FDA Grants Orphan Drug Designation to Azeliragon for Pancreatic Cancer

Stephen G. Marcus, MD

The FDA has granted orphan drug designation to azeliragon (TTP488) as a potential therapeutic option for patients with pancreatic cancer, according to an announcement from Cantex Pharmaceuticals.¹

Azeliragon is an oral, small molecule designed to inhibit the interaction between the receptor for advanced glycation endproducts (RAGE) and certain ligands, including the proteins HMGB1 and S100, in the tumor microenvironment.^1,2 In preclinical animal models evaluating the agent in several types of cancer, including pancreatic cancer, glioblastoma, and brain metastasis from breast and lung cancer, azeliragon demonstrated efficacy via RAGE inhibition.²

Safety data from previous clinical trials evaluating the agent in patients with Alzheimer’s disease have demonstrated that azeliragon is well tolerated. A phase 1/2 trial (NCT05766748) is currently evaluating the agent in patients with metastatic pancreatic cancer that is refractory to first-line treatment.¹

“Receiving FDA orphan drug status for azeliragon for the treatment of pancreatic cancer underscores the significant unmet need for novel treatment options for patients with pancreatic cancer, particularly for those patients with locally advanced, unresectable, or metastatic disease,” Stephen G. Marcus, MD, chief executive officer of Cantex Pharmaceuticals, stated in a news release. “This designation strengthens our continued commitment to developing new azeliragon treatment options for patients with pancreatic cancer, as well as for other cancers and their complications, including glioblastoma, brain metastasis, and breast cancer.”

The open-label phase 1/2 trial is enrolling patients 18 to 80 years of age with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas who do not have potential curative measures available. Other key inclusion criteria include prior treatment with gemcitabine plus nab-paclitaxel (Abraxane) or a FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin)–based regimen; resolved toxicities from prior chemotherapy to grade 1 or less, or baseline, other than alopecia; adequate biological blood count parameters; and an ECOG performance status (PS) of 2 or less.³

The trial is excluding patients who have a life expectancy of less than 3 months; who have active, uncontrolled bacterial or fungal infections requiring systemic therapy; who are receiving CYP 2C8 inhibitors; who have a concomitant serious medical or psychiatric illness; or who have a gastrointestinal condition that could interfere with swallowing or absorption of azeliragon.

During dose escalation, the study is enrolling patients into 3 groups consisting of 6 patients each to evaluate 3 different doses of azeliragon. In group 1, patients will receive a loading dose of azeliragon at 15 mg once daily for 6 days, followed by a continuous dose of 5 mg per day for the remainder of the study. Group 2 will be given 15 mg of azeliragon twice per day for 6 days, then 10 mg per day thereafter. In group 3, the agent will be administered at 30 mg twice daily for 6 days, followed by 20 mg per day thereafter. Escalation will continue until stopping rules are reached or the highest defined dose level is identified. Accrual will halt if the first dose is deemed intolerable.

Determining the recommended phase 2 dose of azeliragon is the trial’s primary end point. Secondary end points include the frequency of adverse effects (AEs) and serious AEs; pain after the start of treatment; average daily opioid consumption; change in CA19-9 levels in the plasma; disease control rate; overall survival; change in ECOG PS; change in serum albumin; and change in body weight.

The pancreatic clinical trial is currently enrolling patients at several cancer centers across the United States. The agent is also being investigated in phase 1 and/or 2 trials patients with glioblastoma (NCT05986851; NCT05635734; NCT05773664), brain metastasis (NCT05789589), and breast cancer (NCT05256745).¹

References

1. Cantex Pharmaceuticals receives FDA orphan drug designation for azeliragon for the treatment of pancreatic cancer. News release. Cantex Pharmaceuticals. May 20, 2024. Accessed May 21, 2024. https://cantex.com/2024/05/20/cantex-pharmaceuticals-receives-fda-orphan-drug-designation-for-azeliragon-for-the-treatment-of-pancreatic-cancer/
2. Pipeline. Cantex Pharmaceuticals. Accessed May 21, 2024. https://cantex.com/pipeline/
3. Study of effect of azeliragon in patients refractory to first-line metastatic pancreatic cancer. ClinicalTrials.gov. Updated October 11, 2023. Accessed May 21, 2024. https://clinicaltrials.gov/study/NCT05766748