Written by Jill Condello on Thursday 23rd May 2019
The 71st Annual Meeting of the American Academy of Neurology (AAN) was held May 4–10, 2019 in Philadelphia, PA, drawing over 15,000 participants from around the globe. I had the opportunity to attend a variety of plenary, scientific, and poster sessions, as well as to peruse the experiential learning areas and exhibit hall, all of which confirmed that the field of neurology is experiencing a time of great growth and opportunity, though there are some evolving challenges to overcome. Herein, I highlight some of the most relevant themes and impactful takeaways from the meeting.
Three aspects of digital health were well covered at the meeting. The practice of telemedicine was highlighted as a potential mechanism to overcome the current shortage of neurologists. Use of telemedicine as a means of enhancing clinical trial participation was highlighted in a session on patients with amyotrophic lateral sclerosis (ALS), who may have difficulty reporting to the clinic for evaluations. Challenges such as audiovisual quality and integration with electronic medical records remain.
Numerous digital apps were highlighted at the AAN’s Innovation Hub as well as in numerous poster presentations, wherein they were said to have a role in enhancing patient screening, monitoring, and overall care, particularly in diseases such as multiple sclerosis (MS), Parkinson’s disease (PD), and Huntington’s disease (HD). Future challenges to overcome in this arena include privacy concerns, ease of data sharing, and how to best apply the collected data to clinical decision making. The notion of using digital apps and video games as therapeutics was also discussed at the meeting. The benefits of gaming on the brain, particularly with regard to enhancing the brain’s competence for visuospatial skills, were highlighted.
Finally, the role of big data in increasing patient access to effective therapy and high-quality care was tackled in an Experiential Learning session on the AAN’s Axon Registry®. The registry includes ~40 quality measures that are specific to neurology practice (rather than to population health) and to date, has gathered real-world data on 1.5M patients from 4.5M encounters. The AAN recently announced collaboration with Verana Health to license deidentified data, which could be used to facilitate anything from trial accrual to indirect therapy comparisons.
Historically, the field of neuroimmunology has included diseases such as neuromyelitis optica (NMOSD), which has recently experienced its own revolution. Positive results from phase 3 programs of 3 distinct immune system–targeted therapeutic modalities in development for NMOSD were featured at this year’s meeting. Eculizumab, a terminal complement inhibitor, satralizumab, a monoclonal antibody targeting IL-6, and inebilizumab, a B cell–depleting monoclonal antibody targeting CD19 were all associated with significant reductions in relapse rate; the study designs varied with regard to inclusion criteria (eg, aquaporin-4 [AQP-4] status, background immunomodulatory therapy). These breakthroughs have paved the way for the potential near-term introduction of 3 treatment options for a disease that currently has no available treatments.
In contrast, the already robust MS treatment landscape continues its evolution, with new immune-targeted pipeline agents in development. Two additional CD20-targeted monoclonal antibodies (to the already-approved ocrelizumab [Ocrevus®]) currently in phase 3 development, ofatumumab and ublituximab, were represented in the program. Also presented were positive 48-week data from a phase 2 study in relapsing MS of evobrutinib, a Bruton’s tyrosine kinase inhibitor, which also mediates B-cell receptor signaling. Notably, many of the more recent mechanisms being extended to the MS treatment landscape have their roots in oncology, which is undergoing an immunologic revolution of its own. As in oncology, adoptive cell therapy may not be too far off in the field of neuroimmunology. In fact, results of a phase 1b study of the effects of autologous tolerogenic dendritic cells loaded with myelin and AQP-4 peptides, showed successful elicitation of antigen-specific IL-10 production by T regulatory cells in patients with NMOSD or MS.
Recent discoveries have expanded the neuroimmunologic disease umbrella to include Alzheimer’s disease, PD, and ALS, which have been traditionally regarded as primarily neurodegenerative diseases. Recent research suggests that inappropriate immune responses contribute to PD pathogenesis, underpinning poster presentations at this year’s meeting that reported phase 2 study designs of the tyrosine kinase inhibitors, K0706 (PROSEEK) and nilotinib (Tasigna®; NILO-PD), the latter of which is approved in chronic myeloid leukemia. Researchers who undertook preclinical studies of imatinib (Gleevec®) in the G93A-SOD1 mouse, a model of ALS, which has also more recently received attention for its associated immune system alterations, said that the observed effects of delayed age of onset and slowed disease progression, coupled with the ability of the drug to cross the blood-brain barrier, suggest that further exploration of the therapeutic potential is warranted.
The advent of immune checkpoint inhibitors (ICIs) in the era of immuno-oncology had influence over the AAN meeting program. During the meeting, a review from the Mayo Clinic showed a 1.5% risk of neurologic autoimmune side effects with ICI use, potentially greater with combination therapy and retreatment. Overall, there were over 10 oral and poster presentations reporting on such adverse effects included in this year’s meeting program.
Based on this year’s scientific sessions, I suspect many neurologists would agree that across their discipline, rare disease is not actually that rare at all. Promising clinical study data for therapeutics in development for Angelman syndrome, Charcot-Marie-Tooth disease, neuronal ceroid lipofuscinoses (or Batten disease), and Leber’s hereditary optic neuropathy were featured in numerous oral presentations, including the Emerging Science session. Presentations on spinal muscular atrophy (SMA), a disease that is on the cusp of having a second gene therapy available for afflicted patients, were abundant.
