Continuing Rare Disease Treatment With A Compassionate Use Program (CUP)

By Davelyn Eaves Hood, head of medical & patient affairs, Rezolute, and Ana Paula Tediosi, head of expanded access program strategy, WEP Clinical

Small biotechnology companies are pivotal in advancing treatments for rare diseases, often spearheading the introduction of innovative, transformative therapies for conditions that previously had few or no effective treatments. These companies possess a unique agility, allowing them to concentrate on niche areas that larger pharmaceutical firms may avoid due to limited market incentives or overall R&D capacity.

However, with more innovation needed to achieve both regulatory approvals and payer recommendations, drugs have to be developed for conditions with huge unmet clinical need and often very little established data on the actual indication or disease area. Therefore, R&D investment in rare disease areas is considerably higher than in more common indications.¹ This financial pressure drives smaller companies to adhere to established development pathways to help control expenses.² The trade-off often results in prolonged development timelines, delaying access to promising therapies for patients with significant unmet needs.

With regulatory agencies increasingly open to real-world evidence, we explored the benefits and challenges of harnessing a compassionate use program (CUP) to further embrace our patient-centric approach to drug development.

In part one of this series, we detail our unique circumstance in pursuing ersodetug, an investigational drug for treating congenital hyperinsulinism (cHI), and how it led to the pursuit of a compassionate use program. We also detail some of the challenges, in general, for enrolling rare disease patients in a clinical trial. Then in part two, we’ll discuss the benefits of a CUP and strategies for implementing one.

Exploring “Compassionate Use” With Rare Disease Patients

Rezolute is a late-stage rare disease company focused on significantly improving outcomes for individuals with hypoglycemia caused by multiple forms of hyperinsulinism (HI). In 2021, as the world began emerging from the global pandemic shutdown, Rezolute was actively recruiting participants for its global Phase 2b study, RZ358-606 (RIZE). The RIZE study aimed to evaluate the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of RZ358 (ersodetug), an investigational drug for treating congenital hyperinsulinism (cHI). Ersodetug is a novel, fully human monoclonal antibody that allosterically binds to the insulin receptor, reducing insulin's binding affinity and signaling in target tissues.

Congenital HI is a rare pediatric disease affecting approximately one in 28,000 individuals of European ancestry³ and up to one in 2,600 in limited gene pool populations.⁴ It is characterized by persistent hypoglycemia due to dysregulated insulin secretion from pancreatic β-cells. Frequent hypoglycemia in cHI can lead to severe neurological outcomes, including seizures, permanent brain damage, and death. The treatment landscape for cHI, like most rare diseases, is dominated by standard-of-care therapies not specifically designed for cHI or pediatric use. These existing treatments often fail to manage the disease adequately, forcing physicians and families to balance significant adverse side effects with the urgent need to prevent hypoglycemia.⁵

The RIZE study commenced in early 2020, aiming to enroll four to eight participants across four ascending, open-label dose cohorts in participants aged 2 years and older with persistent hypoglycemia due to cHI. By mid-2021, only the first cohort had been filled. To accelerate enrollment as study centers could once again perform elective inpatient stays and travel became more feasible, Rezolute implemented several strategies to enhance enrollment and attract participants. A key strategy at the time was committing to a CUP for participants who expressed interest in continuing ersodetug after experiencing significant benefits during RIZE.

Despite challenges such as the lack of in-country regulations allowing compassionate use and incentives for site participation, a handful of RIZE investigators transitioned from study PIs to CUP treating physicians. Currently, three children from the RIZE study continue to use ersodetug, including two who have been on monotherapy for over two years, helping to demonstrate the long-term safety and durability of the therapy for cHI, Rezolute's primary indication.

The establishment of the CUP infrastructure also yielded an unexpected benefit. In August of 2022, shortly after the last participant completed the RIZE study, a request for ersodetug was received for a critically ill patient with metastatic insulinoma, who was dependent on high rates of intravenous glucose in the ICU when standard therapies failed to manage their severe hypoglycemia. Ersodetug therapy began 11 days after the initial request, and approximately six weeks later, the patient was discharged home. The patient’s glycemic stability allowed them to receive tumor-targeted therapy, significantly improving their quality of life for an additional 15 months until they ultimately succumbed to tumor progression. A summary of this case was published in a highly regarded peer-reviewed journal,⁶ leading to additional compassionate use requests, with each patient experiencing similar promising outcomes. The accumulation of proof-of-concept data not only accelerated plans to seek tumor hyperinsulinism (tumorHI) as a second indication for ersodetug but also facilitated favorable regulatory interactions to advance these plans resulting in alignment on a Phase 3, multicenter, double-blind, randomized, controlled, safety and efficacy registrational study for ersodetug in patients with hypoglycemia resulting from tumorHI.

Rare Disease Enrollment Challenges

Enrolling rare disease clinical trials poses several challenges due to the unique characteristics and complexities associated with rare diseases, including but certainly not restricted to:

Limited Patient Population: Rare diseases, by definition, affect a small number of individuals. This limited patient pool makes it difficult to find and recruit eligible participants who meet the specific criteria for a clinical trial.

Geographic Dispersion: Patients with rare diseases are often scattered across wide geographic areas, sometimes globally. This dispersion complicates recruitment efforts and increases logistical challenges related to travel and coordination.

