FDA Gives RPD Designation to Alrizomadlin for Pediatric Neuroblastoma

The targeted inhibitor alrizomadlin (APG-115) was granted a rare pediatric disease (RPD) designation by the FDA for the treatment of neuroblastoma, according to a press release from Ascentage Pharma.¹

Alrizomadlin is a novel oral MDM2-p53 inhibitor that has demonstrated antitumor activity in in vitro and in vivo models of neuroblastoma. It has previously been granted 6 orphan drug designations (ODD) and 2 RPDs by the FDA. The RPD designation will qualify the drug for the priority review voucher (PRV) program meant to encourage development of novel therapies for rare pediatric diseases.

"In addition to the benefits provided by the ODD, the RPD designation offers sponsors the additional incentive of priority review status for their future marketing applications, and [encouraging] the drug development for the treatment of rare pediatric diseases,” said Dajun Yang, PhD, chairman and CEO of Ascentage Pharma, in a statement. “Alrizomadlin is a key drug candidate in our apoptosis-targeted pipeline.”

Neuroblastoma, an embryonic tumor of the peripheral sympathetic nervous system, is the third most common pediatric cancer and the most common cancer in infants.² It is mostly diagnosed in infancy at an average of 1 to 2 years old. There are an estimated 700 to 800 new cases of neuroblastoma each year in the United States.

While low and intermediate-risk neuroblastoma have a very high rate of survival, high-risk neuroblastoma has a 5-year survival rate of about 50%, and it has a high likelihood of recurrence even with intense multimodal treatments. There is currently no standard treatment for patients with relapsed/refractory neuroblastoma.

Alrizomadlin selectively inhibits the MDM2 protein from interacting with p53, leading to tumor-suppressing activity that would be blocked due to overexpression of MDM2 in tumors. It has shown antitumor activity in preclinical studies of solid tumors as well as acute myeloid leukemia.³

In a phase 2 trial (NCT03611868) of patients with multiple solid tumor types who had failed to benefit from immunotherapy, alrizomadlin in combination with pembrolizumab (Keytruda) showed antitumor activity and was well tolerated.⁴ It is being investigated as monotherapy in a phase 1 trial (NCT02935907) of patients with advanced solid tumors or lymphoma. Early-phase trials of alrizomadlin in combination with other agents are also recruiting patients.

The RPD will provide more opportunities for clinical studies of alrizomadlin in patients with high-risk neuroblastoma who have few other treatment options.¹ The PRV enables the drug sponsor to receive priority reviews of future New Drug Applications or Biologics License Applications. Ascentage Pharma plans to launch a clinical study of patients with neuroblastoma in the near future.

"This RPD will qualify this program for a PRV, which should help us better communicate with the FDA to hopefully accelerate the clinical development of alrizomadlin,” Yang stated. “We will initiate the clinical study in neuroblastoma as soon as possible in order to develop a new treatment option for those pediatric patients in need."

_References:

_{1. Ascentage Pharma's MDM2-p53 inhibitor alrizomadlin (APG-115) granted rare pediatric disease designation by the US FDA for the treatment of neuroblastoma. Ascentage Pharma. March 21, 2022. Accessed March 24, 2022. https://prn.to/3iAERv}

_{2. Neuroblastoma. American Cancer Society. Accessed March 24, 2022. https://bit.ly/37ZVK0c}

_{3. Fang DD, Tang Q, Kong Y, et al. MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models. Cell Death Discov. 2021;7(1):90. doi:10.1038/s41420-021-00465-5}

_{4. Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J Clin Oncol. 2021; 39(suppl 15; abstr 2506). doi:10.1200/JCO.2021.39.15_suppl.2506}