ALRN-6924 is a first-in-class, stabilized cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disrupt p53’s interactions with its endogenous inhibitors, MDMX and MDM2.
Our clinical development program is focused on an ongoing Phase 2a clinical trial combining Aileron’s lead product candidate ALRN-6924 and Pfizer’s palbociclib (IBRANCE™), for the treatment of patients with MDM2-amplified cancers, and our planned Phase 1b/2 clinical trial to evaluate ALRN-6924 as a myelopreservative agent to protect against chemotherapy-induced toxicities. Our first myelopreservation clinical trial will be in small cell lung cancer patients treated with the chemotherapy topotecan.
Amplification of the gene encoding MDM2, an endogenous inhibitor of the p53 tumor suppressor protein, is an oncogenic event found in 2-4% of all cancers. In November 2018, we announced a collaboration with Pfizer to evaluate the combination of ALRN-6924 and palbociclib in patients with MDM2-amplified solid tumors. The rationale for evaluating this combination is supported by the synergistic activity observed in preclinical models; single-agent ALRN-6924 activity in MDM2-amplifed patients in earlier clinical trials; and the frequent co- amplification of MDM2 (the target of ALRN-6924) and CDK4 (the target of palbociclib) due to their co-localization on chromosome 12. Tumors with the highest frequency of MDM2 amplification include sarcomas, urothelial cancers, lung cancers, gliomas and a number of other tumor types. There are no approved therapies that specifically target tumors that are driven by MDM2 amplification or MDM2/CDK4 co-amplification, thereby creating an opportunity to develop ALRN-6924 in this patient population.
In early 2019, we commenced a Phase 2a trial to test the combination of ALRN-6924 and palbociclib in patients with MDM2-amplified tumors. This is a multicenter, non-randomized trial which is designed to enroll up to 35 patients in the United States. The objectives of this trial include evaluation of safety, tolerability, and activity of the combination.
We expect to report interim results from our Phase 2a trial at the European Society for Medical Oncology (ESMO) Congress in Barcelona on the 28th of September 2019.
Chemotherapies used to treat cancer patients cause toxicities in normal tissues and organs, thereby limiting the dose and schedule of these drugs and reducing their efficacy. This is because these drugs lack specificity for cancer cells, and instead target mechanisms that are common to both cancer cells and normal cells that reside in the bone marrow, gut lining, and skin. Chemotherapy-related toxicities of the bone marrow include anemia, neutropenia and thrombocytopenia, which lead to fatigue, increased risk of infection, sepsis, or bleeding, and can be life threatening. Because ALRN-6924 pauses cell division in cells with non-mutated, or “wild type” p53, including normal bone marrow cells, and because ALRN-6924 has no activity against cancer cells with mutations in p53, we believe that treatment of patients with ALRN-6924 can reduce the toxic effects of chemotherapy in the bone marrow while having no adverse effect on the anti-cancer activity of chemotherapy against p53-mutant tumor cells. We refer to this therapeutic concept as “myelopreservation.”
In preclinical studies, ALRN-6924 successfully activated wild-type p53 and induced cell cycle arrest in normal bone marrow cells, but ALRN-6924 did not affect mutant p53 cancer cells. Administration of ALRN-6924 in advance of the chemotherapeutic drug topotecan protected bone marrow cells from chemotherapy-induced toxicity. In a mouse model of p53-mutant cancer, ALRN-6924 did not diminish topotecan’s anti-tumor activity, while the ALRN-6924 + topotecan combination yielded modest enhancement of survival. Therefore, we believe ALRN-6924 may serve as a myelopreservative agent for bone marrow cells of patients without affecting the activity of chemotherapy in mutant p53 cancers.
We plan to start a Phase 1b/2 trial of ALRN-6924 in September of 2019 in patients with small cell lung cancer who are treated with topotecan to assess the efficacy of ALRN-6924 to mitigate and reduce neutropenia, anemia and thrombocytopenia caused by topotecan.