Comparative Pharmacokinetics and Local Tolerance of Tenofovir Alafenamide (TAF) From Subcutaneous Implant in Rabbits, Dogs, and Macaques.

The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of n = 5), beagle dogs (2 groups of n = 6), and rhesus macaques (2 groups of n = 3). Placebo implants were placed in rabbits (n = 10) and dogs (n = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100 fmol/106 cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6 months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform.

Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women.

BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents.

The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.

Neuron navigator 2 (Nav2) was first identified as an all-trans retinoic acid (atRA)-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, RAINB1) that extend neurites after exposure to atRA. It is structurally related to the Caenorhabditis elegans unc-53 gene that is required for cell migration and axonal outgrowth. To gain insight into NAV2 function, the full-length human protein was expressed in C. elegans unc-53 mutants under the control of a mechanosensory neuron promoter. Transgene expression of NAV2 rescued the defects in unc-53 mutant mechanosensory neuron elongation, indicating that Nav2 is an ortholog of unc-53. Using a loss-of-function approach, we also show that Nav2 induction is essential for atRA to induce neurite outgrowth in SH-SY5Y cells. The NAV2 protein is located both in the cell body and along the length of the growing neurites of SH-SY5Y cells in a pattern that closely mimics that of neurofilament and microtubule proteins. Transfection of Nav2 deletion constructs in Cos-1 cells reveals a region of the protein (aa 837-1065) that directs localization with the microtubule cytoskeleton. Collectively, this work supports a role for NAV2 in neurite outgrowth and axonal elongation and suggests this protein may act by facilitating interactions between microtubules and other proteins such as neurofilaments that are key players in the formation and stability of growing neurites.