The Promise and Pitfalls of Long-Acting Injectable Agents for HIV Prevention

REVIEW

CURRENT OPINION The promise and pitfalls of long-acting injectable agents for HIV prevention

Raphael J. Landovitza, Ryan Kofrona, and Marybeth McCauleyb

Purpose of review Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention. Recent findings Oral RPV is United States Food and Drug Administration approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in phase 2a safety/tolerability/ pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions. Summary Long-acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration. Keywords cabotegravir, HIV-1, long-acting injectable antiretroviral, preexposure prophylaxis, rilpivirine

INTRODUCTION TDF/FTC in rectal and cervicovaginal matrices Chemoprophylaxis for the prevention of HIV infec- [10]. The challenges of daily or near-daily oral dos- tion has been revolutionized by recent studies show- ing strategies, and the long-term maintenance of ing high levels of protection against rectal exposures such dosing have driven interest in preexposure by daily oral tenofovir/emtricitabine (TDF/FTC) prophylaxis (PrEP) agents that have more con- [1,2& –4&] and against vaginal exposure in a study venient dosing schedules. of HIV discordant couples [5]. Robust efficacy data The field of long-acting injectable agents has led to the approval of daily oral TDF/FTC by the US substantial precedent among antipsychotics (e.g., Food and Drug Administration (FDA) in 2012, for paliperidone palmitate) and contraception (e.g., men and women who are at high risk of becoming medroxyprogesterone acetate). Removable depots HIV infected. The registrational studies also indicate of contraceptive agents (Norplant), and transdermal a clear dose-response relationship of protection and patches for sustained drug delivery are attractive, adherence [6,7]. Although rectal protection afforded but are limited by molecular size and chemical by daily oral use of TDF/FTC has been modeled to be properties, including hydrophobicity and charge. 99% when taken 7 days per week as prescribed, modeled data and clinical cohorts suggest some a forgiveness of missed doses for protection against UCLA Center for Clinical AIDS Research & Education, Los Angeles, California and bFHI 360, Connecticut Avenue, Washington, District of rectal exposures – as few as 4 doses per week appears Columbia, USA & to preserve high levels of protective efficacy [2 ,8]. Correspondence to Raphael J. Landovitz, MD, MSc, UCLA Center for Protection against vaginal exposures has been less Clinical AIDS Research & Education, 11075 Santa Monica Blvd, Suite rigorously described, but is modeled to be much less 100, Los Angeles, CA 90025, USA. Tel: +1 310 825 3782; fax: +1 310 forgiving of missed doses than are rectal exposures 477 7657; e-mail: [email protected] [9]. This is believed to be attributable to differential Curr Opin HIV AIDS 2016, 11:122–128 tissue pharmacokinetics of the components of DOI:10.1097/COH.0000000000000219 www.co-hivandaids.com Volume 11 Number 1 January 2016 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Long-acting injectable agents for HIV prevention Kofron et al.

intravenous routes of administration. Once admin- KEY POINTS istered, a long-acting injectable agent for prevention PrEP effectiveness is compromised by challenges of HIV would anticipate provision of ‘coverage’ around need for regular adherence. for HIV exposures during the period at which protective levels of the agent remained in the indivi- Long-acting injectable agents offer pharmacokinetic dual. Although the exact tissue and/or or plasma advantages, but do not entirely solve adherence correlates of protection remain undefined, long- challenges. acting injectable agents are intended to provide Use of a long-acting agent that cannot be removed sustained drug levels in serum, plasma, and relevant after administration obligates a short-acting lead-in to mucosal tissues. They additionally have the poten- establish safety and tolerability. tial for reduced gastrointestinal toxicity, as well as Prolonged pharmacologic tail makes discontinuation avoiding some drug–drug interactions. Although challenging, particularly if exposures/risk are long-acting agents would obviate the need for daily ongoing – with concern for seroconversion with pill taking, they raise novel challenges regarding resistant viral quasispecies. adherence, safety, and optimizing starting and Injections may be differentially acceptable in diverse stopping mechanisms. Two chemical entities are populations. in advanced stages of clinical development for long-acting prophylactic use (Table 1). It will be important to evaluate whether cultural or social norms will make the use of injections Technologies are evolving rapidly, and a recent for HIV prevention differentially acceptable in presentation of an implantable system appears diverse populations globally. For this reason, evalu- capable of delivering tenofoviral-afenamide in sus- ation of such perceptions and acceptability are tained fashion in a dog model [11]. important to capture as part of early phase develop- For HIV, long-acting agents have the potential ment programs. advantage of requiring less-than-daily dosing intervals, some dosed as infrequently as every Cabotegravir 2–3 months. All long-acting HIV antiviral agents Cabotegravir (CAB, formerly GSK 1265744, currently in development require parenteral injec- ViiVHealthcare) is a novel investigational strand- tions – via subcutaneous, intramuscular (IM), or transfer integrase inhibitor. CAB is a chemical

