IND-enabling preclinical development of a system for the multipurpose prevention of HIV and unintended pregnancy

SUMMARY (changes are underlined) The broad, long-term goal of this research program is to develop an intravaginal multipurpose prevention technology (MPT) product to provide HIV pre-exposure prophylaxis (PrEP) and contraception to women in the developing world. MPT is a high priority for the NIH, the WHO and for leading NGOs. Our strategy is based on delivering the best-in-class HIV PrEP candidates using our proprietary and novel “intravaginal beads” in conjunction with FDA-approved contraceptive IVRs. Truvada® (TDF-FTC combination) is the only FDA-approved drug product for HIV PrEP. However, recent studies have shown NRTI-associated vaginal mitochondrial toxicity, including the data found in our Phase I SBIR efforts. In our original Phase II SBIR (Jan ’18) submission, we presented pre-clinical results for a TDF- FTC bead formulation, and a proposal to adapt the bead technology to the cabotegravir (CBT)-rilpivirine (RPV) combination. At that time, the FDA had just approved Juluca®, which till date remains to be the only two-drug (dolutegravir [DTG] + rilpivirine) medication for HIV treatment. In the past twelve months, several post- marketing studies of Juluca® have been published showing enhanced safety and efficacy. Additionally, the DTG-RPV combination can also act as PrEP agents at very low levels and has a long half-life with lesser known potential for mitochondrial toxicity than NRTIs. On the other hand, the CBT-RPV combination, although in late-stage clinical trials, is not yet approved by the regulatory agencies. Hence, given the significant regulatory and scientific advantages of DTG-RPV drug combination over CBT-RPV, we shifted our product development focus towards the former. One of the main concerns with our original submission was the lack of preliminary data. In response, we resubmit this application with pre-clinical results for the proposed drug selection. Briefly, a 1-month pharmacokinetics (PK) study was performed in a sheep model to evaluate feasibility of the DTG-RPV beads when delivered in combination with a contraceptive IVR (NuvaRing®). The beads demonstrated an average in vivo release of 2.4 mg/d DTG and 0.6 mg/d RPV. The resulting average cervicovaginal fluid (CVF) levels were 537 ng/ml DTG and 807 ng/ml RPV suggesting sustained delivery at concentrations greater than their respective EC50 levels. The drug loading capacity of these beads allows us to formulate them as 3-month beads making it feasible for use in combination with either a monthly Nuvaring® (in this scenario, one bead will be used for three consecutive monthly IVRs over a 3-month period) or a yearly Annovera® (here, four beads will be required for one IVR over a 12-month period), depending on the user’s choice. This Phase II SBIR resubmission proposes the following revised plan: In Year 1, we will manufacture pre- clinical batches of DTG and RPV beads; and conduct IND-enabling safety/PK studies in sheep and macaques. In Year 2, we will test the formulation for efficacy in a macaque model. Finally, we will perform IND-enabling chemistry, manufacturing and controls (CMC) activities for the lead formulation to submit an IND. We have been granted 13 IND approvals, and the only sustained release antiviral drug delivery device ever approved by the FDA (the Vitrasert®) was developed by the Principal Investigator of this proposal. Successful completion of the work described in this proposal will allow human testing of this novel intravaginal MPT.NARRATIVE (changes are underlined) The broad, long-term goal of this research program is to develop an intravaginal multipurpose prevention technology (MPT) product that will provide HIV pre-exposure prophylaxis (PrEP) and contraception to women in the developing world. We propose the development of intravaginal “beads” of the long acting potent drugs, dolutegravir (DTG) and rilpivirine (RPV), to be used in conjunction with an FDA-approved contraceptive intravaginal ring (IVR). The DTG-RPV combination is the only commercially available 2-drug regimen for HIV treatment. Thus, we expect significant regulatory advantage with this choice of agents. The specific aims of this Phase II SBIR proposal are to build on the demonstrated feasibility of the bead platform we demonstrated in Phase I. The milestone of this application is to achieve an IND approval for a first-in-human safety and pharmacokinetics testing of the proposed bead-IVR product.