Heterogeneous Patient Populations: Rare diseases can exhibit significant variability in symptoms and progression among patients. This heterogeneity can complicate the establishment of consistent eligibility criteria and the assessment of treatment efficacy.

Regulatory and Ethical Considerations: Conducting clinical trials for rare diseases often involves navigating complex regulatory requirements and ethical considerations, especially when dealing with vulnerable populations such as children.

High Costs and Resource Constraints: Rare disease trials often require specialized resources and expertise, leading to relatively higher per-participant costs. Smaller biopharmaceutical companies, which frequently focus on rare diseases, may face financial and resource constraints that limit their ability to conduct extensive global recruitment efforts.

Competing Trials and Treatment Options: With a limited patient pool, multiple ongoing clinical trials for the same rare disease can compete for the same participants, further complicating recruitment.

Psychosocial and Emotional Factors: Patients and their families may experience fear, anxiety, or mistrust regarding experimental treatments and clinical trials. These emotional factors can influence their willingness to participate.

Addressing these challenges requires innovative recruitment strategies, collaboration among stakeholders, careful selection of specialized pharmaceutical service providers, and patient-centric approaches to enhance trial enrollment and retention for rare disease clinical studies.

In part two of this series, we unearth the benefits of implementing a CUP and learn how to implement a CUP strategy.

Acknowledgments:

The authors extend our sincere thanks to Erin O’Boyle at Rezolute for her invaluable operational support of the CUP since its inception. We also wish to thank Gabby Sorenson Jones, Julia Waters, and Mona Salih at WEP Clinical for their dependable management of the Rezolute CUP project. In addition, we wish to recognize Jasmine Sidhu at Rezolute and the broader WEP team for their relevant input and review during the development of this white paper. Most importantly, we are grateful for the opportunity to offer ersodetug under compassionate use to patients which has inspired our teams and provided meaningful insights about this investigational therapy.

References:

1. Conti, R. M., Gruber, J., Ollendorf, D. A., & Neumann, P. J. (2020). Valuing Rare Pediatric Drugs: An Economics Perspective. Cambridge: National Bureau of Economic Research. Retrieved from https://www.nber.org/system/files/working_papers/w27978/w27978.pdf
2. Barrett, J. S., Betourne, A., Walls, R. L., Lasater, K., Russell, S., Borens, A., . . . Roddy, W. (2023). The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP). Journal of pharmacokinetics and pharmacodynamics, 50(6), 507-519. doi:10.1007/s10928-023-09859-7
3. Lapidus, D., DeLeon, D. D., Thornton, P. S., Hood, D., Breit, J., Raskin, J., & Pasquini, T. L. (2024). The Birth Prevalence of Congenital Hyperinsulinism: A Narrative Review of the Epidemiology of a Rare Disease. Hormone Research in Paediatrics, 1-8. doi:10.1159/000539464
4. Mathew, P., Young, J., Abu-Osba, Y., Mulhern, B., Hammoudi, S., Hamdan, J., & Sa'di, A. (1988). Persistent Neonatal Hyperinsulinism. Clinical Pediatrics, 27(3), 148-151.
5. Banerjee, I., Raskin, J., Arnoux, J., De Leon, D., Weinzimer, S., Hammer, M., . . . Thornton, P. (2022). Congenital hyperinsulinism in infancy and childhood: challenges, unmet needs and the perspective of patients and families. Orphanet Journal of Rare Diseases, 17(1).
6. Osataphan, S., Vamvini, M., Rosen, E., Pei, L., Erlikh, N., Singh, G., . . . Patti, M. (2023). Osataphan, S., Vamvini, M., Rosen, E., Pei, L., Erlikh, N., Singh, G., Dhorajiya, P., Parker, J., Dreyfuss, J., Rattani, A., & Patti, M. The New England Journal of Medicine, 389(8), 767-769.

About The Authors:

Davelyn Eaves Hood, MD, MBA, BCMAS, is the head of medical and patient affairs at Rezolute, Inc., where she brings decades of leadership in rare disease advocacy and patient-centric healthcare administration. With a robust background in primary care and the U.S. payer system, Dr. Hood has been instrumental in advancing Rezolute's rare disease drug development efforts, particularly in hyperinsulinism clinical trials, strengthening KOL engagement, and spearheading the creation of the company's compassionate use program. As a rare disease parent, former Board President of Congenital Hyperinsulinism International, and previous, founding principal investigator of the HI Global Registry, Dr. Hood fosters collaboration between industry and rare disease community stakeholders to advance shared goals.

With over 10 years of experience in the pharmaceutical industry, Ana Paula Tediosi, MPharm is a recognized expert in the field of Expanded Access Programs (EAP). Her expertise lies in oncology, hematology, and rare diseases, and she has held various roles in Big Pharma (Roche, Menarini-Stemline), including leading asset transitions, commercial project lead, and pharmacovigilance and compliance. Throughout her career, Ana has consistently demonstrated strong communication skills and a proven track record of successfully driving projects in challenging and international environments. Her commitment to delivering the best healthcare solutions to patients is unwavering, and she is equally passionate about promoting gender equality in both business and society. Ana is currently based in Switzerland working as a Business Development Director and Head of Expanded Access Strategy at WEP Clinical.