Table 1. Comparison of agents in advanced clinical development

Cabotegravir Rilpivirine

Class of agent Strand-transfer integrase inhibitor Nonnucleoside reverse transcriptase inhibitor Oral half-life (plasma) 40 h 50 h Injectable half-life (plasma) 21–50 days 35 days in women 33 days in men Stage of development Treatment: phase 2b (oral/LA) Treatment: approved for treatment of HIV-1 infection, May 2011 (oral); phase 2b (LA) Prevention: phase 2a (oral/LA) Prevention: phase 2 (oral/LA) Toxicity Headache Headache Nausea Nausea Diarrhea Diarrhea Insomnia Nasopharyngitis Increased LFTs Insomnia Dizziness Increased serum creatinine Increased LFTs Decreased serum cortisol To date exposure to LA 500 >150 Percentage ISR (IM) 74% 95%

LA, long acting; IM, intramuscular; ISR, injection site reactions; LFT, liver function test.

1746-630X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-hivandaids.com 123 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. The PrEP revolution: from clinical trials to routine practice congener of dolutegravir, with nanomolar in-vitro enrolled 127 US-based HIV-uninfected low-risk activity against HIV-1 clinical isolates. It is avail- men in a safety, tolerability, and pharmacokinetic able as both a short-acting oral formulation with a evaluation that employed a 4-week oral lead-in half-life of 40 h, and a long-acting injectable formu- followed by 3 quarterly IM injection doses, with lation comprised solely of active drug nanocrystals a 52-week follow-up period after the final injec- and not encased in a polymer, micelle, or lipid tion. E´CLAIR is randomized 5 : 1 active CAB : matrix. The long-acting formulation has a plasma placebo, with results expected in early 2016. The half-life of 21–50 days. Macaque rectal and vaginal ongoing HPTN 077 is enrolling 194 low-risk men challenge models demonstrate high levels of pro- and women globally to further evaluate safety, tection against SHIV acquisition at supraphysio- tolerability, and pharmacokinetic in broader logic challenge doses at drug levels above three- populations. A 3 : 1 active CAB : placebo random- fold the PA-IC90 for rectal exposures and four- ization is being used, with data expected in early fold PA-IC90 for vaginal exposures (PA-IC90 is 2017. It is anticipated that these phase 2a studies 0.166 mg/ml) [12,13]. Oral CAB 10 mg QD approxi- will be followed by efficacy studies in populations mates such levels at steady state. CAB LA at a dose of men, transgender women, and women at high of 600–800mg administered every 8–12 weeks risk of acquiring HIV infection. Considerations for provides trough levels approximately six-fold the design of phase 3 efficacy studies for preven- PA-IC90. The 800 mg dose is administered as 2 tion of rectal exposures are complex and nuanced simultaneous gluteal IM injections of 2 ml each, now that daily oral TDF/FTC has a robust suppor- after which plasma levels are detectable up to 52 tive body of evidence for HIV prevention; the weeks after an injection. Because there is no way to results of upcoming dapivirine ring studies, if remove the drug once injected, a 4-week ‘lead-in’ positive, may additionally