MMV Stakeholders meeting
Transcript of MMV Stakeholders meeting
Defeating Malaria Together
MMV Stakeholders meeting Siem Reap, Cambodia, 24-26 February 2015 OZ439 Development Update Wiweka Kaszubska, PhD, Head of Product Development
OZ439 is in phase IIb development
Single Dose Cure (SDC) in combination with a drug partner for the treatment of acute uncomplicated malaria
in children and adults
OZ439 development strategy
Select one 4-AQ (PQP or FQ) drug combination
partner for OZ439 for next stage development
Continuously evaluate other drug combination
partners for OZ439 as data becomes available
Test OZ439 activity in
ART resistant parasites as part of the main
clinical program
Single Dose Cure (SDC) in combination with a drug partner for the treatment of acute uncomplicated malaria
in children and adults
Completed phase I and IIa clinical studies with OZ439
OZ439 alone Number of treated subjects
First in Human MMV_OZ439_09_001 56
PhIIa Patient PoC MMV_OZ439_10_002 81
Formulation prototype BA MMV_OZ439_11_001 52
Formulation prototype BA MMV_OZ439_12_003 11
3-Day dose escalation MMV_OZ439_12_005 22
Induced Blood Stage Malaria QP12C10 24
OZ439 in combination Number of treated subjects OZ/MQ combination safety MMV_OZ439_12_001 27
OZ/PQP combination safety MMV_OZ439_12_002 75
OZ/PQP prototype BA MMV_OZ439_13_002 24
OZ/PQP prototype BA MMV_OZ439_13_004 55
OZ/PQP prototype BA MMV_OZ439_13_007 22
OZ/FQ combination safety TDU12511 55
TOTAL 504
To-date OZ439 has an acceptable safety profile
• Acceptable safety and tolerability for single and multiple
(3 day) doses up to 800 mg
• GI dose limiting effects at doses >800mg (diarrhea, hypermotility, nausea)
• Adverse Effects (AEs) generally mild in intensity and reversible up to 800 mg doses
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log10 Parasite Reduction Ratio
Median Parasite Clearance Half Life (h)
Median Fever Clearance Time (h)
P. falciparum 2.8 - 3.6 4.1 - 5.3 8
P. vivax 3.9 - 4.8 2.3 - 3.2 14
Phase IIa study: OZ439 clears 98% of pf and pv parasites by 36 hours in Thai patients
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Phase IIa study: no significant difference in clearance of Kelch mutant vs. wild-type parasites by OZ439
• P. falciparum Kelch 13 status was assessed in parasite isolates from each patient
• Parasites from 19 out of 40 patients carried mutations
N. White manuscript in preparation
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Induced Blood Stage Malaria (IBSM) model
• Volunteers inoculated with ~1,800 viable P.falciparum-infected human erythrocytes
• Daily qPCR from day 3
• Parasite levels reach 1,000/ml on day 6-7
• Start treatment
• F/U for 28 days
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IBSM study: defining the OZ439 dose-range
Australian volunteers
Log10 Parasite Reduction Ratio
Average Parasite Clearance Half Life
Minimal Inhibitory Concentration
4.0 (3.8-4.3) 3.6 h (3.4-3.8 h)
2.4 ng/ml (56% CV)
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Single dose cure: two active pharmaceutical ingredients
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OO O
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NCl
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Cl
Targeting fixed dose combination
OZ439 PQP
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OZ439/PQP Phase IIb trial started in July 2014
• Primary Endpoint: PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28 >95%
• Other Endpoints: parasite clearance times, fever clearance time and safety (particularly cardiac)
• Doses: for patients >35kg and scaled down A) OZ439 800mg + PQP 1440mg
B) OZ439 800mg + PQP 960mg
C) OZ439 800mg + PQP 640mg
• Adaptive design: max 495 patients
NB: OZ439/FQ phase IIb protocol about to be submitted for first country approval
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OZ439/PQP Phase IIb trial recruitment status
Patients with 'Higher' Immunity
Africa >15 yr 45
Africa >5 yr and <15 yr 22
Patients with 'Lower' Immunity
Africa >2 yr and <5 yr 36
Africa >6 mo and <2 yr 0
Vietnam (all age groups) 34
Total
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Sites open
Burkina Faso (3)
Gabon (2)
Mozambique (1)
Uganda (1)
Vietnam (4)
Sites waiting for approval
Colombia
Benin
DRC
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THANK YOU and the OZ439 Project Team
Project Leader: Marc Adamy Clinical Lead: Fiona Macintyre CMO: Stephan Duparc Medical Director: Steve Toovey (consultant) Clinical Operations Lead: Helen Demarest Clinical Scientist: Myriam El Gaaloul Regulatory Lead: Angela Windt (consultant) Technical Lead: Anil Patel (consultant) Discovery Lead: Didier Leroy Non-clinical Lead: Thomas Rueckle Access & Product Management: Adam Aspinall Business Development: Joan Herbert
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Site Status
Nanoro, Burkina Faso Screening (FPI - 11/20/2014)
Banfora, Burkina Faso Screening (FPI – 09/03/2014)
Niangoloko, Burkina Faso Screening (FPI – 09/22/2014)
Lambarene, Gabon Screening (FPI – 07/23/2014)
Libreville, Gabon Screening (FPI - 11/12/2014)
Maputo, Mozambique Approval target February
Tororo, Uganda Screening (FPI – 12/15/2014)
Gai Lai, Phu Thien, Vietnam Screening (FPI - 11/28/2014)
Binh Phuoc, Bu Dang, Vietnam Screening (FPI – 12/17/2014)
Quang Tri, Huong Hoa, Vietnam Screening (FPI – 12/18/2014)
Khanh Hoa, Khanh Vinh, Vietnam Screening (FPI – 12/02/2014)
Cali, Colombia Approval granted Dec, import license target February
Benin Approval target May
DRC Approval target March
OZ439/PQP Phase IIb recruitment site status
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Study population
Assumption – a therapy that treats the most vulnerable / most difficult to treat population ( low/ no immunity) will be able to treat everyone
Safety and efficacy: • African Patients < 5 years old:
• A targeted minimum of 60% of total number of patients (maximum 80%)
• African Patients < 2 years old:
• A targeted minimum of 10% of the total number of patients
• Asian Patients:
• Minimum of 18% of total number of patients
• Maximum of 36% of total number of patients recruited
Safety: • African Patients > 5 years old
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Phase IIb safety step-down process