Parkinson's disease: Still waiting for a cure

The author has lived with Young Onset Parkinson's Disease since 2009. Professionally he is a biopharmaceutical executive with knowledge of drug development. He offers a unique commentary on the (1) Patient experience participating in regulatory and scientific meetings, (2) Impact of the patient voice in PFDD, (3) Longitudinal portrait of living with a progressive disease, (4) Field of patient engagement, and (5) Convergence of biomarkers, biologic disease staging and novel clinical trial design. I am trained as a clinical pharmacist and have worked in the biopharmaceutical industry for over 30 years which provides me a depth of understanding of the complexities of drug development and the regulatory process. Fifteen years ago, I was diagnosed with Young Onset Parkinson's Disease (YOPD) and have experienced firsthand the Parkinson's journey and its progression over time.1 With this unique vantage, I have a front row seat in observing and commenting on the lengthy duration and challenges in developing novel treatments that offer meaningful benefit to me and my Parkinson's patient tribe.2 In May 2024, I was invited to attend the Michael J. Fox Foundation's Annual Parkinson's Progression Marker Initiative (PPMI) Investigators' Meeting.3 PPMI is a biomarker discovery initiative where I have served as a patient advisor for the past 7 years. Over these years, I have greatly enjoyed attending these meetings and learning the updates from this global neuroscience community. Each year, this event kicks off where a growing conference room of over 300 investigators, biopharma scientists, regulatory advisors, and a few patients all stand up and introduce themselves. This year, I introduced myself with the tagline, "Kevin Kwok, Patient Council Member…Still waiting for a cure." This "Still waiting for a cure" tagline elicited several waves and salutes from fellow attendees who have become ardent supporters and friends over my years as a Parkinson's patient advocate. Included in this group of supporters is Dr. Diane Stephenson from Critical Path for Parkinson's and Dr. Billy Dunn, former Neurology Division Head at the Food and Drug Administration. During his panel, Dr. Billy Dunn called on me by asking what year it was when I had traveled to the FDA headquarters in Bethesda where, as part of PDUFA,4, 5 I had provided patient testimony on my experience living with Parkinson's. I responded this patient event was September 2015, which led me to reflect on what had changed since that testimony. Here are excerpts from my personal blog 9 years ago after participating at this FDA led patient meeting (see Box 1). "On a Fall day [in 2015], I traveled to Washington DC, and had the fortune of addressing the US Food and Drug Administration (FDA) representing the Parkinson's community. As a career biopharma guy, this was the first time I participated with the FDA in this patient capacity. It was humbling and emotional." Other patient audience members raised issues of debilitating fatigue, precipitous drops in blood pressure when standing up, GI manifestations, behavioral aberrations, sexual dysfunction (both hyper and hypo) and the challenges to simply communicating. Social withdrawal and self-isolation were admitted… the latter not really a medical symptom but endemic of the disease. Many of these issues were not on the list of the FDA's top symptoms and often not asked about by physicians uninformed or caregivers too weary to ask. I presented as a 50-ish y.o. male who pretends to still be 30. I shared how I laughed when first diagnosed in my mid 40s. Initially, I thought PD was no big deal, but increasing muscle rigidity combined with a constellation of non-motor symptoms came to a head in 2013 as I feigned being ok but knew I was worsening. I shared how escalating medications were making me crawl out of my skin, relegating me to 3 h of sleep at night, affecting my behavior, mood, and executive function and how it impacted my own career track and my relationship with family and close friends. I also attempted to demonstrate how my Deep Brain Stimulation (DBS) completely "cured" my muscle rigidity, and how with a flick of a remote control, my left side, which with stimulation on looks normal, yet when turned off becomes grotesquely debilitated in just 30 s, and how instantly when turned back on, would again be normal. This is the razors edge I live… I shared with the FDA that my priority of needs was (1) to slow progression and prolong my surgical benefits for as long as I could, (2) treat (and educate society) the constellation of non-motor symptoms (NMS), (3) recognize the shortcomings of existing medications, (4) identify patients earlier so as to really make an impact, and (5) redefine the very definition and diagnosis criteria beyond motor symptoms when intervention might be too late. I spoke of how exercise and well-being were buying me back life. So, what did I gain from this FDA experience? Living with PD, you often feel a loss of control and relevance. Being allowed to present to the highest healthcare regulatory body in the country and having their focused attention was the ultimate form of control in what is often viewed as "well there is no cure and nothing we can do" world. Speaking out, learning more and most importantly, teaching others to destigmatize our ailments IS perhaps the ultimate control. While I am not so naive and star struck to expect a sea change to come from one FDA meeting, I was, however, approached by the FDA Director of the Neuro Division, Dr. Billy Dunn who was truly compassionate to our cause. He pulled me aside as we were disbanding and told me "Today, we heard and saw your stories and thank you … we understand your needs and while you may not see what goes behind federal doors … you all spoke loudly as one … and it was heard." "Now I am no rah rah, cheerleader … but I think this is something to cheer about … " My FDA patient testimony blog on living with