Dr. Fahar Merchant reports

MEDICENNA ANNOUNCES POSITIVE SINGLE-AGENT ACTIVITY OF MDNA11 FROM DOSE EXPANSION COHORT AND ENCOURAGING SAFETY PROFILE IN COMBINATION WITH KEYTRUDA (PEMBROLIZUMAB) AT THE 39TH ANNUAL MEETING OF SITC

Medicenna Therapeutics Corp. has presented updated clinical results from the continuing monotherapy dose expansion and combination dose escalation portions of the phase 1/2 Ability-1 (a beta-only IL-2 immunotherapy) study evaluating MDNA11, a long-acting beta-enhanced, not-alpha interleukin-2 (IL-2) superagonist, as monotherapy or in combination with Merck's (known as MSD outside of the United States and Canada) anti-PD-1 therapy, Keytruda (pembrolizumab), in patients with advanced solid tumours, at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), held in Houston, Tex., on Nov. 9, 2024.

Highlights:

• Single-agent MDNA11 shows a 30-per-cent objective response rate (three of 10) in the monotherapy dose expansion cohort among patients with advanced and/or metastatic solid tumours who had disease progression with immune checkpoint inhibitor (ICI) therapy.
• Among ICI-resistant, high-dose-MDNA11, phase 2 eligible patients in the monotherapy escalation and expansion cohorts (N equal to 20), the response rate is 25 per cent (five of 20), including one complete response (CR) and four partial responses (PRs).
• Treatment responses have been observed in two of three microsatellite instability-high (MSI-H) patients, both with pancreatic cancer, and in three of 11 patients with cutaneous melanoma, including one CR.
• With no dose-limiting toxicities (DLTs) or new safety signals observed in combination with Merck's (known as MSD outside of the United States and Canada) anti-PD-1 therapy, Keytruda (pembrolizumab) to date, the combination dose escalation is enrolling patients at the highest dose of MDNA11 evaluated in monotherapy (120 micrograms per kilogram).
• Among five efficacy-evaluable patients in the combination dose escalation arm, tumour control (PR or SD (stable disease)) was observed in four patients, including a PR in a microsatellite-stable (MSS) colon cancer patient.

"We are thrilled to share promising results from the phase 1/2 Ability-1 study, with MDNA11 continuing to show deep and durable single-agent activity in patients resistant to checkpoint therapy, including two patients with metastatic, treatment-refractory pancreatic cancer," said Dr. Fahar Merchant, PhD, president and chief executive officer of Medicenna. "We are especially pleased to see that MDNA11 in combination with Keytruda is demonstrating a favourable safety profile, robust pharmacodynamics and early signs of anti-tumour activity in heavily pretreated patients, allowing us to bolster the dose of MDNA11 to 120 micrograms per kilogram every two weeks and begin to evaluate dosing at a more convenient frequency of once every three weeks. We look forward to sharing additional clinical updates from the monotherapy and combination arms at medical conferences in the first half of 2025."

Key findings from the continuing monotherapy and combination dose escalation portions of the Ability-1 study at the time of data cut-off (Oct, 15, 2024) include the following.

Monotherapy tumour response in checkpoint-resistant patients

MDNA11 continues to demonstrate encouraging deep and durable single-agent anti-tumour activity among patients who progressed on prior ICI therapy:

• An objective response rate (ORR) of 30 per cent in the monotherapy dose expansion arm with three PRs among 10 patients who had all previously failed ICI therapy and had advanced and/or metastatic melanoma, non-melanoma skin cancer, or MSI-H/dMMR tumours irrespective of tumour origin.
• The ORR is 25 per cent (one CR, four PRs) from a total of 20 patients when including 10 phase 2 eligible patients from the MDNA11 monotherapy dose escalation arm who received at least 60 micrograms per kilogram.
• Objective responses included:
  • Two PRs among three MSI-H patients (ORR of 66.7 per cent), with both responders having pancreatic ductal adenocarcinoma (PDAC); one patient with MSI-H PDAC was initially misclassified as MSI-H small bowel cancer with metastases in the pancreas;
  • One CR and two PRs among 11 patients with cutaneous melanoma (ORR of 27.3 per cent);
  • SD in six patients including three with duration greater than 24 weeks, yielding a clinical benefit rate of 40 per cent (eight of 20).

Monotherapy safety profile

Key findings from the monotherapy dose escalation and continuing monotherapy expansion arms of the Ability-1 study demonstrate MDNA11's favourable safety profile.

