Comparing Novel Antagonist of IAPs Versus Immunotherapy in Head and Neck Cancer

Locally advanced head and neck cancer represents a group of diseases that have seen limited new treatment options over the past 20-plus years. However, in March 2021, Swiss-based Debiopharm reached an exclusive license agreement with Merck KGaA, Darmstadt, Germany, for a potentially transformative therapy.

Bertrand Ducrey, PhD, CEO of Swiss-based global biopharmaceutical company Debiopharm, explains below why his company decided to develop an oral inhibitor of apoptosis proteins (IAPs) antagonist and how it may improve outcomes when combined with current standard of care therapies.

Q: Why was an unknown cancer drug class developed instead of another immunotherapy option?

Ducrey: A growing number of immunotherapy options are undoubtedly showing great promise to help patients with cancer gain control over their disease; however, we know that one drug does not fit all. The development of resistance and certain toxicities show that many patients still need additional options. At Debiopharm, we try to be forward-thinking, identifying the unmet needs in certain cancer types while focusing our efforts on novel drug classes that could offer new ways of treating, and ultimately curing, patients.

Focusing on developing treatments with growing competition and a vast number of trials in progress, such as immune checkpoint inhibitors, does not align with our business model. Instead, we select more rare classes and innovative molecules to take through the clinical development phases to offer interesting licensing opportunities for larger pharmaceutical companies.

For example, when we identified xevinapant as an early-stage antagonist of IAPs from the University of Michigan, we recognized its potential to help a large range of patients due to its enhancement effect in combination with chemoradiotherapy (CRT). Research revealed that IAPs regulate a wide range of cellular processes that help tumor cells to survive and spread, from inhibition of apoptosis to regulation of cell proliferation and migration, and modulation of immune and inflammatory responses.

So, IAP antagonism represents a unique alternative mechanism of action to fight cancer, which can serve as a complement to immunotherapy and a booster of the antitumor effects of CRT.

Q: Are immunotherapy and IAP antagonism really that different?

Ducrey: Immunotherapy specifically targets the human immune system to help fight against cancer while IAP antagonists work to promote programmed cell death, or apoptosis, a universal phenomenon that contributes to the antitumor efficacy of many cancer therapies. We know that despite antitumor therapies such as CRT, cancer cells react by employing self-defense mechanisms to survive and proliferate.

One of these survival mechanisms involves the evasion of apoptosis, which is in part carried out by IAPs that strengthen the resistance of cancer cells to CRT treatment and ultimately contribute to tumor progression. By aiding tumor cells to avoid apoptosis, IAPs are believed to contribute to treatment resistance, disease progression, and tumor cell survival.

By acting in opposition to these IAPs, IAP antagonists are expected to weaken this evasion of programmed cell death, thereby boosting treatment-induced apoptosis resulting from a broad diversity of cancer treatment modalities, including CRT, which remains the backbone in the treatment of many cancers today. Interestingly these compounds have also been shown to possess immunomodulatory properties in addition to their pro-apoptotic properties, suggesting a dual mode of action.

This pro-apoptotic and immunomodulatory effect could create some confusion by misclassifying the compound as a new immunotherapy agent. But IAP antagonism is indeed a different way of treating cancer, with xevinapant being the most clinically advanced to date.

Q: Has xevinapant demonstrated this dual mode of action?

Ducrey: Xevinapant is believed to boost tumor cell apoptosis through the dual mode of action when administered in combination with the standard-of-care head and neck cancer treatment, chemoradiotherapy. Pharmacological studies suggest that the compound works by releasing the brake on apoptotic pathways induced by cancer treatments, thus enhancing programmed tumor cell death while co-stimulating immune cells and the production of pro-apoptotic cytokines.

Debiopharm’s antagonist of IAPs was recently licensed to Merck KGaA, Darmstadt, Germany. Along with our partner, Merck KGaA, Darmstadt, Germany, which operates its health care business in the US and Canada as EMD Serono, the number one priority is clearly to complete the ongoing phase 3 study (TrilynX) that is expected to lead to registration of the compound globally.

We hope to get the first readout of the study in 2024. Of note, the addition of xevinapant to CRT reduced the risk of death by 51% against the current standard of care in a phase 2 clinical trial in locally advanced squamous cell carcinoma of the head and neck. And if the results of the ongoing phase 3 trial even approach that level of efficacy, xevinapant will be poised to become the new standard of care for these patients. In the future, together with Merck KGaA, Darmstadt, Germany, we also hope to explore the potential of the product in other cancer types currently treated with CRT.

The development of this compound, beginning from the academic research setting with the University of Michigan, through clinical development at Debiopharm and now subsequent development towards potential commercialization by Merck KGaA, Darmstadt, Germany, further demonstrates our unique business model at work. Through strategic partnerships, this way of working allows us to bring innovative treatments to patients and to continue to establish tomorrow's standard of care.