Skip to main content
Premium Trial:

Request an Annual Quote

Aileron Using Biomarker Strategy to Shoot for Broad Application of Chemo-Protective Drug


NEW YORK – Aileron Therapeutics last week articulated its vision to develop ALRN-6924 as an agent that can help any patient with a p53-mutated cancer avoid the toxicities of chemotherapy.

Boston-based Aileron said that it has begun giving ALRN-6924 to patients with p53-mutated breast cancer receiving neoadjuvant chemotherapy in a Phase Ib trial. The drug, which has already demonstrated its chemo-protective properties in p53-mutated small cell lung cancer studies, is designed to protect healthy cells in patients with p53-mutated cancers.

"While some might think employing a biomarker strategy narrows our opportunity to select our targeted patient population, the fact is that our targeted patient population is enormously large," Aileron CEO and President Manuel Aivado said in an investor presentation last week. He estimated that a million patients are diagnosed with p53-mutated cancer in the US each year, leading to "incredible market potential in the US alone."

ALRN-6924 is administered an hour before a chemotherapy infusion. It then activates p53 in normal cells, temporarily arresting their cell cycle. Because the patient's cancer cells carry a mutation in p53, ALRN-6924 does not protect those from the effects of the chemotherapy drugs.

Preclinical data indicates that the drug can protect bone marrow stem cells, gut mucosal cells, and hair follicles, according to Aileron. At the European Society of Medical Oncology meeting last year, the Boston-based company presented data from a Phase Ib trial of ALRN-6924 in patients with p53-mutated small cell lung cancer receiving second-line topotecan treatment demonstrating improvement in neutropenia, thrombocytopenia, and anemia compared to historical controls. It is now evaluating the drug as a supportive therapy for patients with breast cancer in a new clinical trial and advancing it into a Phase Ib in p53-mutated non-small cell lung cancer patients.

The lung cancer studies are focusing exclusively on chemotherapy-induced side effects. In the breast cancer trial, however, in addition to exploring the protective effect of ALRN-6924 against hematologic and other toxicities in patients who are receiving doxorubicin plus cyclophosphamide and docetaxel, the company is also interested in measuring the anti-tumor activity of ALRN-6924 when combined with paclitaxel. Researchers will track patients for their objective response rate, duration of response, progression-free survival, and overall survival on the combination.

While breast and lung cancer are the two first proving grounds for ALRN-6924, Aileron believes its drug has pan-tumor potential given the prevalence of p53 mutations in cancer. "Because of the ubiquitous nature of p53 mutations across all cancer types, and because we treat healthy cells, not cancer cells, our ultimate goal is to collaborate with the FDA to make [ALRN-6924] available to all patients with p53-mutated cancer who undergo myelo-suppressive chemo," Aivado said.

Ralf Paus, a professor of dermatology at the University of Miami, presented new ex vivo data at a recent medical meeting demonstrating that ALRN-6924 protected human hair follicles and their stem cells from paclitaxel-induced damage. The findings also shore up Aileron's previous work showing that the chemo-protective effects of ALRN-6924, a dual inhibitor of p53 regulators MDM2 and MDMX, derive from its ability to arrest the cell cycle.

"Nobody is going to die from hair loss," Aivado said, but highlighted that the cell cycle arrest mechanism confirmed by Paus' research suggests "there is no reason why our drug wouldn't protect all cells in our body that are dependent on self-renewal, and therefore are the prime point of collateral damage by chemotherapy."

That's important because while Aileron's clinical trials focus on chemotherapy-induced toxicities that are objectively measurable, such as neutropenia or anemia, for another set of toxicities like nausea, fatigue, and mouth sores, the measures are much more subjective and not as easily quantified in clinical trials. In Aivado's view, if all these adverse events are controlled by the same mechanism, there's hope that the benefits of ALRN-6924 will extend generally to those less easily quantified toxicities.

If that proves true in clinical trials, Aivado has high hopes that ALRN-6924 could be a "revolutionary" advance in supportive care. "Why wouldn't you, as an oncologist, want to give one drug that can take care of most toxicity instead of giving half a dozen different drugs, leaving out certain side effects that you cannot remedy today with available medicine?" he said.

Aivado added that the data on ALRN-6924's ability to protect against alopecia were encouraging and raise hopes that they will eventually see some evidence of protection for toxicities such as fatigue, vomiting, and mucositis. He cautioned though that it may not show up in the upcoming interim analysis for the NSCLC trial because those toxicities are not that frequent in a clinical trial setting. "Toward the end of the year, when we get to the top-line results from all 60 patients, then it's going to be very interesting what the non-hematologic toxicities will look like."

