Along with Chris Comish, President and CEO of Charcot-Marie-Tooth’s parent company BioNews Services, I recently had the opportunity to attend the FDA Patient-Focused Drug Development (PFDD) Meeting for Charcot-Marie-Tooth disease. Hosted by the Hereditary Neuropathy Foundation in conjunction with the Food and Drug Administration, this meeting was one in an ongoing series across a wide range of diseases (many of which are rare or orphan diseases) that allows patient and caregiver discussion panels to talk candidly about the unique challenges of living with chronic and rare diseases, as well as provide both the FDA and drug development companies with value insights into the most critical unmet medical needs.
Chris and I attended our first PFDD meeting for spinal muscular atrophy (SMA) in the spring of 2017. The experience continues to resonate for us even today. As publishers of over 70 disease-specific news websites (and growing), that meeting helped to focus our editorial mission to serve SMA patients and their families with the content that they need to better manage the disease. Now, after attending the PFDD for Charcot-Marie-Tooth, we come away with the fresh insights from another truly inspiring patient-focused meeting.
Opening remarks and the meeting’s keynote was delivered by Allison Moore, Founder and CEO of the Hereditary Neuropathy Foundation (HNF). Herself a CMT patient, Ms. Moore opened by saying that,”today is a celebration,” adding that, because “people with CMT rarely get the diagnosis and treatments they need at the time they need them,” the first Patient-focused Drug Development meeting for CMT offers the patient-caregiver community a much-needed opportunity to address the critical needs of patients with CMT. “Today is the beginning of a new future” she stated in closing.
PFDDs typically feature an FDA advisor or representative who speaks prior to the patient and caregiver discussion panels. Meghana Chalasani, Office of Strategic Programs at CDER, spoke at length about the FDA’s understanding that CMT is indeed a “complex and serious condition” that has “significant unmet medical need for patients” — a recurring theme throughout the meeting, as patients and parent went on to underscore the largely unrecognized level of disability that CMT patients face. Ms. Chalasani concluded by acknowledging that the “FDA plays a critical role” in working in tandem with drug development companies to bring new therapies to market for meeting the medical needs of rare disease patients, and that she was “really happy to see a high level interest from all of the critical stakeholders” in CMT drug development.
The meeting’s focus on CMT patients’ needs were introduced by a moving, intimate documentary entitled “A Day in the Life of CMT,” which featured the Warren family. The film interviewed and followed Phillip Warren, an adult CMT patient and father to young Reagan Warren, who has the disease as well. Brooke Warren spoke of her role as wife, mother, and caregiver to both Phillip and Reagan, discussing the specific challenges that face their family. While there are over 2.6 million people living with CMT in the world, and nearly 125K in the US, the Warren’s short documentary put the impact of CMT into focus for those in attendance, illustrating the effect of the disease not only on adults, but on children as well.
An CMT expert also spoke about the disease at length. The “What is CMT?” overview, hosted by Michael Shy, MD, outlined the hallmark symptoms of CMT, which were later on reinforced by polling data among the meeting attendees. Balance problems and fatigue are among the most predominant symptoms of CMT, and the patient advocates at the meeting generally agreed that therapies that address these two symptoms are the most needed. (Dr. Shy added that balance issues and fatigue are inter-related in CMT, since “it takes a lot of work to make sure that you don’t fall.)
Additional symptoms noted by Dr. Shy and reinforced by polls conducted with the PFDD audience included impaired hearing, vision problems, vocal chord strain or weakness, breathing difficulty, peripheral neuropathy, scoliosis, hip dysplasia, and hand tremors. Of these, breathing difficulties became an ongoing theme throughout the panel discussions, with patients from the panels and in the audience talking about how the progression of CMT led to serious breathing issues, and even death in the case of many loved ones who lived with the disease for decades.