complicate these issue strategy using oral CAB has been utilized to for women. A detailed discussion of the ethics of establish safety parameters. A 30 mg QD dose has phase 3 efficacy study designs for HIV prevention been chosen for the oral lead-in to provide suffi- is provided in an additional article in this issue cient margin of excess above the 3–4-fold PA-IC90 [28]. prophylactic target level, while being a sensitive probe for drug-related adverse events. Ideally, a Rilpivirine long-acting injectable agent aimed at those chal- Rilpivirine (RPV, Edurant, Janssen Scientific, USA) lenged by daily oral pill taking would not require was approved by the FDA in May 2011 for the treat- an oral lead-in period; however, this requirement is ment of HIV-1 infection at an oral dose of 25 mg likely to persist absent extensive safety experience daily. It is a small-molecule non-nucleoside reverse- with such agents. transcriptase inhibitor with picomolar activity CAB, in combination with other anti-HIV anti- against HIV-1 primary clinical isolates [16]. Oral retroviral agents, has been investigated for treat- RPV is indicated for treatment of HIV-1-infected ment of HIV infection in phase 2a and ongoing individuals with viral loads <100 000 cells/ml in 2b studies. In the LATTE trial, oral CAB at doses combination with 2-NRTI’s, and is being developed of 10, 30, and 60 mg daily, in addition to 2 nucleo- as a long-acting injectable preparation (also side-analog reverse-transcriptase inhibitors, were referred to as TMC278LA or RPV LA) [17]. RPV LA virologically noninferior to a dual-nucleoside plus has undergone a series of formulation revisions to efavirenz regimen; and virologic noninferiority was optimize pharmacokinetics: The particle size and maintained after virologically suppressed CAB- suspension fluid have evolved, with the current treated participants ‘simplified’ their regimens to formulation (G001) having a particle size of approxi- CAB plus oral rilpivirine (RPV) at both 48 and 96 mately 200 nm in a poloxamer-338 suspension of weeks of total treatment [14,15]. The ongoing 300 mg/ml of RPV. Like cabotegravir, RPV comprises LATTE-2 trial is evaluating oral CAB 30 mg QD with the pure parent compound and is not encased dual nucleosides as a lead-in to virologic suppression in a nanoparticle or micelle. The dose being prior to transition to IM CAB LA plus IM RPV LA brought into prevention trials is 1200 mg, requir- (dosed 400 mg (1 Â 2 ml) every 4 or 600 mg (1 Â 3 ml) ing 2 Â 2 ml IM gluteal injections. For treatment, every 8 weeks – each with an 800 mg (2 Â 2 ml) RPV LA is being evaluated at doses of 600 mg loading dose, and the every 8-week regimen with (1 Â 2 ml) every 4 weeks, and 900 mg (1 Â 3 ml) every an initial one-time week 600 mg supplement); 8 weeks. again, efavirenz with dual nucleosides is the control Humanized bone marrow/liver/thymus mouse comparator. studies suggest that RPV LA levels remain above the Evaluation of CAB as a potential PrEP agent is IC90 level for 4 weeks after a single IM dose, as currently in phase 2a evaluation. The E´CLAIR study well as providing protection against vaginal viral