As previously reported, DLT or vascular leak syndrome were not observed during monotherapy dose escalation, with a majority (94 per cent) of treatment-related adverse events (TRAEs) being either Grade 1 or Grade 2 and resolving within 48 hours; Grade 3 TRAEs mainly constituted asymptomatic transient LFT elevations; one isolated Grade 4 TRAE was observed with asymptomatic transient lft (liver function test) elevation in the monotherapy dose expansion arm, which resolved within 72 hours without intervention. Repeat administration of MDNA11 at the target doses continues to improve tolerability.

Monotherapy pharmacodynamics

Pharmacodynamic analyses showed potent and durable systemic immune responses following MDNA11 administration with clear evidence of immune activation in the tumour microenvironment:

• MDNA11 showed significant increases in markers of stemness, central and effector memory and enhanced effector function in circulating CD8+ T cells and NK cells.
• Analysis of paired biopsies showed increased tumour infiltration of CD25+ activated CD8+ T cells and NK cells after MDNA11 treatment.

Combination dose escalation safety profile

No DLTs or Grade 4 or Grade 5 TRAEs were observed in combination dose escalation cohorts 1 or 2 (60 micrograms per kilogram Q2W or 90 micrograms per kilogram Q2W MDNA11 with 400 milligrams Q6W Keytruda) during the DLT observation period. The safety review committee approved enrolment of the next higher-dose cohorts as follows:

• Cohort 3 -- 120 micrograms per kilogram Q2W MDNA11 and 400 milligrams Q6W Keytruda;
• Cohort 4 -- 120 micrograms per kilogram Q3W MDNA11 and 400 milligrams Q6W Keytruda.

Combination dose escalation pharmacodynamics

Early pharmacodynamic analyses demonstrated robust lymphocyte expansion, which was sustained with repeat dosing at both 60 micrograms per kilogram and 90 micrograms per kilogram Q2W MDNA11 in combination with 400 milligrams Q6W Keytruda.

Combination dose escalation tumour response

Encouraging preliminary signs of anti-tumour activity were observed with MDNA11 in combination with Keytruda (400 milligrams Q6W) in dose escalation cohorts 1 (60 micrograms per kilogram Q2W MDNA11) and 2 (90 micrograms per kilogram Q2W MDNA11). Among five heavily pretreated efficacy-evaluable patients, tumour control (PR or SD) was observed in four patients, including a PR in a microsatellite-stable colon cancer patient.

About MDNA11

MDNA11 is an intravenously administered, long-acting, beta-enhanced, not-alpha IL-2 superkine specifically engineered to overcome the shortcomings of aldesleukin and other next-generation IL-2 variants by preferentially activating immune effector cells (CD8+ T cells and NK cells) responsible for killing cancer cells, with minimal or no stimulation of immunosuppressive Tregs. These unique proprietary features of the IL-2 superkine have been achieved by incorporating seven specific mutations and genetically fusing it to a recombinant human albumin scaffold to improve the pharmacokinetic (PK) profile and pharmacological activity of MDNA11 due to albumin's natural propensity to accumulate in highly vascularized sites, in particular tumour and tumour-draining lymph nodes. MDNA11 is currently being evaluated in the phase 1/2 Ability-1 study as both monotherapy and in combination with Keytruda.

About the Ability-1 study

The Ability-1 study (NCT05086692) is a global, multicentre, open-label study that assesses the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of MDNA11 as monotherapy or in combination with Keytruda. In the combination dose escalation portion of the phase 2 study, approximately six to 12 patients are expected to be enrolled and administered ascending doses of MDNA11 intravenously in combination with Keytruda. This portion of the study includes patients with a wide range of solid tumours with the potential for susceptibility to immune-modulating therapeutics. Upon identification of an appropriate dose regimen for combination, the study will proceed to a combination dose expansion cohort.

About Medicenna Therapeutics Corp.

Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 superkines and first-in-class empowered superkines. Medicenna's long-acting IL-2 superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. MDNA11 is being evaluated in the phase 1/2 Ability-1 study (NCT05086692) as a monotherapy and in combination with pembrolizumab. Medicenna's IL-4 empowered superkine, bizaxofusp (formerly MDNA55), has been studied in five clinical trials enrolling over 130 patients, including a phase 2b trial for recurrent GBM (glioblastoma), the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained fast-track and orphan drug status from the FDA (U.S. Food and Drug Administration) and FDA/EMA (European Medicines Agency), respectively. Medicenna's early-stage, high-affinity IL-2-beta-biased IL-2/IL-15 superantagonists from its MDNA209 platform are being evaluated as potential therapies for autoimmune and graft-versus-host diseases. Medicenna's early-stage Biskits (bifunctional superkine immunotherapies) and the T-Mask (targeted metalloprotease activated superkine) programs are designed to enhance the ability of superkines to treat immunologically cold tumours.

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