On September 16, 2021 Aileron Therapeutics (Nasdaq: ALRN), a chemoprotection oncology company focused on fundamentally transforming the experience of chemotherapy for cancer patients, reported new clinical data at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2021 supporting ALRN-6924’s best-in-class potential as a chemoprotective agent (Press release, Aileron Therapeutics, SEP 16, 2021, View Source [SID1234587796]). The company presented final results from its completed Phase 1b trial of ALRN-6924 in patients with small cell lung cancer (SCLC) receiving second-line topotecan treatment, which demonstrated ALRN-6924’s ‘triple-play efficacy’ for the reduction of neutropenia, thrombocytopenia and anemia, as well as a reduction of platelet and red blood cell transfusions, as compared to historical controls. Aileron today also presented preliminary results from its ongoing Phase 1 pharmacology study of ALRN-6924, which confirmed 0.3 mg/kg as the optimal dose for ALRN-6924 and confirmed its novel p53 biomarker-driven mechanism of action, as well as its pharmacodynamic effects, including time to onset, magnitude and duration.

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Aileron is developing ALRN-6924 to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects while preserving chemotherapy’s attack on cancer cells. ALRN-6924, a first-in-class MDM2/MDMX dual inhibitor, is designed to activate p53 in normal cells, which in turn upregulates p21, which pauses cell cycle in normal cells but not in p53-mutated cancer cells.

"We are pleased to present final results from our completed Phase 1b trial of ALRN-6924 in patients with SCLC being treated with topotecan and preliminary results from our ongoing Phase 1 pharmacology study in healthy volunteers. The data presented at ESMO (Free ESMO Whitepaper) further strengthen our belief in ALRN-6924’s best-in-class potential in the emerging chemoprotection space," said Manuel Aivado, M.D., Ph.D., President and CEO of Aileron. "With our precision medicine strategy, our vision is to bring the first selective chemoprotective agent to all patients with p53-mutated cancer while ensuring no interruption of chemotherapy. We believe chemoprotection during chemotherapy, ultimately, should be as compulsory as anesthesia during surgery."

ALRN-6924 Phase 1b SCLC Trial Final Results

Aileron conducted a Phase 1b open-label clinical trial to evaluate ALRN-6924 as a chemoprotective agent against bone marrow-related, chemotherapy-induced toxicities in patients with SCLC undergoing treatment with topotecan. The company reported the final results from this trial in a poster presentation at ESMO (Free ESMO Whitepaper) titled, "A Phase 1b Study of the Dual MDMX/MDM2 Inhibitor, ALRN-6924, for the Prevention of Chemotherapy-induced Myelosuppression" (Abstract/Poster #: 1654P).

A total of 39 patients were enrolled in the trial, 38 of whom were evaluable per the trial protocol. Topotecan (1.5 mg/ m2) was administered on days 1 through 5 of every 21-day treatment cycle. 32 patients (31 evaluable) were treated with ALRN-6924 at 24 hours before each dose of topotecan at the following dose levels: 0.2 mg/kg (N=4), 0.3 mg/kg (N=16), 0.6 mg/kg (N=6; 5 evaluable) and 1.2 mg/kg (N=6). 7 patients were treated with 0.3 mg/kg of ALRN-6924 at 6 hours before each dose of topotecan.

In the Phase 1b SCLC trial, toxicities were evaluated using the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Per the trial protocol, patients were not permitted to receive prophylactic G-CSF treatment in cycle 1. The median number of completed topotecan treatment cycles across all cohorts was 3. 13% of patients required topotecan dose reduction. No patients reported NCI CTCAE Grade ≥3 events of nausea, vomiting, diarrhea; 5% had Grade 3 fatigue.

While chemoprotection effects were observed across all ALRN-6924 dose levels studied in the Phase 1b SCLC trial, the 0.3 mg/kg ALRN 6924 dose level given 24 hours prior to topotecan demonstrated the most robust chemoprotection results. None of the patients treated at the 0.3 mg/kg 24 hour ALRN-6924 dose level had a related serious adverse event (SAE). One patient (6%) at the 0.3 mg/kg 24 hour ALRN-6924 dose level required a red blood cell transfusion and a platelet transfusion. In the topotecan plus placebo arm of a recent third-party randomized Phase 2 trial in SCLC patients receiving topotecan (N=28), 41% and 31% of SCLC patients received red blood cell and platelet transfusions, respectively (Hart et al., ASCO (Free ASCO Whitepaper) 2019).