Parkinson's disease has since been circulated to many leading neuroscientists, including Dr. Billy Dunn and others. Subsequently I have been invited to participate in numerous drug development workshops including those sponsored by Critical Path, the FDA and industry to provide the patient lived experience.6 I even pivoted my own career to lead patient engagement activities with a previous employer by incorporating patient perspectives in developing their select programs. I have personally witnessed Patient Focused Drug Development (PFDD) evolve from being a token afterthought implemented at late stages of clinical development to participating on panels where the patient voice is central in aiding translational research and early development decisions. PFDD has become a more common practice. Although the FDA has developed five regulatory guidance's on PFDD,7, 8 there is still room to grow when it comes to the level of industry adoption and patient participation. The FDA posts Voice of Patient reports on their website for all patient-focused drug development meetings9 which are a valuable resource for regulatory review of new drugs. The biopharmaceutical industry has historically used Key Opinion Leaders (KOL's) to represent patient needs. This secondhand perspective can lead to flawed assumptions resulting in protocol amendments, development delays, and commercial underperformance. The R&D process benefits from triangulating product assumptions by also utilizing Patient Opinion Leaders (POL's). These POLs are the informed experts of their own disease and offer nuanced insights that could make a difference in development strategies and commercial success. Incorporating POL insights is not market research. PFDD is an iterative dialogue between the drug developer and the patients it hopes to serve. PFDD is a shift in corporate culture where patient need is central. This patient centric culture is advancing. Last year, I participated in a company's development of a Patient Focused Target Product Profile as it shapes its Parkinson's asset for clinical development and product labeling. More recently, I have been part of a patient advisory council to a company assessing the feasibility and challenges of its translational stage biologic therapies. Participating in these meetings where the patient voice is valued empowers me with an opportunity to be a meaningful stakeholder in the management of my own Parkinson's journey. As a biopharma executive, I am surprised how often company scientists have not had the opportunity to converse with the actual patient community they dedicate their professional lives to. The patient voice can be powerful in both directions. It has been a long 9 years since my FDA patient testimony. Over this time, the Parkinson's Tribe and I have been "patiently" waiting and my still optimistic cheering personality has been tempered by seeing many of my own PD friends pass away from complications of a disease that was supposedly billed as "one that you would not die from."10 My own Parkinson's has markedly progressed, and many of the symptoms that were once merely nuisance symptoms have advanced to the point where they are debilitating and impact my activities of daily living. For those who only saw me at that 2015 FDA meeting, you might not recognize me today. My symptoms have devolved from manageable muscle rigidity and bradykinesia. I now experience debilitating off periods where I am incapacitated and physically frozen until my polypharmacy dosing regimen kicks in. Today I struggle with non-motor symptoms (NMS) such as extreme daytime fatigue, dizziness when standing, apathy, cognitive decline, and challenges with speech and communication. Many of these advancing symptoms were similar to the ones I had observed of my fellow Parkinson's panel members back in 2015 but had not yet experienced myself. I no longer can feign my way through these NMS as I did before. Perhaps of greatest impact on my life, I am no longer employed, which is socially isolating. My unmet need has evolved. Disease modifying interventions that provide me extended quality life-years outweighs symptomatic relief. While I was diagnosed as a young onset patient, now that I have entered my 60s, I feel like I am an imposter calling myself a YOPDer. Instruments that measure activities of daily living need to factor my evolving age, stage of disease, and priorities in life. Wearable devices to capture subtle changes could help between neurologist appointments, which are infrequent. I am not the same Parkinson's patient I was in 2015: I am not even the same patient each day. A new Parkinson's drug discovery and development paradigm is needed. Products based on medicinal chemistry modifications, pharmacokinetic improvement, and drug delivery technology that enhance existing medications are not therapeutic game changers. This is often reflected in tepid HCP endorsement, slow patient adoption, and payor reimbursement pushback. The Parkinson's community must have more innovative interventions.11 On May 23, 2024, The US Senate unanimously passed the bipartisan bill (HR 2365) to approve a National Plan to End Parkinson's12 reflecting the growing community groundswell. At the MJFF PPMI meeting, I could sense a newfound energy among the participants where biology constructs of disease outweighed symptomatic intervention. The adoption of an alpha synuclein seed amplification assays (a-syn)13 along with DAT imaging14 as biomarkers, combined with a new integrated Parkinson's biological staging system for research15 has opened a new era for developing new interventions, some that may have disease modifying potential. Dr. Tanya Simuni unveiled a new phase II platform trial targeting early stage 2B patients. This proposed Path to Prevention Trial (P2P)16 is a bold exploratory initiative and will evaluate a few promising investigational agents in parallel in a randomized placebo controlled multi-arm trial looking at biology and not symptoms for