FDA Grants Orphan Drug Designation to AO-176 in R/R Myeloma

The FDA recently granted orphan drug designation to AO-176 for the treatment of relapsed or refractory multiple myeloma, according to a press release issued by Arch Oncology, Inc.¹

AO-176, an anti-CD47 antibody, is being evaluated in phase 1/2 trials–both in multiple myeloma (NCT04445701)² and in solid tumors (NCT03834948)3–as either a monotherapy regimen or in combination with standard-of-care therapies.

“We believe the multiple unique properties of AO-176, including lower binding to normal cells and negligible binding to red blood cells, enhanced binding to CD47 in acidic environments found in tumors, and induction of programmed and immunogenic cell death, in addition to strong preclinical data in multiple myeloma, could make AO-176 a promising new first-in-class therapeutic approach to improving outcomes for these patients,” said Amit Agarwal, MD, PhD, senior vice president of clinical development at Arch Oncology, in a press release.¹

To test the hypothesis that the agent can benefit patients with multiple myeloma, an open-label, multicenter, dose escalation phase 1/2 study of AO-176, both as a monotherapy and a combination regimen, is evaluating the agent’s safety, tolerability, and pharmacokinetics/pharmacodynamics in approximately 102 patients with relapsed/refractory multiple myeloma.²

In phase 1 of the study, investigators will evaluate an ascending dose of AO-176 monotherapy, enrolling 3 patients per cohort, expanding based on dose-limiting toxicities. Following dose escalation and the determination of the recommended phase 2 dose (RP2D), investigators will then evaluate an ascending dose of AO-176 in the escalation portion of the study, this time in combination with dexamethasone alone and also with dexamethasone plus bortezomib (Velcade) in the same 3+3 escalation design. In phase 2, investigators will evaluate the clinical activity and efficacy of the agent, at the RP2D dose, in combination with dexamethasone plus bortezomib.

In the phase 1 portion of the study, the primary end point will be to determine the maximum-tolerated dose and RP2D of AO-176, while the secondary end point will include objective response rate (ORR). In the phase 2 portion of the study, the primary end point is ORR, and the secondary end points include duration of response, disease control rate, progression-free survival, and overall survival.³

To be eligible patients must have a confirmed diagnosis of symptomatic multiple myeloma per International Myeloma Working Group criteria, measurable disease, be relapsed or refractory to a least 3 prior lines of systemic therapy for multiple myeloma, have an ECOG performance status of 0 or 1, have resolved prior adverse events, and be a minimum of 2 weeks post cancer therapy or radiotherapy. The study excludes patients who have had previous grade 3 or 4 infusion reactions or hypersensitivity to an infusion, and patients with asthma or chronic obstructive pulmonary disease that may require hospitalization or steroids. In terms of prior treatment, patients cannot have received a checkpoint inhibitor or therapeutic agent that targets the CD47 axis.

Explaining the need for further development of AP-176 in the relapsed or refractory setting of myeloma, Agarwal stated, in the press release; “multiple myeloma is a type of hematological cancer affecting about 35,000 individuals each year in the United States. There is currently no cure for multiple myeloma, and while first-line treatment may result in remission, there remains a significant unmet need for patients with relapsed/refractory multiple myeloma.”

_References:

_{1. Arch Oncology receives U. S. FDA orphan drug designation for ao-176, a next-generation anti-CD47 IgG2 antibody, for the treatment of multiple myeloma. News release. Arch Oncology. January 21, 2022. Accessed January 24, 2022. https://bit.ly/3FWWvlY}

_{2. Study of AO-176 as monotherapy and in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Clinicaltrials.gov. Accessed January 24, 2022. https://bit.ly/3tVUsfq}

_{3. AO-176 in Multiple Solid Tumor Malignancies. Clinicaltrials.gov. Accessed January 24, 2022. https://bit.ly/3Av0Uvt.}