MDNA.TO: MDNA109 Shows Synergy with Checkpoint Inhibitors in Preclinical Models…

By David Bautz, PhD



Business Update

MDNA109 Long Acting Variants Show Synergism with Checkpoint Inhibitors

On June 20, 2019, Medienna Therapeutics Corp. (TSX:MDNA) (OTC:MDNAF) announced the presentation of new preclinical data for long-acting versions of the company’s lead IL-2 Superkine program, MDNA109, in a poster session at the inaugural Immuno-Oncology Pharma Congress.

MDNA109 is an engineered version of IL-2 designed to increase the ability of T cells to fight cancer. IL-2 (Proleukin®) was one of the first cancer immunotherapies approved by the FDA based on data showing a 16% ORR in patients with metastatic melanoma (Atkins et al., 2000). IL-2 activates a wide range of leukocytes, including T cells and natural killer (NK) cells. While effective as an anti-cancer agent, its use has been limited by a range of adverse side effects, including the potentially deadly capillary leak syndrome, as well as its necessity for frequent dosing and ability to stimulate regulatory T cells along with effector T cells (Boyman et al., 2012).

IL-2 is a 16 kDa protein that exerts its effects through binding various IL-2Rs (IL-2Rα, IL-2Rβ, and IL-2Rγ), with the arrangement of these receptors dictating the response seen. Binding of IL-2 to a heterodimer consisting of IL-2Rβ and IL-2Rγ is relatively ‘low affinity’, whereas a heterotrimer consisting of all three IL-2Rs is a ‘high affinity’ complex. The heterotrimer is typically found on activated T cells (including regulatory T cells) while naïve T cells and NK cells only express the heterodimer. Thus, modifying IL-2 signaling to enhance binding to the β−γ complex could enhance T cell activation while diminishing the effect of regulatory T cells.

An engineered version of IL-2 that exhibited increased affinity to IL-2Rβ was first described in 2012 (Levin et al., 2012). The researchers used in vitro evolution in which point mutations were randomly created in the IL-2 coding sequence, with each of the mutated versions of IL-2 tested for IL-2Rβ affinity. Following the first round of in vitro evolution, a predominant IL-2 variant was identified containing a L85V mutation in the hydrophobic core of the protein, and not a direct IL-2Rβ contact residue. For the second round of in vitro evolution, mutations were restricted to six amino acids in the hydrophobic core. The following table shows the consensus sequence that resulted in the identification of MDNA109 (denoted as H9 in the table), which exhibited high affinity binding to IL-2Rβ.

View Exhibit I

MDNA109 shows excellent in vivo synergism with the checkpoint inhibitor (CPI) antibodies targeted against PD-1 and CTLA-4. The following figures show synergistic anti-tumor activity of MDNA109 when combined with anti-PD-1 in a syngeneic M38 murine colon cancer model (left panel) and also when combined with anti-CTLA-4 in a CT26 colon cancer model (right panel).

View Exhibit II

The new data presented by Medicenna has to do with the production of long-acting versions of MDNA109, MDNA109-LA and MDNA-LA1 (which has low IL-2Rα affinity). MDNA109-LA was shown to synergize with anti-CTLA-4 therapy in a CT26 colon cancer mouse model, as shown in the following figures. MDNA109-LA treatment showed minimal activity as a monotherapy (1 complete response [CR] out of 9 mice treated), however the combo therapy of MDNA109-LA and anti-CTLA-4 resulted in 6 CR and 2 partial responses (PR) out of 9 mice treated.

View Exhibit III

MDNA109-LA treatment results in immunological memory as shown by tumor rejection upon re-challenge. The following figure shows the experimental design for tumor re-challenge in mice that achieved a CR upon treatment with MDNA109-LA and anti-CTLA-4 following injection with CT26 tumor cells. All mice maintained a CR upon the secondary challenge and 75% maintained a CR on the tertiary challenge. Note that there was no additional treatment with MDNA109-LA following the secondary or tertiary tumor challenges.

View Exhibit IV

In addition, MDNA109-LA exhibits superior pharmacokinetics (PK) compared to MDNA109. The following figure shows that MDNA109-LA gives similar tumor control in an aggressive B16F10 melanoma tumor model when dosed biweekly compared to MDNA109 dosed daily. Finally, MDNA109-LA1, with reduced binding to CD25, achieved similar tumor control with a weekly dosing schedule, which is similar to what is seen with other long-acting IL-2 variants in development, such as Nektar Therapeutics’ NKTR-214.

View Exhibit V

Financial Update

On June 25, 2019, Medicenna announced financial results for fiscal year 2019 ending March 31, 2019. The company reported a net loss for fiscal year 2019 of CAD$4.7 million, or CAD$0.18 per share, compared to a net loss of CAD$7.5 million, or CAD$0.31 per share, for fiscal year 2018. R&D expenses in fiscal 2019 were CAD$3.0 million compared to CAD$5.1 million in fiscal 2018. The decrease was primarily due to decreased regulatory costs, clinical trial costs, salaries and benefits, and stock-based compensation. G&A expenses in fiscal 2019 were CAD$1.7 million compared to CAD$2.3 million in fiscal 2018. The decrease was primarily due to lower stock-based compensation and reduced legal, professional, and finance expenses.

Medicenna exited fiscal 2019 with approximately CAD$2.4 million in cash and cash equivalents. In May 2019 and July 2019, the company received payments of US$0.76 million (approximately CAD$1.02 million) and US$1.9 million (approximately CAD$2.5 million), respectively, from the Cancer Prevention and Research Institute of Texas (CPRIT), which are part of a US$14.1 million grant related to the development of MDNA55. Medicenna has approximately US$1.4 million remaining on the grant. The company also recently received approximately CAD$0.3 million from the exercise of warrants. We estimate that the company has sufficient capital to fund operations through the end of 2019.

Medicenna has approximately 28.8 million shares outstanding and when factoring in the approximately 3.3 million stock options and 5.1 million warrants a fully diluted share count of approximately 37.2 million.


Medicenna continues to produce encouraging data with its pipeline candidates, and we are excited for the potential of MDNA109 based on its synergism with checkpoint inhibitor therapy in preclinical models. We look forward to additional updates on the MDNA109 program later in 2019. We also anticipate an update on the MDNA55 program following the company’s ‘end-of-Phase 2’ meeting with the FDA in the second half of 2019 and the potential for 12-month survival data in the first quarter of 2020. We are maintaining our valuation of CAD$5.00 per share.

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