Frontline Eprenetapopt Plus Venetoclax/Azacitidine Elicits CR Rate of 37% in TP53-Mutated AML

The 3-drug combination comprised of eprenetapopt (APR-246), venetoclax (Venclexta), and azacitidine was found to induce a complete remission (CR) rate of 37% in patients with TP53-mutant acute myeloid leukemia (AML), meeting the prespecified primary efficacy end point of an ongoing phase 1/2 trial (NCT04214860).¹

Moreover, among the 30 evaluable patients, the composite response rate of CR plus CR with incomplete hematologic recovery was 53% at the time of the analysis. At the time of the data cutoff, 11 patients were still on the trial, and they continue to be followed for safety and efficacy.

Aprea Therapeutics, Inc., the drug developer of eprenetapopt, shared that they anticipate discussing the data with the FDA in the second half of 2021. Additionally, they plan to present the data from the early-phase trial at an upcoming medical meeting.

“We are pleased with these results from the combination of eprenetapopt with venetoclax and azacitidine in this very difficult-to-treat TP53-mutant AML population, a patient group with significant unmet medical need,” Eyal Attar, MD, chief medical officer of Aprea Therapeutics, stated in a press release. “These data, which follow the recent granting of fast track and orphan drug designations by the FDA, provide further demonstration of the potential for eprenetapopt in the treatment of myeloid malignancies.”

Eprenetapopt is a small molecule that has demonstrated reactivation of mutant and inactivated p53 protein through restoration of wild-type p53 conformation and function; this then elicits programmed cell death in human cancer cells. Preclinical findings with the agent have demonstrated that it can induce antitumor activity in AML, as well as myelodysplastic syndromes (MDS) and ovarian cancer.

In November 2020, the FDA granted eprenetapopt a fast track designation for patients with TP53-mutant AML.² More recently, in April 2021, the agent was also granted an orphan drug designation from the FDA for this population.³

Previously, data from a phase 2 trial demonstrated encouraging response rates with eprenetapopt plus azacitidine in patients with very high-risk, TP53-mutant MDS and AML.⁴ Among patients who were evaluable for response, the doublet induced an objective response rate of 77%, which comprised a CR rate of 49%.

Among those with AML specifically who had 20% to 30% blasts, the ORR achieved with the agent was 78%, with a CR rate of 33%. In 28 patients with MDS, the regimen induced an ORR of 75%, with a CR rate of 57%. In the intent-to-treat (ITT) population, the ORR was 58% with a CR rate of 33%.

A phase 3 trial (NCT03745716) examining frontline eprenetapopt plus azacitidine in patients with TP53-mutant MDS has been completed and missed the primary statistical end point of CR, although a higher CR rate was reported with the doublet vs azacitidine alone.⁵ Specifically, in the ITT population comprised of 154 patients, the CR rates achieved in the investigational and control arms were 33.3% (95% CI, 23.1%-44.9%) vs 22.4% (95% CI, 13.6%-33.4%), respectively (P = .13).

Another phase 2 trial (NCT03931291) is evaluating eprenetapopt in combination with azacitidine for the treatment of patients with TP53-mutated AML or MDS following allogeneic stem cell transplant.⁶ Attar shared that the company looks forward to providing an update in July 2021 on this trial.

Other trials examining eprenetapopt in hematologic malignancies and solid tumors are ongoing.

References

1. Aprea Therapeutics announces phase 1/2 trial of eprenetapopt + venetoclax + azacitidine in TP53 mutant AML meets complete remission primary efficacy endpoint. News release. Aprea Therapeutics, Inc. June 16, 2021. Accessed June 16, 2021. https://bit.ly/2SFXNz1
2. Aprea Therapeutics receives FDA fast track designation for eprenetapopt in the treatment of TP53 mutant acute myeloid leukemia (AML). News release. Aprea Therapeutics, Inc. November 30, 2020. Accessed June 16, 2021. https://yhoo.it/3oaW4w0
3. Aprea Therapeutics receives FDA orphan drug designation for eprenetapopt for the treatment of acute myeloid leukemia (AML). News release. Aprea Therapeutics, Inc. April 8, 2021. Accessed June 16, 2021. https://bit.ly/3vBtuHg
4. Cluzeau T, Serbert M, Rahme R, et al. APR-246 with azacitidine in TP53 mutated myelodysplastic syndromes and acute myeloid leukemia: a phase 2 study by Francophone Des Myelodysplasies. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181. https://bit.ly/3fsqKVz
5. Aprea Therapeutics announces results of primary endpoint from phase 3 trial of eprenetapopt in TP53 mutant myelodysplastic syndromes (MDS). News release. Aprea Therapeutics, Inc. December 28, 2020. Accessed June 16, 2021. https://bit.ly/3gwUpjm
6. APR-246 in combination with azacitidine for TP53 mutated AML (acute myeloid leukemia) or MDS (myelodysplastic syndrome) following allogeneic stem cell transplant. ClinicalTrials.gov. Updated April 27, 2021. Accessed June 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03931291