124 www.co-hivandaids.com Volume 11 Number 1 January 2016 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Long-acting injectable agents for HIV prevention Kofron et al. challenges for 3–4 weeks after dosing [18]. Phase I injectable PrEP formulation would not be expected studies after single doses suggest pharmacokinetics to solve adherence challenges for all patients. supporting every 8-week dosing for prevention, as well as approximately two-fold excess con- SAFETY AND TOLERABILITY centration in rectal tissue over cervico-vaginal As both cabotegravir and RPV’s LA preparations tissues [19]. Explant challenge models suggest contain nanocrystals of the pure parent compound, rectal tissue protection as delayed as 4-months after there is hope that the long-acting preparation dosing, but absence of such protection in a com- will not have a substantially different safety parable cervicovaginal model [20]. One female profile from the short-acting version of each participant, followed after a single dose of 300 mg respective agent – save for complications from IM of RPV LA in a compartment pharmacokinetic the injection itself, injection site reactions. A study reporting an HIV exposure approximately potentially serious safety concern is the nonremov- 40 days after injection, seroconverted approxi- ability of the preparation if an idiosyncratic or mately 120 days after dosing (80 days after known adverse event (AE) occurs after the injectable exposure) with K101E virus, conferring resistance is delivered. to the non-nucleoside reverse-transcriptase inhibitors class [21&]. Cabotegravir – clinical experience to date RPV LA is now being evaluated in HPTN 076, Approximately 1000 individuals have received the a phase 2a safety and acceptability study enrolling non-FDA approved cabotegravir, divided approxi- 132 HIV-uninfected low-risk women in the USA mately equally between HIV-infected and HIV- and sub-Saharan Africa in a 2 : 1 active RPV : uninfected individuals, and with half receiving placebo randomization. The study also employs a the short-acting oral tablet formulation only, and 4-week oral lead-in (uniquely employing direct half receiving the long-acting preparation or both observed therapy to assure oral drug exposure the oral tablet and the long-acting preparation. In prior to long-acting dosing), followed by a series the LATTE study, doses of 10, 30, and 60 mg daily of 6 injections of 1200 mg each at 8-week intervals, were administered to HIV-infected treatment naı¨ve followed by a 32-week observational period participants in combination with 2 nucleoside during drug ‘washout.’ Results are expected in reverse-transcriptase inhibitors, and compared with early 2017. 2 nucleoside reverse-transcriptase inhibitors with efavirenz. Treatment emergent AEs included head- ADHERENCE ache, nausea, and diarrhea for cabotegravir-treated Although long-acting agents obviate the need for a participants. Insomnia appeared to be the only AE daily or peri-coital pill-taking activity, adherence to for cabotegravir with an AE dose–response associ- injections still requires consumers to comply with ation [24&]. Treatment emergent elevations in ala- even infrequent injections. During clinical trials, nine aminotransferase (ALT) were more common in injections are administered in a clinic-based setting cabotegravir groups, and were correlated with dose as a gluteal intramuscular injection – essentially a level. Three participants (2 with evidence of steato- directly observed therapy strategy if the individual hepatitis at baseline and 1 HIV/HCV coinfected) presents to the clinical appointment. If a long- developed serious ALT elevations. All were clinically acting agent becomes approved for prevention by asymptomatic and ALT abnormalities resolved with regulatory agencies, issues regarding administration withdrawal of the study medication. For the long- will require thoughtful consideration, either acting preparation, no ALT abnormalities have been employing family members/friends to give the reported requiring discontinuation of study product injections or potentially allowing self-adminis- to date. tration. Although potentially offering the advantage In completed studies, ISRs occurred in the of not requiring clinic visits for administration, majority of participants following IM (74% with towards: homedosing becomes challenging to any ISR) dosing; however, the reactions were gener- characterize and track. Decay pharmacokinetics will ally mild to moderate (overall ISR Grade 2: 14% in IM need to be sufficiently well defined as to allow clear without any Grade 3 or 4 ISRs) [25]. The most fre- guidance to users how ‘late’ after the next injection quent ISRs for IM dosing were pain (71%), erythema is due protection would be expected to be main- (9%), and nodules (7%). Median IM ISR durations tained, and careful guidance developed for late or were approximately 5 days for pain and erythema, missed doses. The injectable contraception litera- and approximately 22 days for nodules [26]. ture suggests a high rate of nonadherence after Data from the ongoing E´CLAIR and LATTE-2 initial injectable hormonal contraception use studies are preliminary, but has generally been [22,23], and for this reason, even a long-acting consistent with prior data with few withdrawals

