Medicenna Therapeutics (TSXV:MDNA) is advancing a targeted dual-action immunotherapeutic, MDNA55, that consists of an engineered version of interleukin-4 (IL-4) plus a tumor-killing cytotoxin for the treatment of recurrent glioblastoma, the most common and uniformly fatal form of brain cancer.
“Cancer cells proliferate with the help of IL-4, so our approach is to trick the cell to ingest our toxin-laden IL-4 Empowered Cytokines, which makes MDNA55 a powerful Trojan horse,” Fahar Merchant, chairman, president and CEO, says in an interview with BioTuesdays.
“Because MDNA55 is so targeted and so potent, we don’t need to use much of the drug,” he adds, noting that one-gram of MDNA55 is enough to treat 10,000 patients.
Medicenna, which is derived by combining the word, medicine, with Avicenna, the father of evidence-based medicine, is currently enrolling patients in a Phase 2b study, which if successful, could lead to an application for accelerated approval of MDNA55 for patients with recurrent glioblastoma.
Dr. Merchant explains that MDNA55 enters a cancer cell by binding to the IL-4 receptor on the cell surface and, after entering the cell, initiates apoptosis, or cell death.
According to Dr. Merchant, the IL-4 receptor is over expressed in about 20 different cancers, affecting more than one million cancer patients every year, but is not generally associated with normal brain cells or healthy tissue.
Based on an analysis of biopsies, the IL-4 receptor is widely seen in many other CNS cancers, including newly diagnosed glioblastoma, metastatic brain cancer, meningioma, diffuse intrinsic pontine glioma, CNS lymphoma, pediatric brain tumors and pituitary adenomas.
Recurrent glioblastoma has an annual incidence of 33,300 in the U.S., EU and Japan, representing a market opportunity of $650-million based on current pricing assumptions.
Medicenna also is developing MDNA55 as a potential treatment for metastatic brain cancer and pediatric glioma, which have a total annual incidence of 95,300 patients and a market opportunity of more than $1.3-billion.
MDNA55 has Orphan Drug status from the FDA and European Medicines Agency, and Fast Track designation from the FDA. More than 40 issued and filed patents cover Medicenna’s IP portfolio.
Dr. Merchant points out that the IL-4 receptor is also found on non-malignant cells that protect the tumor from being attacked by the immune system. This immunosuppressive tumor micro-environment comprises some 40% of a glioblastoma tumor mass.
“So our drug candidate has a two-prong approach, targeting tumor cells and the immunosuppressive tumor micro-environment,” he adds.
Pointing to potential advantages of MDNA55, Dr. Merchant suggests that 55% of glioblastomas are resistant to chemotherapy, while MDNA55 targets these same chemo-resistant cells.
“We are looking to treat patients with glioblastoma that relapse after surgery, radiotherapy and chemotherapy,” Dr. Merchant explains, adding that 75% of these relapsed patients are not candidates for another bout of surgery.
In addition, MDNA55 is delivered by direct injection to the tumor in the brain using a minimally invasive image-guided catheter, enabling high drug doses without systemic exposure. The delivery system also by-passes the blood-brain barrier, which would otherwise block transport of therapeutics to the brain.
Seventy-two patients have been treated with MDNA55 in three early-stage clinical trials in the U.S. and Germany. The drug was well tolerated with no adverse systemic side effects.
In one study with 25 patients who were not candidates for surgery, Dr. Merchant says five patients had a complete response and nine had a partial response, where the tumor shrunk by more than 50%, after one treatment with MDNA55. The objective response rate in the study was 56%.
He also notes that the 14 responders to MDNA55 had a median survival of 379 days, while the 11 non-responders had a median survival of 98 days.
In addition, 20% of the 57 patients in two of the three early studies, including those that had and those that didn’t have surgery, achieved long-term survival of three-to-four years, which Dr. Merchant says is typical of “what we see with today’s checkpoint inhibitors approved for other types of cancer.”
He also points out that in clinical trials that cleared Roche’s Avastin to treat recurrent glioblastoma, all patients died after 14-to-18 months. “Despite an inferior patient population, compared with the Avastin studies, MDNA55’s response and survival rates are compelling,” he adds.
In April, Medicenna treated the first of the planned 43 patients, who have progressed or recurred following previous therapy, in a Phase 2b clinical trial at nine sites in the U.S., including Duke, UCSF, Cleveland Clinic and Weill Cornell - Sloan Kettering.
Patients will receive MDNA55 with a second-generation image-guided catheter in order to bypass the blood-brain barrier as well as an imaging agent for real-time monitoring of drug distribution.
The primary endpoint is overall response rate, with secondary outcome measures including, progression-free survival, overall survival, and exploratory predictors of outcome assessed by IL4 receptor expression in archived tumor biopsies.
“With those nine clinical sites, we expect to complete enrolment before the end of 2017, with top-line results anticipated in the first quarter of 2018, and an end-of-Phase 2 meeting with the FDA in the second quarter,” Dr. Merchant suggests.
If the company succeeds in obtaining accelerated approval of MDNA55 for the treatment of recurrent glioblastoma, it would likely move into a Phase 3 study with patients having newly-diagnosed glioblastoma.
In the second half this year, Medicenna plans to begin a Phase 2 study with MDNA55 in patients with metastatic brain cancer, with data available towards the end of 2018.
Medicenna also is collaborating with MD Anderson Cancer Center in Houston to develop next generation fusion protein therapeutics targeting the IL-4 receptor. The multi-year collaboration will focus on advancing preclinical development of IL-4 Empowered Cytokines and a Superkine platform, which Medicenna licensed from Stanford University.
Dr. Merchant points out that analysis of patient biopsies consistently shows over-expression of the IL-4 receptor in many solid cancers outside the brain as well as leukemia and lymphoma. “We hope to have a candidate ready for IND-enabling studies ready by the end of 2018.”
Medicenna has been funding its recurrent glioblastoma clinical trial and next-generation IL-4 Empowered Cytokine programs with a $14.1-million non-dilutive grant from the Cancer Prevention & Research Institute of Texas (CPRIT) along with an additional $14-million (Canadian) of private capital raised prior to going public early this year. In return, CPRIT is eligible for low single-digit royalties following commercial launch of MDNA55 to a maximum of four times the original grant.
“The CPRIT grant provides solid third-party validation of our platform,” Dr. Merchant contends.