Artefenomel

Artefenomel/ferroquine

The combination of artefenomel (formerly known as OZ439) and ferroquine (FQ) has the potential to become the first of a new generation of antimalarials not based on artemisinin and therefore an important tool in the context of drug resistance. MMV and Sanofi are currently conducting a phase IIb programme to determine the safety and efficacy of the combination as a single-dose cure.

Dr Charles Wells, Head of Development/Associate Vice President, Infectious Diseases Therapeutic Area, Sanofi, USA, talks about the potential of artefenomel/FQ as a next-generation drug combination.

Artefenomel (OZ439) plus ferroquine

Artefenomel, a novel trioxolane, is a front-runner candidate for inclusion in a new antimalarial combination with ferroquine. The combination is being specifically formulated for children and to allow for once-daily dosing. However, achieving an equivalent efficacy and safety profile in fewer doses than current 3-day ACT regimens is a major challenge. In partnership with Sanofi, MMV is aiming to overcome that challenge. The combination is currently in a phase IIb trial, which is expected to be completed in the fourth quarter of 2018.

Artefenomel - a novel trioxolane

Artefenomel, a novel trioxolane, is a lead candidate for inclusion in a new antimalarial combination with a simpler dosing regimen, specifically formulated for children. Achieving an equivalent efficacy and safety profile in fewer doses than current 3-day ACT regimens is a major challenge. In partnership with Sanofi, MMV is aiming to overcome that challenge and is conducting a phase IIb trial of artefenomel in combination with ferroquine.

Artefenomel Project Leader at MMV, Dr Marc Adamy describes the potential of this compound, its current status and future plans.

Artefenomel/ FQ

Sanofi

Product vision
  • Novel agents in combination for treatment including resistant strains; single-dose potential
MoA
  • Artefenomel (OZ439): novel, synthetic trioxolane 

  • Ferroquine (FQ): inhibition of heme detoxification

Key features

Artefenomel

  • Fast killing of parasites 

  • Active against artemisinin-resistant parasites 

  • 800mg human dose stays above Minimal Parasiticidal Concentration for >8 days

  • Transmission-blocking activity in a Standard Membrane Feeding Assay

Ferroquine

  • Long duration of plasma exposure

  • Active against chloroquine, mefloquine and piperaquine-resistant P. falciparum

Challenges
  • OZ439 food effect/formulation

Status
  • Phase llb combination study ongoing
Next milestone
  • Phase IIb study completion in 2019

Previously
  • OZ439: discovery partnership with Monash University, University of Nebraska and Swiss Tropical Institute

  • Ferroquine discovered by CNRS Lille

MMV Project Director
  • Dr Florian Wartha (interim)

All shots on goal for a single-dose cure

While ACTs are available and access to them is improving, MMV cannot rest on its laurels, but must continue to innovate and develop better medicines for uncomplicated malaria. There is a real need for medicines that are simpler and easier to take, such as a single-dose cure. Not only would such a medicine facilitate ‘directly observed therapy’, which would help to prevent the emergence of drug resistance, it would also reduce the cost of treatment.

Single-dose cure for malaria edges closer to the clinic

8 February 2011, Geneva. A novel synthetic peroxide antimalarial drug candidate, OZ439 has successfully completed Phase 1 clinical trials where it was shown to be safe. It has progressed to trials in malaria patients. The secrets of OZ439’s success have been published today in Proceedings of the National Academy of Sciences.

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Susan A. Charman, Sarah Arbe-Barnes, Ian C. Bathurst, Reto Brun, Michael Campbell, William N. Charman, Francis C. K. Chiu, Jacques Chollet, J. Carl Craft, Darren J. Creek, Yuxiang Dong, Hugues Matile, Melanie Maurer, Julia Morizzi, Tien Nguyen, Petros Papastogiannidis, Christian Scheurer, David M. Shackleford, Kamaraj Sriraghavan, Lukas Stingelin, Yuanqing Tang, Heinrich Urwyler, Xiaofang Wang, Karen L. White, Sergio Wittlin, Lin Zhou, and Jonathan L. Vennerstrom

Proceedings of the National Academy of Sciences of the United States of America

DOI: 10.1073/pnas.1015762108

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate.

OZ439: A winning network of partners

The synthetic endoperoxide project was the very first discovery project taken into MMV’s portfolio back in 2000. Today, OZ439, one of the key molecules to emerge, and one of the next generation antimalarials, is on track to potentially replace artemisinin and become a part of the much-needed one-dose cure for malaria.

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