Summary of Final Key Efficacy Findings from ALRN-6924 Phase 1b SCLC Trial

ALRN-6924 (given 24h prior to chemotherapy) Phase 1b Trial
Bone Marrow-Related Key Toxicity Findings
Adverse Events (AEs)* NCI CTCAE ≥ Grade 3

Third Party
Randomized Phase 2
Trial in SCLC
Historical Control‡

Toxicity ALRN-6924
0.3 mg/kg +
Topotecan
N (%)
N=16 ALRN-6924
(All Dose Levels)
Topotecan
N (%)
N=39
Placebo
+ Topotecan
N (%)
N=28
All AEs 14 (88) 35 (90) 27 (96)
Neutropenia 13 (81) 34 (87) 24 (86)
Thrombocytopenia 7 (44) 18 (46) 20 (70)
Anemia 3 (19) 6 (15) 18 (63)
Febrile Neutropenia 0 1 (3) 5 (17) †
Fatigue 1 (6) 2 (5) 2 (7)
Nausea 0 0 1 (4)

Neutropenia
Grade 4 5 (31)** 14 (36)** 21 (76)

*AEs based on laboratory values, as applicable
**For cycle 1
‡ Hart et al. ASCO (Free ASCO Whitepaper) 2019
† Febrile neutropenia assessed in 29 patients

Dr. Vojislav Vukovic, M.D., Ph.D., Chief Medical Officer at Aileron, commented, "The final results from the Phase 1b SCLC we are presenting at ESMO (Free ESMO Whitepaper) are fully consistent with the interim, proof-of-concept data we presented from this trial last year demonstrating ALRN-6924’s ability to protect this very sick patient population against severe and life-threatening bone marrow-related side effects associated with a highly toxic chemotherapy. With the Phase 1b SCLC trial successfully completed, we look forward to continuing our ongoing Phase 1b randomized, double-blind, placebo-controlled trial of ALRN-6924 in patients with advanced non-small cell lung cancer treated with first-line carboplatin plus pemetrexed."

ALRN-6924 Phase 1 Pharmacology Study Initial Results

Aileron is conducting a multi-part Phase 1 pharmacology study in healthy volunteers to evaluate the pharmacokinetics and pharmacodynamics of ALRN-6924. In a poster presentation at ESMO (Free ESMO Whitepaper) titled, "A Phase 1 Study of the Dual MDMX/MDM2 Inhibitor, ALRN 6924, in Healthy Volunteers" (Abstract/Poster #: 1791P), Aileron presented the findings from Parts 1 and 2 of the study. The objectives of these first two parts were to determine a dose of ALRN-6924 that initiated p53-mediated transcriptional regulation and yielded transient cell cycle arrest via p21 induction in human bone marrow while minimizing the signal for apoptosis (Part 1), and to determine the time to onset, magnitude, and duration of bone marrow pharmacodynamic effects (Part 2). The study is ongoing, and Aileron anticipates presenting additional findings at a later date.

Aileron reported results for a total of 37 subjects (females and males aged 18-65) enrolled and evaluated in Parts 1 and 2 of the study. In Part 1, a total of 14 subjects (6 placebo, 4 each at 0.3 and 0.6 mg/kg of ALRN-6924) received one intravenous infusion of ALRN-6924, and bone marrow samples were obtained 8 hours post-infusion. Immunohistochemistry analysis showed that both dose levels yielded robust induction of p21, a p53-regulated mediator of cell cycle arrest, in bone marrow cells, with minimal evidence of apoptosis compared to placebo. In Part 2, 23 subjects allocated to 8 groups received one 0.3 mg/kg infusion of ALRN-6924. Bone marrow samples were obtained at 4, 8, 12, 16, 20, 24, 36, and 48 hours post-infusion. The 0.3 mg/kg dose demonstrated favorable tolerability, with subjects experiencing only mild, transient adverse events. Robust p21 induction was observed in bone marrow cells, with peak expression observed between 4 hours and 16 hours following ALRN-6924 administration.