Rare Community Profiles is a Patient Worthy article series of long-form interviews featuring various stakeholders in the rare disease community, such as patients, their families, advocates, scientists, and more.
A New Treatment Option on the Horizon: Zevra Therapeutics’ Dan Gallo Discusses Arimoclomol, the NDA PDUFA Date, and the Needs of the NPC Community
Arimoclomol stands out as a first-in-class, orally administered investigational agent for the treatment of Niemann-Pick disease type C (NPC). This investigational agent acts as a heat shock protein co-inducer that upregulates natural nascent protein folding in diseases such as amyotrophic lateral sclerosis (ALS), shares an article in ScienceDirect. Evidence suggests that arimoclomol also works on multiple transcription factors within the cell to improve lysosomal function, which is necessary in lysosomal storage disorders such as NPC.
Arimoclomol has received multiple designations from the U.S. Food and Drug Administration (FDA), including Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations; these acknowledge the drug’s potential to address significant unmet needs within the NPC community.
The clinical evidence supporting arimoclomol’s potential is robust. In trials, the drug has shown promise in slowing NPC progression, offering hope to families facing NPC diagnoses. Arimoclomol has been studied in several indications including ALS in 500+ people across 10 phase 1, four phase 2, and three phase 2/3 clinical trials with no significant safety issues identified. Yet its path to potential FDA approval has been fraught with challenges.
While many families frequently laud the impact of arimoclomol on their child’s development, the FDA has not yet seen the same benefits. In 2021, the FDA denied the drug’s approval, citing the need for additional qualitative and quantitative data. Gathering additional data and robust clinical evidence can be challenging, though, considering the small patient population.
Despite these obstacles, Zevra Therapeutics, a rare disease therapeutics company, acquired the product candidate from its former sponsor and has continued developing arimoclomol. In a promising development for the NPC community, the FDA has accepted Zevra’s New Drug Application (NDA) resubmission for arimoclomol. The Prescription Drug User Fee Act (PDUFA) date—the date when the FDA must respond regarding the approval—is set for September 21, 2024. This marks a pivotal moment not just for Zevra, but for the NPC community at large.
Dan Gallo: A Push to Advance Arimoclomol
A recent interview with Dan Gallo, PhD, the Senior Vice President of Medical Affairs and Advocacy at Zevra Therapeutics, delves into the hurdles encountered during the NDA submission process, the trial data that supported the NDA resubmission, and why it is imperative to include the voice of the patient and caregiver in everything the company does.
Gallo, a scientist by training, earned his doctorate in cell and molecular biology at Northwestern University before moving into a career in medical affairs—more specifically, supporting drug launches and global medical strategy at organizations such as Sanofi Genzyme, AbbVie, and Johnson & Johnson. During this time, he was introduced to rare diseases while working in the rare hematology space. Gallo found himself quickly fascinated, noting:
“I developed a strong appreciation of rare diseases and the complexities of drug development within this space. With rare diseases, there tends to be very limited or no treatment options—a high unmet need. Many times, if you’re working to develop therapies, you’re the only people working in that space. To me, this creates a sense of urgency and an incredibly collaborative environment.”
As his exposure to rare diseases grew, Gallo also found himself learning more about the individual, patient, and family experience. He shares:
“I’ve developed an increasing appreciation of how important it is to build that knowledge and experience into everything we do in pharma, whether that’s developing a study and identifying the best endpoints or thinking about the burden of a study on families or, even more recently, building an expanded access program where there’s a high unmet need with no approved options and limited opportunities to collect data.”
Gallo learned about arimoclomol when he joined biotechnology company Orphazyme as the Head of Medical Affairs in 2020. The company was eagerly preparing for the drug’s launch, and Gallo was a key part of the team building out the expanded access program. This began by building sites that would provide access to patients in a way that wasn’t burdensome—as Gallo explains, during the COVID-19 pandemic, this meant identifying clinicians who would be interested in assisting families through telehealth.
As the company began moving through its first regulatory review, Gallo and his team focused on the best pathways to collect data. He explains:
“Given the limitation of data in the rare disease space, and in NPC in particular, we had a unique opportunity to capture long-term data in these patients. Our approach captured real-world data and we worked with the International Niemann-Pick Disease Registry to put together a plan on how these patients would continue to be followed if the drug was approved.”
