All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.

The Multiple Myeloma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your Multiple Myeloma Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.

The Multiple Myeloma Hub is an independent medical education platform, sponsored by Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, Roche and Sanofi. The levels of sponsorship listed are reflective of the amount of funding given. Digital educational resources delivered on the Multiple Myeloma Hub are supported by an educational grant from Janssen Biotech, Inc. View funders.

2022-01-26T14:46:11.000Z

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

Jan 26, 2022
Share:

Bookmark this article

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

  1. ARCH Oncology. 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. https://archoncology.com/press-releases/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/. Published Jan 21, 2022. Accessed Jan 25, 2022.
  2. Puro RJ, Bouchlaka MN, Hiebsch RR et al. Development of AO-176, a next-generation humanized anti-CD47 antibody with novel anticancer properties and negligible red blood cell binding. Mol Cancer Ther. 2020; 19(3):835-846. DOI: 1158/1535-7163.MCT-19-1079
  3. ARCH Oncology. AO-176’s differentiated mechanisms of action. https://archoncology.com/science/#moa. Accessed Jan 25, 2022.
  4. Clinicaltrialsgov. AO-176 in multiple solid tumor malignancies. https://clinicaltrials.gov/ct2/show/NCT03834948. Updated: Jul 8, 2021. Accessed Jan 25, 2022.
  5. Clinicaltrialsgov. Study of AO-176 as monotherapy and in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma. https://clinicaltrials.gov/ct2/show/NCT04445701. Updated: Jul 7, 2021. Accessed Jan 25, 2022.

Your opinion matters

Which dosing schedule for belantamab mafodotin do you think is optimal for providing an efficacy benefit while managing toxicities?
2 votes - 41 days left ...

Newsletter

Subscribe to get the best content related to multiple myeloma delivered to your inbox