MIV-150

New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within ∼10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ∼198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies (H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague-Dawley rats for at least 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.

On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005.

HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours.

Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity.

MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate.

NCT03408899.