In this interview, Dr. Stephen Marcus, CEO of Cantex Pharmaceuticals, discusses the innovative cancer therapy, Azeliragon. He explores its potential to transform the treatment landscape for aggressive cancers such as glioblastoma and breast cancer by targeting the RAGE pathway. Dr. Marcus sheds light on Azeliragon’s clinical trials, its promise beyond oncology, and the drug development challenges.
Moe: What is Azeliragon, and How Does It Work?
Dr. Stephen Marcus: Azeliragon is an orally administered small molecule experimental medication that inhibits the activity of the Receptor for Advanced Glycation End-products (RAGE), that has been implicated in promoting tumor growth, metastasis, and the evasion of the immune system. By effectively blocking the interaction between RAGE and its various ligands that bind and activate it, Azeliragon may interrupt a pathway by which many cancers exploit to thrive and spread. This strategic blockade not only aims to halt the progression of the disease but also opens the door to potentially enhancing the efficacy of existing treatments by mitigating the cancer’s resistance mechanisms.
Moe: Which indications is Cantex targeting?
Dr. Stephen Marcus: The development of azeliragon is focused on aggressive cancers such as glioblastoma multiforme (GBM), breast cancer, pancreatic cancer, and brain metastases all of which are in need of advancements in cancer therapy. These types of cancer are not only difficult to treat due to their robust resistance mechanisms but also have a profound impact on patient survival and quality of life.
Azeliragon also has the potential to amplify the benefits of other cancer treatments and could potentially treat cancers traditionally marked by poor outcomes. Azeliragon, through its action on the RAGE pathway, may impair the tumor cells’ ability to survive cancer treatments, thereby reducing the likelihood of recurrence and potentially improving long-term survival rates.
Moe: Can you tell me about the design of the Phase 2 GBM study?
Dr. Marcus: The phase 2 GBM study that is ongoing in the US is enrolling patients with unmethylated GBM, which comprises about 60% of people with GBM and traditionally shows poor responsiveness to the standard chemotherapy agent temozolomide. These patients have a median survival rate of roughly one year, and we are seeking to improve that and delay the progression of the disease.
Azeliragon is also the subject of a second Phase 2 trial involving both methylated and umethylated GBM. The trial, which is being conducted in Spain with trial sites in Madrid and Barcelona, is investigating azeliragon in combination with radiation and temozolomide. Based upon the results of these two studies, we will determine whether to advance azeliragon into a Phase 3 trial in GBM.
Moe: With the FDA Orphan Drug Designation for Azeliragon in GBM, what are your expectations for studies targeting this form of brain cancer, and are you also considering EMA approvals?
Dr. Marcus: Receiving FDA orphan drug status for azeliragon highlights the significant unmet need for novel treatment options for patients with glioblastoma, the most common and lethal primary brain cancer. This designation validates our continued commitment to developing new treatment options for patients with glioblastoma, as well as for other cancers and their complications. Importantly, the FDA’s Orphan Drug Designation for azeliragon provides Cantex with seven years of azeliragon marketing exclusivity from the time of product launch for the orphan indication, and several other important benefits, including assistance in the drug development process, tax credits for clinical costs, and exemptions from certain FDA fees. Cantex Pharmaceuticals is also considering regulatory pathways beyond the United States, including the European Medicines Agency (EMA), given the universal challenge GBM presents to patients and clinicians worldwide.
Moe: Given Azeliragon’s extensive evaluation in over 2,000 patients, how does its safety profile influence the design and outlook of ongoing and future cancer trials?
Dr. Marcus: Azeliragon was originally developed by another company, vTv Therapeutics, for Alzheimer’s disease. Over the course vTv Therapeutics’ Alzheimer clinical studies, , azeliragon was administered to over 2,000 patients, many of whom were participating in randomized placebo-controlled trials. There wasn’t any substantive difference in safety between the placebo arms and the treatment arms in these studies, even though a biologic effect was evident based upon changes in cytokine levels and changes in the MRI scan. Unfortunately, Alzheimer’s disease is a difficult disease to study, and they failed to show efficacy on the primary endpoint. So, we were able to acquire a license to azeliragon to develop it for indications for cancer and inflammatory disease.
Moe: What does the Phase 2/3 trial for preventing acute kidney injury in hospitalized COVID-19 patients reveal about Azeliragon’s potential in addressing complications outside oncology?
Dr. Marcus: Azeliragon has potential to treat diseases other than cancer. RAGE has been identified as a driver of inflammatory disease in the lung and other systemic inflammatory diseases. We were contacted by investigators with the University of Michigan that were interested in testing the drug in COVID-19. That study, which is Phase 3, has actually been expanded to include all patients with pneumonia who are hospitalized. As it turns out, about one-third of those patients hospitalized with pneumonia develop acute kidney injury as well as respiratory failure. Unfortunately, pneumonia remains a major cause of death primarily in people who whose health is compromised, and such as the elderly, patients with diabetes, patients with cancer, and those with immune system disorders, whereby a systemic inflammatory response occurs which can cause multiple organ failure. RAGE appears to play a role in that, and so the ongoing Phase 3 study in patients hospitalized with pneumonia is examining azeliragon’s ability to prevent acute kidney injury. Additionally, we’re looking at the length of hospitalization, admission to the ICU, mortality, and the incidence of respiratory failure. It’s a very important study, and if that study shows efficacy, it has major implications not only for the vast number of people hospitalized with pneumonia, which is about one million people each year but also has implications for other systemic inflammatory diseases such as sepsis in general.
Moe: What are the primary challenges you face in conducting clinical trials for Azeliragon, and how do you navigate these obstacles?
Dr. Marcus: The first, of course, which every company faces is accrual, getting patients into the study. Second is that clinical trials are expensive, and so raising the capital to do the clinical trial and to do it properly is also a critical challenge. And third, there is competition among the many companies testing compounds, both big, big pharma, and small pharma, for the same patient pools, as well as research centers to conduct the trials. But what we found is that the the profile of azeliragon is extremely attractive, and since it’s a well-tolerated once-a-day pill, which is a vast contrast to so many other treatments that are in development. Azeliragon is also supported by good science and a good rationale for testing it, so we’ve had tremendous interest from investigators who have put it to the top of their list as far as their interest in participating in the azeliragon clinical trials.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