The first panel featured a discussion on symptoms and daily challenges that matter most to pediatric and young adults living with CMT. The panel of five young adults, ranging from grade school to college, spoke about the significant social challenges that children and young adults face with CMT, such as the inability to engage in athletics and other physical activities, as well as how some of the health challenges of the disease can lead to social stigmas and bullying. The panelists expressed their desire for next-generation therapies to address the health issues that keep pediatric CMT patients from having a normal childhood.
The second panel discussion on symptoms and daily challenges that matter most to adults living with CMT. The adult panelists spoke of the long-term effects of the disease on their lives, with some of them having lived for a significant period of their life without a proper diagnosis and not understanding why they experienced physical limitations or where their often debilitating symptoms came from. Just as the pediatric panel talked about how CMT limits their ability to do normal activities, the adult panelists also discussed the impact of their limitations. However, as spouses, parents, and providers, the adults also spoke of their struggle to perform these roles on a consistent basis.
Further group facilitated discussion and polling indicated that the top three symptoms experienced in everyday quality of life included balance and ability to stand, mobility issues such as foot drop, walking, tripping, and frequent falls; and coordination with hands and arms, such as difficulty grasping, holding objects, and fine motor skills.
Most impactful effects of the disease include the ability to participate in or perform daily activities, emotional impacts such as fear, embarrassment, self-esteem, and the ability to get around easily.
Future worries about the progression of the disease include balance and the ability to stand; mobility issues, and coordination with hands.
The loss of hand dexterity and movement was reported by a wide range of CMT patients at the meeting, with the progression of the disease leading many to have to change or lose jobs, give up driving, and experience the inability to use eating and writing utensils. One gentleman, who was forced to retire early from his career in the Navy, explained that the inability to write and type was the main cause of no longer being able to work in his field.”We express ourselves in many ways through our hands,” he noted, explaining that, from his perspective, losing strength and coordination in his hands has had the most significant impact on his life.
Breathing problems were underscored by many of the panelists and audience members, who spoke of the lack of understanding among many in the medical community in how to identify and treat this aspect of the disease. Issues with breathing range from shortness of breath and the ability to speak for long periods of time without feeling breathless to serious breathing issues that led CMT patients to pass away due to ineffective or damaging treatments.
For as much as the Charcot-Marie-Tooth PFDD meeting was filled with emotion in discussing the dire effects of the disease on so many people’s lives, there was also a great deal of hope and excitement running through the meeting as well. Much like SMA, which benefitted immensely from the FDA approval of landmark therapy Spinraza in December of 2016, CMT may also be on the cusp of getting its first substantial therapies. French pharmaceutical company Pharnext is developing PXT3003 for treatment of CMT in both children and adults with the CMT1a mutation. The results from their pivotal phase 3 clinical trial testing the therapy in adults patients is just due to wrap up this month, after reporting promising top-line results in June.
Additionally, Sarepta Pharmaceuticals, developers of muscular dystrophy therapy Exondys 51, recently acquired the rights to a promising gene therapy for the treatment of CMT. Gene therapy is now the vanguard of drug development for many rare diseases, with AveXis’ AVXS-101 reported to be possibly close to an approval for the treatment of SMA. Similarly, researchers are looking to gene therapy to address CMT in order to halt the progression of the disease — an approach that could eventually improve the quality of life in adults with the disease as well as virtually erase it for young people who are diagnosed early.
The attendees of the PFDD came away from the meeting with a sense of optimism for the future of treating the disease, as well as a sense of satisfaction that patients of an otherwise unknown and misunderstood disease finally had an opportunity to talk about their experience with CMT with stakeholders in the medical industry. Instead of scientists and regulators leading the way in discussing CMT, patients, their families, and caregivers had the floor. As noted, it was a critically important listening opportunity for the Charcot-Marie-Tooth News team, as well as for the pharmaceutical companies and FDA. While there is no doubt that those with Charcot-Marie-Tooth have suffered from the disease for well over 100 years since its identification, and will continue to struggle with CMT going forward, there is indeed hope in the near future in treating and living with the disease.