Medicenna Therapeutics Corp. (TSX:MDNA.TO) (OTC:MDNAF) is a clinical stage immunotherapy company developing novel versions of the cytokines Interleukin (IL)-2, IL-4, and IL-13, which they term ‘Superkines’. The Superkines can be utilized as monotherapies, used in combination with other immune modulating agents (e.g., checkpoint inhibitor antibodies), or fused with toxic agents to generate ‘Empowered Cytokines’ (EC) that precisely deliver cell-killing moieties to tumors. The company’s lead EC is MDNA55, which has completed enrolment in a Phase 2b clinical trial for the treatment of recurrent glioblastoma (rGBM), the most common and deadly form of brain cancer. In addition, the company has a rich pipeline of pre-clinical assets, including its lead Superkine MDNA109, an enhanced version of IL-2.
IL-4R as a Biomarker in Recurrent GBM
On June 3, 2019, Medicenna announced the presentation of a poster at the American Society of Clinical Oncology (ASCO) 2019 meeting that reported on the use of the IL-4 receptor (IL-4R) as a biomarker in patients with rGBM. The analysis was performed using data from the low dose cohort in the ongoing Phase 2b clinical trial of MDNA55 in patients with rGBM. IL-4R levels were assessed quantitatively at the first diagnosis of GBM using an IL-4R immunohistochemistry (IHC)-based assay on archived tissue samples. Examples of no expression, low expression, high expression, and very high expression of IL-4R are shown below.
A score was then established based on the level of IL-4R expression by summing the percentage of tumor cells with intensity of expression multiplied by their corresponding intensity on a four-point semi-quantitative scale. This resulted in an ‘H-Score’ that ranged from 0-300, with IL-4R expression > 75 classified as ‘High’ and an H-Score ≤ 75 classified as ‘Low’.
The company had 21 matched paired GBM biopsy samples taken from the initial diagnosis and at recurrence from the same patient. The following graph shows that 18/21 (86%) patients had similar or increased IL-4R expression at recurrence.
To examine the relevance of IL-4R as a biomarker, analyses were performed to determine any relationship between IL-4R expression and study outcomes. 18/21 patients enrolled in the first part of the MDNA55 Phase 2b trial were analyzed, with eight patients being classified as IL-4RHigh and 10 patients classified as IL-4RLow. The following graphs show that IL-4RHigh expression is associated with a faster time to relapse (lower left), thus supporting the notion that IL-4R may represent a key biomarker in identifying aggressive forms of GBM. In addition, IL-4RHigh expression is associated with a longer survival following one treatment with MDNA55 (lower right), with a median overall survival (mOS) of 15.2 months in IL-4RHigh patients compared to 8.1 months in IL-4RLow patients. Survival rates for IL-4RHigh and IL-4RLow were 100%, 88%, and 60% compared to 70%, 30%, and 20%, respectively.
Lastly, an analysis of best responses from nadir based on volumetric tumor measurements for patients in the IL-4RHigh and IL-4RLow groups showed that 8/8 (100%) IL-4RHigh patients experienced stable disease or better compared to only 3/8 (38%) IL-4RLow patients (2 patients in the IL-4RLow cohort were not evaluable for best response). In addition, when examining best responses from baseline the IL-4RHigh cohort also showed a higher rate of tumor control, with 6/8 (75%) IL-4RHigh patients exhibiting stable disease or better compared to only 2/8 (25%) IL-4RLow patients.
MDNA55 is Medicenna’s lead development candidate currently in a Phase 2b clinical trial for the treatment of rGBM. The compound consists of a fusion protein containing a circularly permuted version of IL-4 linked to a fragment of the potent bacterial toxin Pseudomonas Exotoxin A (PE). A cartoon representation of the compound is shown in the following figure.
The mechanism of action for MDNA55 is depicted in the following figure. The entire complex is endocytosed following its binding to the IL-4R. The PE domain is then cleaved from the IL-4 domain through proteolytic cleavage by furin-like proteases. Once liberated in the cytoplasm, PE ADP-ribosylates the eukaryotic elongation factor-2 (eEF-2) on ribosomes (Iglewski et al., 1977). This inactivates eEF-2 and effectively shuts down protein biosynthesis in the cell, which leads to apoptosis and cell death. The PE domain in MDNA55 is identical to the PE domain of Lumoxiti™ (Astra Zeneca), which was recently approved by the FDA for the treatment of adult patients with relapsed hairy cell leukemia.
Phase 2b Clinical Trial
Medicenna has completed enrollment in the MDNA55-05 Phase 2b clinical trial in 46 rGBM patients experiencing their first or second relapse (NCT02858895). In this multi-center, open label, single arm study the primary endpoint is median overall survival (mOS) and objective response rate (ORR) is the secondary endpoint following a single intra-tumoral infusion of MDNA55 in adult rGBM subjects. In February 2019, the company reported positive interim data in a podium presentation at the 5th Annual Immuno-Oncology 360 Conference.
The following table gives a comparison between the data seen thus far for MDNA55 and prior clinical trials of approved rGBM therapies. MDNA55 treatment, irrespective of IL-4R expression, results in superior median overall survival (mOS = 11.8 months) as well as OS at six, nine, and 12 months when compared to Avastin®, lomustine, and TMZ.
We anticipate topline data for all 46 patients in the Phase 2b trial to be presented at a scientific conference in June 2019.
The data presented by Medicenna at ASCO 2019 are very encouraging, and support the use of IL-4R as a predictive biomarker for determining aggressive forms of GBM along with those patients that are more likely to respond to IL-4R targeted treatments such as MDNA55. We look forward to the topline data from the Phase 2b clinical trial of MDNA55 being presented at a scientific conference later this month. Heading into the data release our valuation stands at $3.50.
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