The FDA has granted orphan drug designation to two novel therapies for acute myeloid leukemia (AML), marking significant regulatory milestones for both PTX-252 from Hyloris Pharmaceuticals and ocifisertib from Treadwell Therapeutics. These designations underscore the critical unmet medical need in AML treatment, particularly for patients with relapsed or refractory disease.
PTX-252: Novel Molecular Entity for Enhanced Chemotherapy Response
PTX-252 represents a novel molecular entity designed to improve the responsiveness of cancer cells to chemotherapy. The therapy is being developed through a collaboration between Hyloris Pharmaceuticals and Pleco Therapeutics, with a phase 2 study expected to launch in 2024.
"Securing orphan drug designation for a product candidate incorporating a novel molecular entity not yet approved by any regulatory agency underscores our unwavering commitment to advancing the frontiers of scientific discovery within the repurposing space," stated Stijn Van Rompay, chief executive officer of Hyloris.
The development of PTX-252 is part of Pleco's broader Plecoid™ therapy platform, named after the Plecostomus fish that clean aquariums from the inside. Each therapy is designed to target underlying causes of cancer rather than the tumor itself, aiming to change the balance of protein expression within the cancer microenvironment by removing toxic metals from cells. This approach could potentially result in improved chemotherapeutic anticancer activity.
Dr. Henno Welgemoed, appointed as chief medical officer of Pleco Therapeutics in September 2023, will lead the development of PTX-252 in AML throughout 2024. His oversight extends to several other investigational agents, including PTX-062 in lung cancer, PTX-142 in pancreatic cancer, and PTX-081 in other cancers, all currently undergoing candidate selection or preclinical study.
Ocifisertib: First-in-Class PLK4 Inhibitor Shows Promise
Treadwell Therapeutics' ocifisertib (CFI-400945) has received orphan drug designation as a first-in-class PLK4 inhibitor that regulates centriole duplication in AML patients. The therapy has previously received FDA Fast Track designation, highlighting regulatory recognition of its potential.
"The FDA's decision to grant orphan drug designation, along with the previous FDA Fast Track designation for ocifisertib, underscores [our] dedication to addressing this patient population with few treatment options," said Roger Sidhu, MD, acting CEO of Treadwell Therapeutics.
The PLK4 enzyme is typically overexpressed in cancer cells and has been associated with adverse survival outcomes. Inhibiting PLK4 intensifies genomic instability in cancer cells, leading to cell death. Ocifisertib has demonstrated significant single-agent activity in both solid and liquid tumors.
Clinical Development Progress
A phase I dose-escalation trial established the safety and tolerability profile of ocifisertib in 43 patients with advanced solid tumors. The study evaluated continuous daily oral dosing across doses ranging from 3 mg to 96 mg per day, with an additional nine patients receiving 64 mg in the expansion phase.
After dose-limiting toxicities were observed at both 96 mg and 72 mg doses, investigators established 64 mg as the recommended phase II dose. The therapy was well-tolerated at this dose level, with dose-dependent neutropenia being the primary concern.
The most common treatment-related adverse events (>5%) included fatigue (37%), nausea (29%), diarrhea (21%), neutropenia (21%), anorexia (19%), vomiting (8%), dyspepsia (6%), hypomagnesemia (6%), and dehydration (6%). These adverse events were generally low grade and did not show a clear dose-dependent trend except for neutropenia.
Currently, a phase Ib and II trial is confirming the safety, efficacy, pharmacokinetics, and pharmacodynamics of ocifisertib in patients with relapsed or refractory AML following standard-of-care therapy. The study is also examining the drug in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia, both as monotherapy and in combination with azacitidine.
Addressing Critical Unmet Need in AML
AML represents a heterogeneous and highly proliferative cancer originating from immature white blood cells in the bone marrow. The disease can present as de novo disease or occur secondarily due to progression of other diseases or treatment with cytotoxic therapy. With a median age of diagnosis at approximately 67 years and higher prevalence in males, AML poses significant treatment challenges.
Global projections indicate the disease burden will continue to grow, with newly diagnosed cases expected to increase from 148,352 in 2022 to 185,232 by 2032. Patients with relapsed and/or refractory AML, particularly those with TP53-mutated disease, face poor overall survival rates and represent a high unmet clinical need.
"This milestone underscores our commitment to innovative therapies for rare diseases and it brings hope to AML patients who have limited treatment options," noted Ivo Timmermans, MD, MBA, chief executive officer of Pleco Therapeutics.
The orphan drug designations for both PTX-252 and ocifisertib provide regulatory advantages including market exclusivity, tax credits, and fee waivers, potentially accelerating their development timelines and eventual availability to patients facing this challenging disease.
