Update from the Targeted, Long-acting and Combination
Anti-Retroviral Therapy (TLC-ART) program

Speaker: Rodney Ho, co-Principal Investigator of the TLC-ART GLAD Project at University of Washington

Rodney Ho

Discussed the Global Long-Acting drug combination Development (GLAD) project, which is using innovative (drug combination nanoparticle platform [DcNP]) technology to develop and transform oral into long-acting injectable (LAI) TLD (tenofovir, lamivudine and dolutegravir) for targeted all-in-one HIV treatment in LMICs.  
GLAD project leverages DcNP technology and public-private partnership to accelerate the timeline of novel product development to market.
DcNP platform technology accelerates research and development to transform current oral combination TLD to LAI TLD with sustained viral suppression intended for 1 month (ideally 3 months). Public-private partnership will facilitate the path to market. Timeline: Pre-clinical studies (2020-2023) – Unitaid; Clinical Development (2024-2027) – seeking public/private partnership; Regulatory and Commercialization (2027 global launch target) – partnership established with CHAI and Medicines Patent Pool.

DcNP technology can integrate up to four current HIV drugs with disparate physical properties into a single injectable suspension, avoiding time-consuming pro-drug synthesis and associated non-clinical development costs. 
GLAD project selected three existing, safe and potent short-acting HIV drugs, but with different physical properties. The DcNP process allows TLD co-solubilization and controlled solvent removal to make solid (powder) intermediated; when put in suspension a stable nano-sized TLD is made as a subcutaneous injectable suspension.

First demonstration project shows that DcNP has enabled targeting of combination ART to HIV host cells with potential for long-lasting viral suppression.
Human oral dose (tablet) vs NHP SC injection of DcNP LPV/RTV/TFV: DcNP created an LA form of all three drugs (lasting 2 weeks) with higher drug levels in lymphocytes vs plasma (AIDS 2017). DcNP composed of LPV/RTV/TFV was quickly loaded in the lymph nodes throughout the body of NHP during first-passage. It is estimated that all 3 drugs remained associated in the lymphatic and blood systems. After subcutaneous injection, about 70% of the 3 drugs in DcNP are estimated to remain in lymph nodes for enhanced exposure in lymphocytes, while the excess (30%) went to the plasma.  

Technical readiness of DcNP platform has been validated in NHPs – significance of targeted all-in-one TLD dosing and potential impact in LMICs. 
Overall: Current data indicate that the DcNP platform can assemble TLD into DcNP injectable formulations. A TLD dosage composed of protease inhibitors and NRTI appears to be safe in preclinical studies. The dosage is fixed, but only one injection is required vs two separate injections of LA-CAB and LA-RPV, and the LA product is projected to be price competitive. 

DcNP results in more drug in lymphoid tissue: Early projections from CEPA (supported by Unitaid) predict a 2.3% increase in viral suppression among PLWH, suggesting significant impact if clinical trials find evidence of improved outcomes. 

Exemplifies public-private partnership to bring next-generation products to LMICs: This new paradigm accelerates product release to market – key stakeholders provide funding and implementation support to top innovative teams.

Future development of LAI TLD.
1) Advance LAI TLD from technical readiness to proof of concept. 
2) Seek support from public-private partnership to support clinical development. 
3) Address risk of DTG clinical issue, perhaps by substituting other INSTI (for safety).

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