MRI-guided convective delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy for the treatment of recurrent glioblastoma

Krystof Bankiewicz1, Achal Achrol2, Manish Aghi1, Martin Bexon3, Andrew Brenner4, Nicholas Butowski1, Bradley Elder5, John Floyd4, Russell Lonser5, Fahar Merchant3, Rosemina Merchant3, Toral R. Patel6, Dina Randazzo7, Mark Souweidane8, Michael Vogelbaum9, Frank D. Vrionis10 and John Sampson7

1Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA, 2Pacific Neurosciences Institute, Santa Monica, CA, USA, 3Medicenna BioPharma, Houston, TX, USA, 4University of Texas Health San Antonio, San Antonio, TX, USA, 5Ohio State University, Columbus, OH, USA, 6University of Texas Southwestern, Dallas, TX, USA, 7Department of Neurosurgery, Duke University Medical Center, Durham, NJ, USA, 8Weil Cornell Medicine, New

York, NY, USA, 9Department of Neurosurgery, Cleveland Clinic, Cleveland, OH, USA, 10Marcus Neuroscience Institute, Boca Raton Regional Hospital, Boca Raton, FL, USA

• MDNA55 is an experimental agent in clinical development for intra-tumoral treatment of rGBM and other CNS tumors by CED

• MDNA55 consists of a bioengineered circularly permuted IL-4 (cpIL-4) fused to the catalytic domain of Pseudomonas exotoxin A (PE)3

• MDNA55 binds to IL-4 receptor (IL-4R) overexpressed by GBM and immunosuppressive cells of the tumor microenvironment4-7

MDNA55: TARGETING THE INTERLEUKIN-4 RECEPTOR

• Realtime imaging with co-infused GdDTPA distribution has enabled optimization of catheter placement and infusion parameters

• Initial results on tumor coverage are encouraging with 75% of enhancing tumor receiving drug by CED at the end-of-infusion imaging

• Significant safety events have been manageable with standard measures• Further refinement of MDNA55 regime can enhance patient benefits

REFERENCES1. Keles GE, Lamborn KR, Chang SM, et al. Volume of residual disease as a predictor of outcome in adult patients with recurrent

supratentorial glioblastoma multiforme who are undergoing chemotherapy. J Neurosurg 2004; 100:41–6.2. Weller M, Cloughesy T, Perry J, Wick W. Standards of care for treatment of recurrent glioblastoma – are we there yet? Neuro-

Oncology 15(1):4-27, 2013.3. Kreitman RJ, Puri RK, Pastan I. A circularly permuted recombinant interleukin 4 toxin with increased activity. Proc Natl Acad Sci

USA 1994;91:6889-6893.4. Puri RK, Leland P, Kreitman RJ, et al.. Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets

for the toxic effects of IL4-Pseudomonas exotoxin chimeric protein. Int J Cancer. 1994 Aug 15;58(4):574-81.5. Puri S., Joshi BH, Sarkar C, et al. Expression and structure of interleukin 4 receptors in primary meningeal tumors. Cancer,

2005, 103: 2132–2142.6. Joshi BH, Leland P, Asher A, et al. In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a

recombinant IL-4 cytotoxin in primary glioblastoma cell cultures. Cancer Res 2001; 61:8058-8061.7. Joshi BH, Leland P, Silber J, et al.. IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular

permuted IL-4-Pseudomonas exotoxin fusion protein. British Journal of Cancer (2002) 86, 285 – 291.

Figure 1: Schematic representation of MDNA55 mechanism of action

MDNA55: A Molecular Trojan Horse

MDNA55-05: PHASE 2 STUDY DESIGNAn open-label, non-randomized, Phase 2, multicenter study of Convection-Enhanced Delivery (CED) of MDNA55 in adults with recurrent or progressive Glioblastoma (n=52)

DIAGNOSIS PLANNING SINGLE TREATMENT FOLLOW-UP

Primary Endpoint:- ORRSecondary Endpoints:- OS- PFS

Current Status: Recruitment ongoingProvisional data available for: 15 subjects (safety) & 12 subjects (drug distribution)

• GB at 1st or 2nd

relapse

• KPS ≥ 70

• Tumor Diameter ≥ 1 cm, ≤ 4 cm

• RANO Radiologic Progression

• MRI - Tumor Size and Location

• Optimal Catheter Trajectory(ies)

• Surgical Placement of 1-4 Catheters

• Real-Time Monitoring of MDNA55 Distribution (GdDTPA)

