The Future of Glaucoma Therapy: Adaptive Trial Design and Patient-Centric Protocols
A conversation with Sevgi Gurkan, MD, founder and chief executive officer, and member of the board of directors, Perfuse Therapeutics
Glaucoma is the leading cause of irreversible blindness worldwide, and there are no approved therapies for it. Symptomatic treatments are many, but none so far address the root cause of optic nerve damage. But recently, Perfuse Therapeutics unveiled promising 24-week data from its Phase 1/2a trial of PER-001, a first-in-class endothelin antagonist intravitreal implant designed to address glaucoma. The trial demonstrated PER-001’s safety and efficacy as an adjunct to intraocular pressure (IOP)-lowering therapies, reporting improved visual field (VF) mean deviation, increased retinal nerve fiber layer (RNFL) thickness, and increased optic nerve head blood flow.
This groundbreaking study represents the first clinical validation of the endothelin pathway in glaucoma treatment, highlighting PER-001’s potential as a disease-modifying therapy. The bioerodible implant offers sustained drug release with a convenient six-month dosing frequency.
In this interview, Perfuse Therapeutics Founder, CEO, and Member of the Board of Directors Sevgi Gurkan, MD, discusses the company’s approach to its Phase 1/2a and Phase 2b trials, including its rationale for incorporating both functional and structural endpoints, exploratory biomarkers, adaptive trial design plans, and patient-centric protocol development.
Clinical Leader: The simultaneous assessment of both functional (visual) and structural outcomes in a Phase 1/2a trial is interesting. What was your rationale for incorporating both endpoints, and how did you design the study for these outcomes to be valuable?
Sevgi Gurkan, MD: Our goal in including both functional and structural “registrable” endpoints was to gain early insights into PER-001's clinical potential and lay a robust foundation for subsequent trial phases — and the data prove it was the right decision.
While the study was not statistically powered for efficacy, and the data are early, we saw vision restored in glaucoma patients, supporting the potential of the PER-001 intravitreal implant as a disease-modifying therapy that could significantly improve the vision and lives of glaucoma patients. Also, the observed improvements in the optic nerve head blood flow and key functional and structural outcomes represent the first clinical validation of the key role of endothelin pathway in glaucoma.
We plan to initiate an adaptive Phase 2b trial in glaucoma in Q4 2025, which could serve as one of two Phase 3 studies required for registration.
Were any exploratory biomarkers included in the protocol to understand the mechanism of action or predict response?
Yes. Exploratory efficacy outcomes included optic nerve head tissue blood flow (ONH-BF) measured by laser speckle flowgraphy (LSFG) from Softcare, as well as VF sensitivity and RNFL thickness measured by optical coherence tomography (OCT), both of which would be Phase 3 endpoints.
As for the design, did the protocol incorporate any adaptive design elements (e.g., dose escalation based on safety, interim analyses for efficacy)? If not, what was the design, and why was it chosen?
The Phase 2a portion of the Phase 1/2a study was a randomized, sham-controlled, patient- and reading center-masked study. The design was enriched for patients with known history of progressive disease where we performed eight VF tests and three OCT tests per patient over six months demonstrating consistency between functional and structural FDA-registrable endpoints.
Our planned Phase 2b trial will have an adaptive design very conservatively powered to reveal PER-001's benefit with an interim analysis that will allow for early efficacy readout and/or sample size adjustment to meet the pivotal study requirements.
Glaucoma trials often require specialized ophthalmology centers with specific diagnostic equipment. Tell us about your site selection process. What were you looking for? What were some challenges along the way, and how did you resolve them?
We designed our trial to enroll patients with different types of glaucoma, with evidence of progression on standard-of-care (SOC) IOP-lowering therapies. We implemented assessments (OCT RNFL and VF) that are gold standard/part of routine clinical care that do not require specialized centers except for the LSFG equipment used to assess optic nerve head blood flow. For the LSFG assessments, we chose Devers Eye Institute, which has the tool and the expertise to conduct this assessment for patients enrolled at this site. We also prioritized sites with a proven track record in glaucoma studies and access to high-volume patient populations for quality data capture for all endpoints.
One challenge in conducting glaucoma trials is ensuring consistency across centers, especially when it comes to VF and OCT reliability and technician training. We had a rigorous qualification/certification process, provided centralized training modules, and used a masked centralized reading center to standardize key data across all locations.
As for patient recruitment, glaucoma can have different subtypes and stages. How did you determine the optimal inclusion/exclusion criteria, understanding the heterogeneity of the enrolled patient population?
We enrolled both normal tension and primary open-angle glaucoma (POAG) patients being treated with SOC IOP-lowering therapies in the Phase 1/2a and plan to do the same in future trials.
Of note, despite having normal IOP, normal tension glaucoma patients are also treated with SOC IOP-lowering therapies. We believe that someday PER-001 might replace SOC for those patients who have normal IOP — called "normal tension glaucoma” as first-line therapy. Furthermore, PER-001’s mechanism of action (MoA) is non-overlapping and additive to SOC and may one day be administered alone or in combination based on the patient's needs.
When writing the protocol and understanding the various abilities of patients (and potentially their need for caretakers), how did you ensure the protocol meets the patients' needs and lifestyle/schedule, as well as that of their caregiver?
When developing the protocol, we took a patient- and caregiver-centric approach from the outset. Glaucoma often affects older adults, many of whom rely on caregivers for transportation or appointment coordination, so we engaged both patients and caregivers during protocol feasibility discussions.
We focused on minimizing visit burden — consolidating assessments where possible, reducing visit frequency without compromising data integrity, and ensuring that required procedures could be performed efficiently during each visit. We accounted for fatigue during VF testing by including instructions for scheduled breaks, a practice that aligns with standard clinical care.
Feedback from site staff was also instrumental. Their input allowed us to refine the protocol to align with real-world patient schedules, reducing participation barriers while improving recruitment, retention, efficiency, and the proper sequencing of tests.
What is most exciting for patients about PER-001?
Eighty million people worldwide are living with glaucoma, including around 4 million in the United States, and the prevalence is expected to double in 15 years.
The current SOC consists of pharmacological, laser, or surgical therapies to reduce IOP, the only known modifiable risk factor for glaucoma. However, even with effective IOP-lowering treatments, many patients continue to lose vision, causing a tragic gap in treatment.
Our vision is to be the first disease-modifying therapy for glaucoma. Early Phase 1/2a data are very promising, with PER-001 actually restoring vision in glaucoma patients on top of the SOC. We are continuing to advance the clinical development of PER-001, with a plan to begin an adaptive Ph2b trial in glaucoma in Q4 2025 that we believe could serve as one of two Phase 3 studies required for registration.
About The Expert:
Sevgi Gurkan, MD is the founder of Perfuse Therapeutics and serves as the chief executive officer and a member of the Board of Directors. She is also a venture partner with OrbiMed. Before founding Perfuse, Sevgi was a director of research at Merck Research Laboratories, South San Francisco Discovery site, leading the launch of a new therapeutic area of research and building a portfolio of novel mechanisms. Previously, she served as an associate professor at Rutgers and director of the Pediatric Kidney Transplant Program at RWJ University Hospital, conducting NIH-funded research as one of the founding scientists of the Child Health Institute of New Jersey, in parallel to her full-time clinical responsibilities as a pediatric nephrologist.
Sevgi received her medical degree from Hacettepe University, a degree in pediatrics from the University of Southern California, and degrees in nephrology and Master of Science in clinical research from Mount Sinai School of Medicine.