With the development of rare disease therapeutics showing no signs of letting up, the conduct of natural history studies will be critical to adequately assessing efficacy. In his Plenary session presentation, Dr. Jonathan Mink spoke of his pioneering natural history work in Batten disease, which led to the development, refinement, and validation of the Unified Batten Disease Rating Scale as a clinical rating instrument. The need for natural history studies in SMA, where life expectancy is dramatically improving and adult patients are receiving treatment, was also emphasized. A handful of presentations on single-center experiences with nusinersen (Spinraza®) all noted that in general, treated patients reported some level of subjective global improvement; however, there is an overall lack of validated objective measures and/or biomarkers to adequately assess potential treatment benefits.
The prospect of implementing platform trials, similar to what we see occurring in the oncology space, was discussed in relation to recent progress in the understanding of and therapeutic development for ALS, particularly genetically defined cases, which make up 5–10% of all cases. Given a high unmet need for therapeutics and at least 5 gene therapies targeting the known genetic disease determinants superoxide dismutase 1 (SOD1) and C9orf72 in development, Dr. Jinsy Andrews emphasized the need to be more efficient in clinical investigations.
The notion of presymptomatic treatment is a real one in the SMA space and a dialogue around this ensued during a platform session on SMA treatments and outcomes. All active participants in the discussion were supportive of presymptomatic treatment, particularly given studies on Spinraza, AVXS-101 (Zolgensma®), and risdiplam that all demonstrated better outcomes with earlier treatment. Another topic of discussion during this session was the concept of combining gene therapies for improved outcomes. It will be interesting to see how these concepts play out in the maturing SMA market, particularly on the backbone of the high costs associated with novel gene therapies. With increased knowledge of genetic determinants of disease and increased development efforts on gene therapies targeting these determinants, the notion of presymptomatic treatment will surely garner debate.
With Zolgensma, a potentially curative one-time gene therapy looking toward an approval this month (and also toward a speculated 7-figure price tag), neurology is primed for outcomes-based payment models. While precedent for such models exists in other fields such as oncology, disease courses and treatment goals are markedly different in neurology. Notably, it will take time to assess treatment outcomes in neurologic disorders, which typically progress slowly over time. Treatment goals for many neurologic diseases are not as clear cut as survival, but rather involve measures including reduced pain and improved walking ability. Consideration of how to adequately and objectively collect and report such data will need to be given. Practitioners are also concerned with how to incorporate rare disease patients into their risk models and stated that high cost drugs have high institutional risks. Beyond the treatments themselves, high-priced administration routes such as intrathecal infusions were also noted as a concern.
Although the prolific gene therapy pipeline underpinned part of the discussion on drug pricing concerns, it was noted that rising drug prices are also affecting therapies that have been around for years, such as the interferons for MS. Indeed, an analysis of data from the IBM MarketScan® Commercial Database (2011–2015) presented as a poster by Kim et al showed that the primary contributor to rapid increases in healthcare costs for patients with MS was increasing cost of disease-modifying therapies. Historically, payer management of the MS space has been challenged by the complexity of the treatment landscape, a lack of comparative data, and lack of straightforward consensus treatment guidelines. With over 15 branded therapies spanning 10 mechanisms currently approved to treat MS and a plentiful late-stage pipeline (data on 6 additional therapies in development were featured at the meeting), management of the space will likely remain challenging. Though it was previously believed that the introduction of generics would drive prices down, data from a handful of posters discussing the potential for cost savings with the available glatiramer acetate generics suggest that the true impact is still being characterized. Beyond MS, audience members cited delays in generic competition and the need for at least 2 generic entrants to have any effect on pricing (which has been minimal to date) as additional prohibitive factors toward affordability.
When the anti-CGRP monoclonal antibodies entered the preventive migraine treatment landscape last year, they made a splash both for their promise of a new therapeutic modality in an area of high remaining unmet need as well as their associated price. During an educational session on “Hot Topics in Headache”, differences in US insurance coverage for the available anti-CGRPs were discussed. Of note is Express Scripts’ Migraine Care Value program, which offers an early discontinuation reimbursement back to the plan sponsor for patients who discontinue treatment within the first 90 days. Related to this, Dr. Peter Goadsby remarked during one of the Headache Clinical Trials scientific sessions that he believes the proportion of patients who will respond to the anti-CGRP mechanism is fixed and that when the mechanism works, it works quickly. Indeed, further classification of treatment responders may be invaluable to easing access to care. As manufacturers seek to improve access to care, the notion of anti-CGRPs as disease-modifying agents may be a potential avenue for value demonstration. At the meeting, data highlighting the impact of long-term treatment with erenumab (Aimovig™) or fremanezumab (Ajovy®) on the conversion from chronic to episodic migraine for many patients were presented. Discussants emphasized that additional research on the impact of long-term treatment on disability, health-related quality of life, allodynia, and acute treatment response would be required to fully understand this potential.
The AAN has put a Drug Pricing Task Force in place, the achievements and ongoing initiatives of which were discussed during the Presidential Plenary Address and a session entitled “Ultra High-Cost Drugs”. Some of the highlighted initiatives included engaging with payers to advocate for drug pricing control policies, engaging patients and their caregivers as advocates, and more closely scrutinizing industry relationships with regard to potential conflicts of interest.
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If you would like to hear more about this year’s AAN Meeting proceedings and their implications for Medical Affairs and Market Access strategy development, please contact me below:
Jill Condello, Vice President, Strategic Services, Peloton Advantage, an OPEN HEALTH company