patient inclusion. Stage 2B Parkinson's patients will have the requisite biologic inclusion (positive alpha-Synuclein and DAT deficiency) and will be early on in their disease progression, with little or no functional impairment. Back in 2015 when I was much earlier in my PD progression, I would have volunteered on the spot to be in this innovative trial. Patient education and study communication will be needed to help catalyze enrollment of these early-stage patients, especially those from diverse backgrounds. Reflecting on my noted priority of needs in my 2015 blog, P2P attempts to address; slowing disease progression, targeting NMS, identifying earlier stage patients and diagnosis that focused on underlying biology. With P2P, I feel like our collective patient voices have been heard. P2P and this new biologic staging potentially looks at the question of when does Parkinson's start, which gets at the heart of my advocacy to create a world where those at risk for Parkinson's can avoid it altogether. For my children, prevention is a cure. I will encourage all newly diagnosed patients to inquire about this P2P trial to see if they are eligible to enroll. Unfortunately, for me personally, time has advanced since 2015, and my own Parkinson's disease progression puts me outside this inclusion window today. For my own Parkinson's management, and for other Tribe members with advanced PD, we focus our attention on optimizing existing treatment and lifestyle practices (exercise, sleep, and mindfulness) that slow Quality of Life (QOL) degradation today. However, for newly diagnosed patients or those at Parkinson's risk, I am extremely excited about the current energy I see in Parkinson's research. As a lifetime veteran of the biopharma industry, I have rarely seen this collective level of enthusiasm. The reason I bring up the passing of time is to remind my biopharma brethren is that in our industry that heralds a patient first mantra, 9 years to a Parkinson's patient can be a lifetime. I am frequently asked to present to patient groups on why it takes so long to develop novel treatments for Parkinson's.17 From my unique vantage, I am able to convey to my fellow patients the complexity of drug development, the importance of regulatory rigor, and the business risk involved. What I have not conveyed as well to my former pharma and research colleagues is the urgency that exists among the patient community. As excited as I was to hear Dr. Tanya Simuni's time and events plan for P2P, my years as a biopharma executive tells me there is still a way to go. She informed the PPMI investigator group that the study drugs for this trial were not yet disclosed due to ongoing negotiations between the MJFF and the interested pharma companies. Having led business development negotiations during my career, I realize just how protracted these discussions can be, and how risk aversion can supersede pace. The planned initiation of this platform study will hopefully begin patient enrollment by the end of 2025. Adding on study site ramp up and a 24-month assessment period, it will still be a few years before a phase II readout is seen. If phase III registration studies are conducted only after phase II results, it is easy to see how another generation of Parkinson's patients will advance like I have these past 9 years. My only request is that while all players here should not sacrifice rigor or take undue risk that they also proceed with urgency and a pulse on patient need through data sharing and collaboration. In my conversations to my fellow patients, I have used the analogy of previous Parkinson's drug research as "cave exploration in the dark." PPMI's biomarker initiative has resulted in the creation of an alpha synuclein "lantern" so we are no longer groping in the darkness but now have biologic illumination of the cavern we are exploring. Continuing with this analogy, the new Integrated Patient Staging for research can serve as a hand drawn map of the complex intertwining caves. The P2P trial provides us four new promising trailheads to explore these catacombs. We are living in a new era, where biomarkers and viewing Parkinson's from a biologic construct combined with the incorporation of new technologies can illuminate a research field that only a few years ago was groping in the dark. These recent initiatives give us hope in the Parkinson's world. I am excited for what these exploratory phase II trials might uncover under this new patient staging and wish to the industry sponsors and neuroscientists godspeed in their courageous explorations until we exit the Parkinson's cave. Meanwhile, as a Parkinson's patient I still continue to wait, but with renewed optimism. The author would like to acknowledge Dr. Billy Dunn and Dr. Diane Stephenson for advancing the PFDD initiative and empowering the patient voice in this new era in Parkinson's drug development. He would also like to thank the Michael J. Fox Foundation and the PPMI Investigators for their dedication to discover a biomarker to shift the research paradigm, and especially to the Parkinson's patient volunteers and their care providers, who make PPMI and drug development possible. No funding was received for this work. The author declared no competing interests for this work. Dr. Kevin Kwok is a retired senior biopharmaceutical executive with 35 years of broad strategic and operational experience. He is an active participant in Parkinson's clinical trials including adaptive (closed loop) Deep Brain Stimulation where he was one of the earliest patients implanted and tested with aDBS. The author has been an unpaid advisor on the lived experience with Parkinsonism's and best practices in patient engagement. In addition to serving on the patient councils for the Michael J. Fox Foundation and Critical Path for Parkinson's, He is a Parkinson's Foundation Advocate for Research. Dr. Kevin Kwok is on the Board of the Davis Phinney Foundation where he is a regular content developer and speaker.