacement that consists of an adeno associated virus serotype 9 (AAV9) expressing SMN1 cDNA. The virus enters patient cells where it promotes the expression of SMN protein. This one-time intravenous treatment was an exciting alternative to the invasive and frequent dosing schedule of nusinersen.

Finally, the third treatment available for SMA patients is risdiplam, a once-daily orally administered small molecule with a similar mechanism to nusinersen offering the least invasive form of SMA treatment administration.

Living with SMA is challenging for patients, their families, caregivers, medical personnel, and society. SMA treatment can be very complex and challenging due to: (1) the need for early screening and intervention; (2) barriers to access the treatments and SMA-specific health services; (3) treatment adverse events; (4) variability in response to treatment; and (5) long-term effects and quality of life. 

Several countries around the world have yet to implement newborn screening for SMA despite the evidence that an early diagnosis allows for a timely-intervention and substantial improvement of neurodevelopmental outcome. Lack of early diagnosis leads to delays in intervention and worse outcomes, increased cost of illness, and lower quality of life, among many other effects.

With nusinersen, the cost of the treatment is up to $750,000 (US) for the first year and then $250,000 per year thereafter. Onasemnogene is distributed with a price point of $2,125,000 for the one-time treatment. The annual price of risdiplam varies between $100,000 to $340,000 depending on age and weight of the patient. Despite the availability of financial assistance through respective drug companies, insurance, or government assistance, there remains a high cost associated with the illness and consumption of medical and non-medical resources.

All 3 treatments have adverse side effects which can contribute to decreased quality of life in SMA patients. Infections and/or respiratory problems and post-lumbar puncture complications are reported following nusinersen treatment. Onasemnogene has caused liver toxicity, thrombotic microangiopathy, thrombocytopenia, and cardiac toxicity in patients. Several concerns were raised around growth impairment, male fertility impairment, retinal toxicity seen in pre-clinical studies with risdiplam. In addition, variability in treatment response remains a significant problem and these inconsistencies in treatment efficacy between patients are not well understood.

The quality of life of patients that is achieved by current SMA treatments remains unclear. We see improvements in survival and motor function, yet in most cases, treatment does not allow patients to truly thrive, nor live a normal life. Long-term clinical benefits of these treatments also remain unknown, especially for the newer treatments like onasemnogene and risdiplam. In the context of treatment with nusinersen in adults with SMA, we tend to see a stabilization of the progression of SMA without necessarily restoring strength over time. This begs the question of whether nusinersen is effective enough to warrant the invasive nature of the treatment. Whether patients will reach significant milestones (walking, standing), regain function over time, or even be free of serious adverse effects and invasive ventilation support and achieve a certain standard of quality of life all remain to be demonstrated. The burden that comes along with the decision to undergo treatment can be a very difficult and therefore we need to understand these gaps to better guide patients and their families.

Where do you see the future of SMA care heading?

With the current treatments, the landscape of SMA disease is shifting rapidly. This is also changing the management outcomes, and costs associated with SMA posing several challenges to patients, their families, as well as to clinicians/researchers. The full impact of the treatments on SMA disease burden and quality of life is currently not well understood and will not be apparent for several years as patients continue to age.

The future of SMA care is heading towards improving the quality of life of SMA patients and developing a holistic approach to treating the patient. So, the focus must shift to optimizing the treatments we currently have to decrease the side effects, developing combinatorial treatments and non-SMN mediated therapies such as muscle enhancing therapies to address the systemic nature of SMA, develop effective treatments for older patients who have been diagnosed long before the availability of these 3 treatments.

We also must build a solid clinical infrastructure and tools to properly follow patients and easily identify the unmet gaps in clinical and scientific research.

What is something you would like payers or formulary decision makers to better understand about the burden of SMA?

The current treatments have made impressive strides in extending patient lives and improving motor function. It is exciting to have drugs that can increase levels of the SMN protein and subsequently improve symptoms in patients. Yet, these approaches are not curative, and the burden of SMA remains heavy for patients, their families, and the entirety of the clinical and scientific community.

We still have so many unanswered fundamental research questions that could guide us in optimizing our treatment approaches and ultimately yield better responses and outcomes. In fact, most gaps in our knowledge lie in the basic scientific understanding of the disease. We still do not understand why low SMN levels leads to motor neuron death in SMA. We lack understanding of the molecular pathways that are SMN dependent or independent that participate in the pathogenesis of the disease, and how peripheral organ pathology contributes to SMA. We also do not understand why there is so much variability between patients, why some benefit from the treatments while others do not. These are some of the questions that absolutely need to be addressed and this is only possible when sponsors, decision makers, clinicians, and basic science researchers collaborate and share their data and materials. It is therefore important that we work together and invest in basic research to understand all aspects of SMA.