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Advancements in Microbicide Development: The MMP Project and Future Directions

This document outlines the research and development efforts in the field of microbicides aimed at preventing HIV transmission. Led by Brigitte Bazin, the MultiMicro Project (MMP) emphasizes pre-clinical and clinical evaluations of various compounds, including plant lectins and fusion inhibitors. Key assessments include antiviral efficacy, toxicity, and safety in in vitro and in vivo models. The research highlights the ongoing need for innovative strategies in microbicide development, addressing considerations such as long-term safety and the effectiveness of different delivery methods.

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Advancements in Microbicide Development: The MMP Project and Future Directions

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  1. ANRS AC26 (2002) MICROBICIDE DEVELOPMENT Hypothesis: Microbicide efficiency: Association >>> Single Molécule MULTIMICRO PROJECT (MMP) 1 Brigitte Bazin

  2. Pre-clinical development Clinicaldevelopment Formulation Safety Anti-HIV tests in vitro Phase I/II clinical trials Safety Phase III Mice Model MMP 2 Brigitte Bazin

  3. MMP: European partnership • INSERM U430 (Paris) • CEA (Paris) • Rega Institute (Leuven) • ITM (Antwerpen) • Laboratory for Pharmacology and Biopharmacy (Leuven) • Instituto Superiore Di Sanita (Rome) 3 Brigitte Bazin

  4. EMPRO 25 Institutions 1 large industry 33 PIs 9 Countries 4 Brigitte Bazin

  5. 5 Brigitte Bazin

  6. Overview ANRS – MMP Project 1.1 Evaluation of the antiviral activity of : - plant lectins HHA, GNA, UDA, CA (HIV gp120 inhibitors) - T20 (HIV fusion inhibitor) - KRV21.10 (HEPT-like NNRTI) in vitro * single-cycle pseudovirus assay (ITM) * co-culture model of MO-DC/CD4+ T cells (ITM) * macrophage model (INSERM) * adsorption / transcytosis assay (INSERM) In vivo * SCID mouse model (ISS) 1.2 Evaluation of synergistic antiviral activity of combinations of compounds HHA (gp120 binder) – T20 (fusion inhibitor) - KRV21.10 (NNRTI) 1.3 Evaluation of the toxicity of compounds - cytostatic / cytotoxic activity in * MO-DC/CD4+ T cell co-cultures * ME180 endocervical cells - toxicity evaluation in slug, cervical explants 6 Brigitte Bazin

  7. In vitro : proof of concept ++ • Associations molécules , T 20 , KRV 2110, HHA clairement synergétiques • Toxicité ?? • In vivo ? souris -> pb de modèle • singe : pb coût (en dévt au CEA, MPRO) • Développement clinique ? : partenariat industriel++ 7 Brigitte Bazin

  8. The future = uncertain • In view of three major failed phase 3 trials • (Nonoxynol-9; Savvy and Cellulose-sulphate) • 1) Be more careful about long-term vaginal toxicity • 2) Understand better the precise mechanisms of transmission • Burning questions: • Is there a future for non-specific inhibitors with relatively low activity and unknown long-term toxicity? • Is it realistic to target entry only? • Should we forget about “coital-dependent” methods (creams, gels) and concentrate on long-term devices (rings, caps or long-acting drugs)? • Can local antiretrovirals be effective or do we have to go systemically? • What about the risk on resistance development and the distinction between prevention and therapy? 8 Brigitte Bazin

  9. Réunion du groupe de travail  ANRS « Microbicides » Vendredi 16 février 2007 (F. Clavel) • Etat actuel de la recherche sur les microbicides Guido Vanham • Le programme ANRS en cours sur les microbicides Laurent Bélec Guido Vanham • Le programme européen sur les microbicides Roger Legrand Guido Vanham • Modèles muqueux • - Modulation des modèles in vitro par le complément Hela Saïdi • - In vitro - Plasma séminal et franchissement de la muqueuse Olivier Delezay • - IgA monoclonales anti-gp41 : modèles de muqueuses immunocompétentes Morgane Bomsel • - In vivo  - Chez la souris : muqueuse humanisée chez la souris SQUID Bettina Salle • - Chez le singe - Muqueuse vaginale Bettina Salle • - Muqueuse rectale Cécile Butor • Autres candidats microbicides ? • - Inhibiteurs de l’interaction gp120/CD4 Martin Loïc- Peptide de la gp41Elmostapha Bahraoui • - Mutants de RANTES Guy Gorochov - Une association de molécules « naturelles » Ali Jenabian • - Le SLPI : Un polypeptide naturel anti-VIH Serge Bénichou- Complexes terpéniques Bernard Gombert • - Interféron- Jacques Martal - Ténofovir sous forme microbicide (Gilead)Aldo Trylesinski • - Dermaseptine Hela Saïdi - Propositions de formulations (Bioalliance)Assia Dembri • Discussion générale Animateurs : • - Quelle suite à donner au projet ANRS MMP ? Guido Vanham • - Quelles collaborations mettre en place ? François Clavel • - Entamer une réflexion sur les questions de galénique ? Laurent Bélec • - Quel partenariat avec les industriels ? 9 Brigitte Bazin

  10. Programme 2008 • Valorisation MMP ; soumission de projets de recherche fondamentale • Groupe de travail ANRS en sciences sociales sur les « Stratégies de prévention » (circoncision, microbicides, vaccin…) • 1ère réunion sur Sciences sociales et microbicides le 21 décembre 2007 • Réunion du groupe « Stratégies de prévention » le 26 mars • Orientation du groupe « microbicides » sur « Herpes et VIH » : 1ère réunion le29 janvier 2008 10 Brigitte Bazin

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