• Infusion Parameters Tailored per Patient

• Patient Safety and Well Being

• Tumor Response Assessment by modified RANO

MDNA55-05: KEY CED PARAMETERSDrug Concentration 1.5-3.0 µg/mL

Volumes of Infusion* 7 - 60 mL; personalized based on tumor volume*

Flow rates Up to 20 µL/min/catheter as higher flow rates improvedistribution

Catheters* 1 - 2 cm tumor: up to 2 catheters2 - 4 cm tumor: up to 4 catheters

Real-Time Infusion Monitoring

First 3-6 hours of infusion; Gadolinium

Catheter Trajectory Planning

Brainlab iPlan® Flow software

*later subjects treated with fixed volume of 60ml via 4 catheters

MDNA55-05: PLANNED AND INFUSED VOLUMES

VolumeEnhancing Mass (ml)

# Catheters for infusion

Vi (ml) Dose (µg) Vd (ml) Vd/Vi

Mean 8.0 2.5 38.2 50 69.3 2.2

Median 5.0 2 35 40.5 59.9 1.8

MAX 30.3 4 66 99 130.2 4.8

MIN 1.6 1 12 18 28.3 0.9

Summary of interim results: analysis was conducted for the first 15 patients

CONCLUSIONS

Disease and Diagnosis: - Initial diagnosis: Gd IV Primary GBM- Date of diagnosis: 04 AUG 2016- Max diameter at initial diagnosis: 4.7cm- Treatments: total resection, radiotherapy (proton beam), temozolomide- Date of most recent PD: 08 MAR 2017- KPS at study entry: 100

Date of CED: 11-APR-2017

Status within study (as of October 14th 2017)Max tumor diameter

(cm)Delivered infusion

volume (ml)Number of catheters Adverse Events Reported

(≥ Grade 2 and suspected to be related to MDNA55)

RelevantAbnormal Labs

(≥ Grade 2)

SAE(s) reported

3.6 17 2 Seizure (Grade 2) 0 0

CASE STUDY: 58 Y/O MALE

Evaluation of infusion

TumorInfusion

Coverage at end of infusion

*Initial estimate

TumorInfusion

Tumor Volume – 12.7 cm3

Tumor Diameter – 2.9 cmVi - 17cm3

Vd of Gad – 30cm3

VD/Vi ratio – 1.8Tumor coverage* - 90%

OVERALL ESTIMATED COVERAGE OF TARGET AREASummary of interim results: analysis was conducted for the first 15 patients

Enhancinglesion

Enhancing lesion+ 1cm Margin

Mean 73% 64%

Median 77% 62%

MAX 94% 95%

MIN 46% 39%

Percentages are the fraction of the target volumes coveredby the determined Gadolinium distribution at

end of infusion.

1

BACKGROUND

• Treatment options for patients with recurrent glioblastoma (rGBM) are very limited and positive outcomes remain very rare1,2

• There is an urgent need to develop effective, tumor-targeted therapies for rGBM to improve patient outcomes and survival

• Intratumoral GBM therapy has been limited by suboptimal delivery of therapeutic agents

• MRI-guided convection enhanced delivery (CED) of MDNA55 (interleukin-4 fused to Pseudomonas exotoxin) is underway in a Phase 2 open label study in patients with recurrent GB (NCT02858895)

• MDNA55 is co-infused with Gadolinium-based contrast agent (GdDTPA) to allow real-time monitoring of drug distribution and to optimize intratumoral catheter placement

Safety (first 15 subjects)

AEs ≥Gd 3Worst CTCAE Grade (n) Related SAE Y / N Outcome

Grade 4 Grade 3I=infusion D=Drug

Cerebral edema 1 I Y ResolvedDehydration 2 Y / Y ResolvedHeadache 1 D N ResolvedHigh glucose 1 N ResolvedLow lymphocytes 4* N / N / N / N ResolvedLow platelets 1 N ResolvedSeizure 1 D Y ResolvedStroke 1 I Y Resolved*Lymphocyteslowatbaseline(inclusion:previousTemodar,LYMPH>500/μL)NodeathsVitalsigns:Somebradycardiaduringcatheterplacement/infusionNoevidenceofCSFtoxicityfollowinglocaladministrationofGadolinium

ACKNOWLEDGEMENTThis Research is Partly Supported by a Product Development Grant from Cancer Prevention and Research Institute of Texas (CPRIT) awarded to

Medicenna BioPharma, Houston, TX