IAS: Novel once-daily CCR5 antagonist, INC9471, appears potent, well tolerated after 14 days monotherapy

A once-daily investigational CCR5 antagonist, INC9471, appears to be potent and well tolerated, according to the results of small phase IIa study in treatment-naive and treatment-experienced individuals presented on Tuesday to the 4^th IAS Conference in Sydney.

The drug is being developed by US biotech company, Incyte, and is the first of two CCR5 antagonists under development by the company. Test-tube studies have demonstrated that INC9471 has potent activity against several clades of HIV-1 and against virus that is resistant to the four established classes of antiretrovirals. Phase I studies have shown it to be rapidly absorbed, with a long half-life of around 60 hours.

Tropism findings

Monogram Bioscience’s Trofile assay suggested that all of the participants carried CCR5-tropic virus at screening and at baseline. However two of the 19 individuals on the drug showed a tropism change during the study. The first was found to have R5-tropic virus at screening and day 1, but had dual/mixed tropic virus at days 7 and 28. This reverted to R5-tropic virus after day 28. The second individual was also found to have R5-tropic virus at screening and day 1, but had dual/mixed tropic virus at day 14, which reverted to R5-tropic virus by day 28.

Dr Cohen said that there was evidence to suggest that both patients had low-level dual/mixed tropic virus at baseline, and that this was missed because the assay they used was not sensitive enough.

In the question and answer session that followed, Dr Cohen suggested that “perhaps an improvement in the sensitivity of the assay, or other assays, will be necessary to increase the confidence that we know the patient populations that we’re treating.” However, he said that missed minority variants are “a challenge for our field in a broader way,” citing the example of low-level NNRTI resistance that may be potentially clinically relevant but which is currently being missed by conventional resistance assays.

A representative of Monogram Biosciences who was present in the auditorium told the conference that the company was currently working on a programme aimed at increasing the sensitivity of their assay “down to 1%” and that this should be able to screen out even low-level dual/mixed tropic virus which, he said, could be found in up to 10% of treatment-experienced and around 3% of treatment-naive individuals, according to their data.

Study drug and design

Dr Cal Cohen, Research Director of the Community Research Initiative of New England and HIV Clinical Management Consultant at Harvard Vanguard Medical Associates presented early phase IIa pharmacokinetic, safety and virologic effect results.

In this randomised, blinded 14 day trial, 19 participants received INCB9471 monotherapy (200mg once daily) and four received placebo. Trial participants were either treatment naive (ten on drug, two on placebo) or were treatment- experienced but had been off antiretroviral therapy for at least three months (nine on drug, two on placebo).

At baseline, the cohort’s mean CD4 cell count was 565 cells/mm³ and their mean viral load was 4.7 log₁₀ copies/ml. Five individuals – all of whom took active drug – had viral loads above 100,000 copies/ml. Mean age of the mostly male (just one woman) participants was 37; 17% were African American and 22% were Latino.

Antiviral response and durability

The individuals taking INCB9471 experienced a mean viral load decline of 0.44 log₁₀ copies/ml by day 4, and a 1.14 log₁₀ copies/ml reduction was achieved by day 7.

Interestingly, the maximal mean viral load decline, 1.81 log₁₀ copies/ml, occurred at day 16 – two days after dosing ended. All but one of the 19 participants achieved a viral load decline greater than 1.0 log₁₀ copies/ml, 16 (84%) had a decline greater than 1.5 log₁₀ copies/ml, and 8 (42%) had a decline greater than 2.0 log₁₀ copies/ml.

In the 17 participants whose virus remained R5-tropic, 1.0 log, 1.5 log and 2.0 log₁₀ copies/ml declines were seen in 100%, 94% and 47%, respectively.

At day 20, six days after the last dose, mean viral load decline was 1.72 log₁₀ copies/ml. And two weeks after the last dose of INCB9471, mean viral load decline was still greater than 0.8 log₁₀ copies/ml. This long suppression time is consistent with the drug’s long plasma half-life.

Pharmacokinetics and future dosing

Pharmacokinetic analysis at the end of the study revealed a mean C_min of approximately 400nM, about ten- to 20-fold higher than the concentration needed to inhibit 90% of viral replication in vitro.

Dr Cohen said that this 200mg once daily dose will be studied in future Phase IIb trials. However, he noted that INCB9471 “is neither an inducer nor an inhibitor of CYP3A4, but it is a substrate for the CYP3A4 system.” Consequently, he said, “work is now going on with other doses in the presence of ritonavir to see how we may have to alter the dose in the presence of ritonavir. Ritonavir does appear to prolong the drug’s half-life, so it could possibly be dosed less than once daily.”

Phase IIb clinical studies are expected to enrol in late 2007 and early 2008.

Safety and tolerability

Overall, INCB9471 appeared to be safe and well-tolerated. There were no serious adverse events and no discontinuations for any reason. Four individuals reported a total of six adverse events during the study: mild constipation; mild diarrhoea; mild nausea; mild headache; mild hiccoughs; and mild rash.

Four individuals on the drug (21%) and one on placebo (25%) experienced grade 1 liver function test (ALT, AST) abnormalities, but otherwise no changes were observed to chemistry and haematology parameters.