Eric Anderson, a medical oncologist and assistant professor of medicine at Oregon Health and Science University, is an investigator in the ongoing NSCLC trial. He spoke about NSCLC and chemotherapy-related toxicities as they manifest in real-world oncology practice, and the potential impact of ALRN-6924 in those patients. He said about 200,000 patients annually are diagnosed with NSCLC, and 60 percent of those patients have a p53-mutated cancer.

Although immune checkpoint inhibitors and targeted therapies against EGFR, ALK, KRAS, ROS1, BRAF, and MET alterations have transformed the treatment paradigm for NSCLC, chemotherapy remains the backbone of treatment, especially for patients with locally advanced or metastatic disease. Anderson's oncology group serves a 250-square mile catchment area in Oregon and Southwest Washington, and he and his partner each see three to four new NSCLC patients per month.

The "vast majority" of patients with non-squamous NSCLC receive carboplatin and pemetrexed with or without immunotherapy as their first-line treatment, and commonly experience both objectively measurable toxicities and experience adverse events that are more subjective and harder to measure. Patients choose to stop treatment most often because of the subjective toxicities, however.

"Fatigue, nausea, neuropathy, diffuse body aches — those are what keep people from coming back to get chemotherapy in many of these settings and choose to stop treatment," said Anderson. "As an example, the first patient that we enrolled on the ALRN-6924 trial [had previously] stopped chemotherapy, not because he had issues with his blood counts going down or any other objective toxicities, but because he could not tolerate many of the subjective toxicities."

There are few supportive therapies on the market to address these symptoms, such as anti-nausea medication and granulocyte colony-stimulating factor (G-CSF) for neutropenia. While in the past erythropoietin was commonly used to boost blood counts for patients with anemia, it has been largely abandoned due to a black box warning issued by the US Food and Drug Administration in 2007 for thromboembolisms. 

The lack of therapies to address these side effects often leads to trade-offs, including lowering or delaying the dose of chemotherapy drugs to increase the odds the patient will tolerate the regimen and successfully complete it. But such less-than-optimal dosing adjustments could limit treatment efficacy for the patient.

In clinical trials for NSCLC, typically up to 30 percent of patients are not able to complete chemotherapy on schedule. But Aivado pointed out that clinical trial patients are "highly filtered," representing between 5 percent and 6 percent of the patient population. "[In] the real world, [we] will see a much, much greater number of patients who can actually not complete the four to six cycles of chemotherapy and a much greater number will not be able to stay on dose without reductions or delays," Aivado said.

In the broader supportive care market, Aileron is in good company in shooting for a broad indication for its chemo-protective drug. Aivado pointed out that out of 15 supportive care drugs approved over the past 30 years, all but three have received a very broad label allowing for their use in any cancer, or nearly any cancer. Only three drugs, Pfizer's Zinecard (dexrazoxane) for cardiac toxicity, Pfizer's Ethyol (dexrazoxane) for renal toxicity, and G1 Therapeutics' Cosela (trilaciclib) for bone marrow toxicity, are approved for a narrow disease indication.

Additionally, he noted that until the first cell-cycle arresting drug, Cosela, hit the market in 2021, each supportive care drug was approved for the treatment of just one toxicity at a time. That leaves "a great deal of room for innovation" in the supportive care space, Aivado said.

Aileron's strategy for getting ALRN-6924 approved as broadly as possible includes the use of a composite endpoint, which has not been done yet for a supportive care drug. Aivado said the components of that endpoint will be grade 3 for neutropenia, grade 3 for anemia, grade 3 for thrombocytopenia, platelet and red blood cell transfusions, chemotherapy dose delays and reductions, and the use of G-CSF. "It's a situation where we can capture multiple different aspects of toxicity and the consequences thereof," said Aivado.

The company will have a first peak at ALRN-6924's effect on the composite endpoint in the upcoming interim analysis in the NSCLC trial. There, 10 patients are receiving ALRN-6924 plus chemo and 10 are in the placebo plus chemo arm. "We want to show more cycles on ALRN-6924 being administered that are free of many or all of that composite endpoint compared to placebo," as well as a favorable safety and tolerability profile, Aivado said.

While there are too few patients right now to report any results with statistical significance, Aivado noted that the company still "expects to see favorable trends" that will be confirmed later, when the study grows to include 60 patients.

An important detail is that the chemotherapy dosing will be at the higher of two common doses — AUC 6. A dose of AUC 5 if often used in advanced NSCLC patients, who tend to be older, to improve their odds of tolerating the therapy. "Carboplatin at AUC 6 is also something that makes this trial so important in order to further inform us about the true toxicity profile when given in combination with pemetrexed," said Aivado.