1746-630X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-hivandaids.com 125 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. The PrEP revolution: from clinical trials to routine practice because of injection-related tolerability (3 discon- number of exposures, an oral phase will likely be tinuations in ongoing studies). The majority of ISRs part of both product’s initial labeling if approved for has been mild or moderate, with a small percentage HIV prevention. of participants reporting more significant (Grade 3) Clearly, a given person’s tolerance of an oral pain/discomfort. lead-in does not obviate concern for an idiosyncratic Concern has been raised about the volume or late-onset toxicity at a later time-point after of injections and their acceptability. The current injection; however, the intent is to prevent pro- preparation of long-acting cabotegravir is 200 mg/ longed exposure in individuals who have a fulmi- ml; doses under evaluation for treatment and pre- nant early reaction or issues with tolerability. vention therefore would be 3–4 ml. A 3 ml injection Adherence to the oral lead-in period may also com- could potentially be delivered as a single injection; a promise sensitivity; counseling around the reason 4 ml total injection volume would have to be admin- for the lead-in will need to be carefully crafted istered as 2 simultaneous 2 ml injections; one in to maximize comprehension of the rationale, each buttock. The acceptability of such injections whereas the lead-in may otherwise be viewed at 4–12 week intervals is currently under evaluation negatively or as expendable, awaiting the desired in ongoing phase 2 trials. injectable preparation. As mentioned, a directly observed therapy strategy in the rilpivirine phase 2a studies attempts to maximize preinjection Rilpivirine – clinical experience to date exposure, however this strategy is unlikely to be Over 2000 study participants were exposed to oral tenable in clinical practice. RPV (TMC278) during its clinical development, and it was approved by the FDA for the treatment of HIV-1 infection in combination with other anti- STOPPING STRATEGIES: THE PROLONGED retroviral agents in 2011. In the phase 3 registra- PHARMACOLOGIC ‘TAIL’ tional studies, the most commonly reported AEs in In considering discontinuation of long-acting the TMC278 group were headache, nausea, diarrhea, injectable products, the timeline for loss of protec- nasopharyngitis, insomnia, and dizziness, all with tive effect will be a critical parameter to determine: similar incidences in the control group, except for How long after the final injection does protection dizziness [27]. The majority of AEs were mild to endure? An additional concern then becomes moderate in severity. Treatment emergent labora- whether as drug levels decline during such a ‘wash tory abnormalities include increases in serum crea- out,’ would exposure to HIV resulting in serocon- tinine (usually 0.1 mg/dl), reductions in serum version select for resistant virus? As noted above, a cortisol (and ACTH-stimulated cortisol), and single case of seroconversion with nucleoside increases in ALT, aspartate aminotransferase, and reverse-transcriptase inhibitors-resistant virus has total bilirubin. Postmarketing experience has found been documented in a seroconversion event during instances of nephrotic syndrome and severe the pharmacokinetic ‘wash out’ period of a single cutaneous reactions including drug reaction with dose of RPV LA 300 mg during a phase I tissue eosinophilia and systemic symptons. pharmacokinetic study [21&]. This single case To date, more than 200 individuals have been suggests that particularly in high-risk populations exposed to TMC278 LA in completed and ongoing in whom long-acting injectables are being used for studies. Overall, the injections have been well tol- HIV prevention, it may be advisable to ‘cover’ the erated and safe. ISRs have been the most common pharmacologic tail of the injectable agent with daily adverse events. There have been no safety or toler- oral TDF/FTC. The strength of such a recommen- ability observations that preclude multiple dosing. dation would likely be governed by the reason for discontinuation and ongoing risk profile of the individual. STARTING STRATEGIES: THE ORAL LEAD-IN As mentioned above, both cabotegravir and rilpir- OTHER LONG-ACTING ivine’s developmental programs are employing CHEMOPROPHYLACTIC AGENTS an oral lead-in period prior to the administration Other pharmacologic preparations are in preclinical of the long-acting preparation. Although it is some- and various stages of clinical development to pro- what antithetical to the purpose of developing a vide prolonged drug exposures either as a result long-acting preparation to obligate a daily oral of nanosuspensions, novel vehicles or delivery run-in, at minimum until the safety profile of the systems, or immunomodulatory effects. These long-acting preparation is informed by a larger include vaginal rings delivering single or multiple

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