Zevra Therapeutics and the Challenges of Arimoclomol Development
In 2021, the prior arimoclomol sponsor, Orphazyme, was prepared to hear that arimoclomol was approved. Instead, the FDA sent a Complete Response Letter which let the company know that the FDA would not be moving forward with the application at that time. Orphazyme worked for months to develop its post-regulatory strategy for resubmission before the assets of the company were acquired by KemPharm in 2022. In January 2023, KemPharm changed its name to Zevra Therapeutics. Says Gallo:
“I joined Zevra because I wanted to see arimoclomol get approved for the NPC community. I felt hopeful that we’d get it to the point of approval. It fueled me and continues to fuel me. But I also loved the opportunity to work within and build a rare disease therapeutics company that focused on the experiences of people with rare diseases.”
Since receiving the Complete Response Letter three years ago, the Zevra Therapeutics team has been hard at work resolving associated issues and preparing the drug and NDA for resubmission. But this process has not been without challenges.
The first questions that the FDA had for Zevra Therapeutics regarded the instrument that studies used to assess clinical benefit—the 5-Domain NPC Clinical Severity Scale (NPCCSS)—and whether the tool could be reliably validated, particularly in the swallow domain. Further questions and concerns held by the FDA included statistical methods used to assess data and confirmatory evidence. Gallo shares:
“We’ve been focused on working to address these points directly over the last three years. While the approach we’ve taken to address each one is slightly different, we’ve held ongoing discussions with the FDA on our approach, as well as worked collaboratively with clinical experts and researchers in the field.”
New Data on Arimoclomol in the Adult NPC Population
Stemming from the research started at Orphazyme, and the continued Expanded Access Program (EAP), Gallo and his team have collected three years of patient data on arimoclomol, culminating, recently in presentation of the first clinical data in an adult population of NPC.
Zevra’s EAP provides access to arimoclomol for both adults and children with NPC and offers the capture of long-term clinical outcomes in patients. There is a minimum age of enrollment of two years old, but no maximum age of enrollment. Since most studies focus on NPC onset in childhood and adolescence, there are scant studies focused solely on the adult population.
Within the Zevra study, researchers followed individuals with adult-onset NPC and their long-term outcomes using the NPCCSS. Gallo shares:
“For the duration of evaluation, which reached two years in some cases, NPC remained relatively stable following arimoclomol treatment. This means there was little to no progression. Finally, from a safety perspective, there were no new safety signals observed with diarrhea, nasopharyngitis and COVID-19 being the most common AEs occurring in 7% to 10% of patients.”
Remaining Patient-Centric
Equally important in this journey to approval has been the voice of the patient community. Gallo emphasizes the critical role that patient experiences and feedback have played in shaping the development of arimoclomol. Understanding the daily challenges and needs of people with NPC has informed the broader advocacy and medical affairs strategies within the company. To maintain patient-centricity, Zevra works closely with patient advocacy groups and the NPC community. Gallo shares:
“Our advocacy partners have been key partners every step of the way. We understand that there are many stakeholders and try to work with each advocacy group and amplify their focus. If we’re planning an activity or looking for particular input, we always turn to these groups for that input. Every single one of them has played an important role in our drug development journey.”
For patients and families who would like to make a difference in the NPC space, Gallo suggests working with advocacy groups to learn what ways there are to contribute. He shares:
“The advocacy groups are there to help you understand what resources you have, what opportunities there are to make a difference, and how to amplify your voice to advocate for change. For example, the National Niemann-Pick Disease Foundation together with Ara Parseghian Medical Research Fund, Firefly Fund, Hope for Marian, SOAR-NPC, Dana’s Angel Research Trust, Hide & Seek Foundation and Hayley’s Hope, recently put together a statement in support of arimoclomol. Nearly 1,000 people signed the petition and provided their stories about the disease, its impact, the unmet need, their experience with arimoclomol in some cases, and how this drug has contributed to meaningful improvement in outcomes. It’s a great example of how every individual’s voice matters. For me, the takeaway is that the patient experience and patient voice is critically important in drug development.”
This patient-centric approach underscores Zevra’s dedication to not just meeting regulatory requirements, but also seeking to fundamentally improve the lives of those affected by NPC. As the PDUFA date approaches, the NPC community remains hopeful. If the FDA approves arimoclomol’s NDA, it will offer hope to the people and families who need it most.
