FDA grants AO-176 orphan drug designation for the treatment of patients with RRMM

On January 3, 2022, the U.S. Food and Drug Administration (FDA) granted AO-176 orphan drug designation for the treatment of patients with relapsed/refractory multiple myeloma (RRMM).¹ AO-176 is a first-in-class anti-CD47 antibody that is being investigated in a phase I/II trial (NCT04445701) as monotherapy and in combination with standard of care treatments.¹

AO-176 mechanism of action

CD47 is a protein expressed on the surface of normal cells and is also highly expressed on tumor cells. Binding of CD47 to signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis. AO-176 binds to CD47 thus preventing it from enabling the signal, and therefore allows for the tumor cells to be phagocytosed.^2,3

As tumor cells are highly metabolic, they are often found in a more acidic microenvironment compared with normal cells. Pre-clinical studies have shown AO-176 to exhibit preferential binding to CD47 at a more acidic pH compared with a more neutral pH, thus AO-176 exhibits a lower binding to normal cells.^2,3

Although CD47 is expressed on red blood cells, AO-176 binding is negligible and does not cause hemagglutination.^2,3

AO-176 can also induce direct killing of cancer cells through programmed cell death type III and immunogenic cell death by inducing damage-associated molecular patterns.³ Its efficacy and safety is being explored in clinical setting for patients with MM, but also in several solid tumors, including epithelial ovarian carcinoma, endometrial carcinoma, and gastric adenocarcinoma.⁴

NCT04445701 trial design

An open label, multicenter, phase I/II trial investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and initial efficacy of AO-176 for the treatment of RRMM.¹

• Phase I, Part 1: Dose escalation of monotherapy with a 3 + 3 design. (n = 3 patients per cohort; cohorts will be expanded in the event of a dose limiting toxicity).⁵
• Phase I, Part 2: Expansion cohort at the recommended phase II dose (RP2D) of AO-176 in combination with dexamethasone.⁵
• Phase II: Dose escalation of AO-176 in combination with dexamethasone and bortezomib.⁵
• Primary outcome measures:
  • Phase I: Maximum tolerated dose/recommended phase II dose, assessed by incidence of dose limiting toxicities and treatment emergent adverse events.⁵
  • Phase II: Objective response rate using International Myeloma Working Group uniform response criteria.⁵
• Estimated enrollment: N = 102 patients with RRMM who have received at least three prior lines of treatment.⁵
• Start date and locations: November 30, 2020, in centers from United States.⁵
• Estimated primary completion date: March 2023.⁵

Obtainment of an orphan drug designation allows for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, as well as 7-year marketing exclusivity upon approval.¹