MDNA55 has been granted Orphan Drug status by USFDA and EMA (European Medicines Agency) for the treatment of gliomas and Fast Track designation for the treatment of GBM and anaplastic astrocytoma (AA) by the USFDA. MDNA55 has completed a Phase 2 clinical study for the treatment of recurrent GBM, a uniformly fatal form of brain cancer.
In previously completed clinical studies 72 patients with recurrent or progressive malignant gliomas (GBM and AA) were treated with MDNA55. More than 40% of the recurrent GBM (rGBM) subjects had multiple relapses or large tumors (>4cm in diameter) and 25% had a poor performance status (Karnofsky Performance Score; KPS of <70) prior to treatment with MDNA55. In two sponsor-initiated Phase 1/2a trials, all patients received a single infusion of MDNA55 using convection enhanced delivery (CED). In the first study, tumors were not resected, whereas in the second study, the tumors were resected 3 weeks post-treatment. Tumor response analysis was only performed in the first study. An additional 46 patients have been treated in the completed Phase 2 clinical study for which we announced that enrolment was complete in April 2019.
To date, there have been no detectable levels of MDNA55 in the blood stream, nor any evidence of significant systemic toxicity following treatment. There have been no deaths attributed to MDNA55. Adverse events (AEs) have been primarily neurological which were generally transient and an aggravation of pre-existing neurological deficits anticipated in this patient population.
Phase 2 Clinical Study
Medicenna completed enrolment in a Phase 2 clinical trial with MDNA55 for the treatment of rGBM at nine clinical sites in the United States in April 2019.
The Phase 2 clinical trial, using enhanced Convection Enhanced Delivery (“CED”) was a multi-center, open-label, single-arm study in up to 52 subjects and at least 46 intent to treat patients with first or second recurrence or progression of GBM after surgery or radiotherapy ± adjuvant therapy or other experimental therapies.
The primary endpoint of the study is median Overall Survival (mOS) comparing a null survival rate of 8.0 months (based on historical control) with an alternative pursue rate of 11.5 months (1-sided alpha = 0.10 and 80% power for 46 ITT subjects). The secondary endpoint is objective response rate (ORR) assessed by the modified Response Assessment in Neuro-Oncology (mRANO)-based criteria incorporating advanced imaging modalities according to a null response rate of 6% with alternative pursue rate of 18% (1-sided alpha = 0.10 and 80% power for at least 35 subjects evaluable for response). IL4R expression levels in tumor biopsies and their potential impact on patient outcomes following treatment with MDNA55, were and are being retrospectively evaluated.
Current Study Results:
On May 29, 2020, Medicenna announced the virtual presentations of data from its completed Phase 2b trial of MDNA55, an IL4-guided toxin, in patients with rGBM, at the 2020 American Society of Clinical Oncology (“ASCO”) Annual Meeting. The oral poster discussion led by Dr. Ian F. Parney, MD, PhD (Mayo Clinic) and a presentation by Dr. John Sampson, MD, PhD (Robert H. and Gloria Wilkins Distinguished Professor of Surgery, Duke University School of Medicine), focused on additional data demonstrating clinical superiority of MDNA55 in patients with rGBM. The study enrolled rGBM patients that had aggressive tumors (de novo GBM, IDH wild-type, not-resectable at recurrence) with limited treatment options and poor survival outcomes [median overall survival (“mOS”) of 6-9 months, median progression free survival (“mPFS”) of < 2 months and progression free survival (“PFS”) at twelve months (“PFS-12”) of 0%].
Highlights from the ASCO presentation included:
Comparison of MDNA55 with an eligibility-matched Synthetic Control Arm (“SCA”) demonstrated an improvement in mOS of 61%. When stratified by IL4R status, IL4R High subjects in the MDNA55 arm demonstrated improved mOS by 155% (Table 1).
|Eligibility-Matched Groups||N||mOS||Improvement in mOS||Hazard Ratio (HR)||OS-12|
|MDNA55 IL4R High||21||15.8||155%||0.54||62%|
|SCA IL4R High||17||6.2||155%||0.54||24%|
Further refinement of the SCA using propensity-score weighting (Li et al), an unbiased approach to select patients that match the baseline characteristics of MDNA55 treated patients based on 11 key baseline prognostic factors, confirms these results (Table 2).
|Propensity-Weighted Groups||N||mOS||Improvement in mOS||HR|
|MDNA55 IL4R High||17||13.2||116%||0.52|
|SCA IL4R High||16.8||6.1||116%||0.52|
Irrespective of IL4R expression, subjects showed tumor control rate (“TCR”) (tumor shrinkage or stabilization) of 76% based on modified RANO criteria; these subjects demonstrated mPFS of 4.6 months, PFS at six months (“PFS-6”) of 40%, PFS-12 of 33%, mOS of 15.0 months and overall survival at twelve months (“OS-12”) of 57%.
Additional updated results (not presented at ASCO) include the following:
Patients with Low IL4R expression (H-Score ≤ 60) had a similar TCR as patients with High IL4R expression (H-Score > 60); TCR of 75% vs. 76%, respectively. However, the majority of the IL4R Low patients (11 of 16) received high doses of MDNA55 (180 – 240 mg; median 180 mg) whereas only 8 of 21 IL4R High patients received the high dose of MDNA55.
The IL4R Low group receiving high dose also showed improved survival (mOS Not Reached, OS-12 of 53%) when compared to the low dose group (mOS = 8 months, OS-12 = 13%).
The Proposed Population (n=32), comprised of all IL4R High (irrespective of dose) as well as IL4R Low patients receiving the high dose, were shown to benefit the most from a single treatment of MDNA55. Median survival and OS-12 in this population was 15.8 months and 62% vs 7.0 months and 18%, respectively, when compared to the eligibility matched SCA. (Table 3).
|Eligibility-Matched||N||mOS||Improvement in mOS||HR||OS-12|
TCR in the Proposed Population was 81% based on radiologic assessment by mRANO criteria.
These data indicate that MDNA55 has the potential to benefit all rGBM patients treated at the high dose (180 mg) irrespective of IL4R expression. The high dose has already shown an acceptable safety profile in this and earlier clinical trials (MTD = 240 mg).
Medicenna plans to have an EOP2 meeting with the FDA in 2020 to discuss the results of the MDNA55 Phase 2b clinical study and the development pathway forward.