The Conference on Retroviruses and Opportunistic Infections (CROI 2016) has heard results from the first phase 2 (safety, acceptability and dose-finding) study of a long-lasting, injectable formulation of the integrase-inhibitor drug cabotegravir for use as pre-exposure prophylaxis (PrEP) in HIV-negative people.
In the cabotegravir PrEP study, dubbed the ECLAIR study, a couple of surprises awaited the researchers. Firstly, the rate of absorption of the drug into the body was faster than expected, meaning that an injection will probably have to be given every eight weeks, instead of every 12 weeks as hoped. Secondly, the duration and severity of pain and other effects of the injections were greater than expected; however few people dropped out of the study because of them, and three-quarters of participants said they would be happy to continue taking cabotegravir injections as PrEP should it become available.
The ECLAIR study lasted for 81 weeks altogether: presenter Martin Markowitz did not present final results as the final, follow-up phase has just finished. For the first four weeks, subjects took a daily oral cabotegravir pill (or a placebo pill – one in five subjects took the placebo). This oral phase was intended as a precaution to weed out any subjects who have unusual adverse reactions to cabotegravir – since one of the problems of an injectable formulation is that is cannot be suddenly stopped.
At weeks five, 17 and 29, three doses of injectable cabotegravir were given. These consisted of 800 milligrams of cabotegravir given as two two-millilitre injections, one in each buttock, or of saline as placebo. The “injection phase” was defined as lasting till week 41, 12 weeks after the last injection. There was then a follow-up phase of 40 weeks till week 81; not all the data has yet been collected from this phase.
The study population consisted of men aged between 18 and 64 defined as being at low risk of HIV infection (as this is largely a safety, not a prevention trial). Their average age was 30.5 years, 57% were white and 32% African-American, and roughly 80% were gay and 20% heterosexual – 126 men entered the trial, 105 allocated to cabotegravir and 21 to placebo.
During the first four weeks on the oral pill, eleven people withdrew from the study who were taking cabotegravir, and one taking placebo. During the injection period, a further seven people, all on cabotegravir, withdrew, four of them due to intolerance of the injections.
The fact that more people withdrew in the oral phase was attributed by Markowitz as being due to caution on the part of the investigators at ensuring that no-one who showed any possibility of side-effects went forward to the injection phase. In particular, three subjects in the oral phase saw an increase in levels of creatine phosphokinase, an enzyme that indicates injury to muscle tissue, and although these were almost certainly not drug-related, they were withdrawn from receiving an intramuscular injection as a precaution.
In the injection phase, the primary adverse event was injection site reactions: these were almost universal in the subjects receiving cabotegravir, with 93% reporting them, and 57% receiving placebo. Injection site reactions largely consisted of pain in the muscle at the injection site. Pain was generally mild in placebo recipients but in cabotegravir recipients 37% defined it as ‘moderate’ and 10% as ‘severe’ and lasting, on average, for 5.4 days. Other injection site reactions included itching, swelling and heat at the injection site. The only non-local side-effect was fever, experienced by 7% of men receiving cabotegravir.
Despite this, 62% of people on cabotegravir said they were satisfied with their study medication, and 74% said they would be happy to continue receiving it. In fact more people said they preferred the 12-weekly injection to having to take a daily tablet.
Drug level measurements of cabotegravir showed that it was absorbed by the body faster than expected. This meant that the peak level of drug in the bloodstream, just after the injection, was higher than expected, and the trough level, just before the next injection, was lower than expected.
A model had forecast that the peak level in blood would be three micrograms per millilitre (mcg/ml) when in fact the average level was 5-6 mcg/ml, and the average trough level would be 1 mcg/ml when in fact it was 0.3-0 0.6 mcg/ml. This is of concern since it is close to the IC90, the level of drug that cuts 90% of viral replication, and drug levels should be well above this to ensure efficacy. The proportion of trial subjects whose trough drug levels fell below the IC90 was 24% after the first injection, 31% after the second and 15% after the third.
Markowitz said that the reason for the faster absorption was unknown but it would probably mean that cabotegravir PrEP would have to be given every two months rather than every three.
There were two cases of HIV infection in the study. One person receiving placebo tested HIV positive at week 23. The other had received cabotegravir, but tested positive at week 53, nearly six months after his last cabotegravir injection. At this point he still tested HIV-antibody positive but had a viral load of over 3m copies/ml, so it must have been a very recent infection. He had no detectable cabotegravir in is bloodstream at this point.
Markowitz concluded that these results indicated that cabotegravir injections were safe and, despite injection site reactions, relatively well-tolerated. A parallel trial is happening in women and when this has concluded the final decision will be taken about taking injectable cabotegravir PrEP forward into a fully-fledged effectiveness trial, where it would be compared with oral tenofovir/emtricitabine (Truvada).
Cabotegravir (CAB, GSK1265744) is an INSTI in development as a long-acting (LA) injectable for treatment and prevention of HIV-1. ÉCLAIR evaluated CAB LA injections for HIV PrEP. Dose selection was based on Phase 1 studies of CAB LA and target trough concentrations of 4X PA-IC90 (0.664mg/mL), supported by animal studies of SHIV transmission.
Phase 2a, randomized, multicenter, double-blinded study in healthy males, excluding subjects at high risk of acquiring HIV-1 at screening. Subjects were randomized (5:1) to QD oral CAB 30mg or placebo (PBO) tablets for 4 weeks. Following a safety assessment, eligible subjects received gluteal IM injections of 800mg CAB LA or saline PBO Q12 weeks X3. Safety, tolerability, and PK results through three injection cycles (Week 41 primary endpoint) are presented.
Of 127 subjects randomized (83% MSM 31% African-American and 15% Hispanic), 126 were treated (CAB: 105; PBO 21). Eighteen individuals withdrew from CAB during the study: Five during oral dosing, six after oral dosing but prior to injections, and seven during the injection phase. In total, Grade 2-4 adverse events (AEs) occurred in 13/21 (62%) PBO and 84/105 (80%) of CAB subjects. Of Grade 2-4 AEs, injection site pain (55/94, 59%) occurred most frequently for subjects receiving CAB LA. During the Oral Phase, 7/105 (7%) CAB subjects had AEs that led to withdrawal (WD) including 3 events each of neutropenia and blood CPK increased, and one event of fatigue. During the Injection Phase, injection intolerability led to WD in 4/94 (4%) CAB LA subjects (none attributed to individual AEs), and 1/21 (5%) of PBO subjects had an AE (HIV-1 seroconversion) that led to WD. Through Week 41, 14/105 (13%) of CAB and 1/21 (5%) of PBO subjects had Grade 2-4 drug-related lab abnormalities. Geometric mean CAB Ct values ranged from 0.302-0.387mg/mL; AUC(0-t) ranged from 3415-4021mg•h/mL, with minimal accumulation upon repeat administration. Following repeat injections, 67/91 (74%) of subjects favored continuing CAB LA compared to Oral CAB.
CAB LA was well tolerated through Week 41 with a majority of subjects reporting satisfaction with CAB LA IM injections. A higher peak to trough fluctuation driven by faster absorption from the depot site resulted in mean Ct below the minimum target of 4x PA-IC90. An alternative dosing strategy of 600mg Q8 weeks is being investigated with the aim of achieving targeted exposure prior to conduct of Phase 3 efficacy trials.