Development of the once-daily nucleoside reverse transcriptase inhibitor (NRTI) DFC (dexelvucitabine, formerly known as D-d4FC and Reverset) has been discontinued due to an "unacceptably high" incidence of grade 4 hyperlipasaemia when 200mg DFC is taken without 3TC (lamivudine, Epivir,) or FTC (emtricitabine, Emtriva). Dr Paul Friedman, President and CEO of Incyte, who had been developing the drug in collaboration with Pharmasset, said in a telephone conference last week that "even though lower doses could be safer, those we've studied have not been effective and we believe it is in the best interest of patients to discontinue DFC's development."
40% incidence of elevated lipase
Hyperlipasaemia is the presence of the enzyme lipase in the blood and may be a sign of damage to the pancreas. A 40% incidence of grade 4 hyperlipasaemia was observed in Study 901, the long-term extension of DFC's first Phase IIb trial, Study 203. Results of Study 203 were reported at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro last July.
Study 203 had found that a combination of DFC with ddI (didanosine, Videx/Videx EC) led to a 50% incidence rate of grade 4 hyperlipasaemia, with seven of the 14 taking 200mg with ddI experiencing extremely elevated lipase levels. However, two (5%) of the 37 participants taking 200mg DFC without ddI also had grade 4 hyperlipasaemia. Although there were also four cases of pancreatitis (inflammation of the pancreas) in the study, these only occurred in individuals taking 100mg DFC.
Study 203 had also found that combining DFC with either 3TC or FTC resulted in reduced efficacy, and last August Incyte had recommended that the study investigators begin to switch participants who had rolled over into Study 901 away from 3TC and FTC. As in Study 203 itself, approximately 70% of participants in Study 901 - all of whom were taking 100mg or 200mg DFC - were also on 3TC- or FTC-containing regimens.
Last week, after reviewing data on 17 individuals who had been on 200mg DFC without 3TC or FTC for 16 weeks, they saw that the incidence of grade 4 hyperlipasaemia was 40%, which in Incyte's view, was "unacceptably high."
Dr Richard Levy, Senior Vice President of Drug Development at Incyte, who oversaw Study 901, said in a telephone conference last week that although he had received five reports of grade 4 hyperlipasaemia since the beginning of the year, it was only when the drug data was collated at the beginning of last week that they saw this 40% incidence rate. Pancreatitis occurred in one of these five individuals, who also had elevated triglycerides, another risk factor for pancreas inflammation.
All studies now discontinued
Incyte immediately stopped enrolment of Study 204. This was the recently initiated Phase IIb trial that was requested by the United States Food & Drug Administration (FDA) last September, rather than approving Phase III studies of DFC. The FDA told Incyte that they had wanted to see additional data to support the efficacy and safety of DFC.
Study 901 was taking place at 25 sites in the United States, Germany and France, involving up to 199 participants. Individuals who were currently taking DFC were advised not to discontinue DFC without consulting their doctor and a follow-up study visit should have been scheduled by today.
DFC was one of the most promising drugs in the next generation of NRTIs, since it appeared to have good activity against thymidine analogue mutations (TAMS) and M184V, which confers resistance to 3TC and FTC. It was also effective against the M41L mutation, the most common NRTI mutation found in recently HIV-infected gay men in the UK.
Other next generation NRTIs currently in development include Avexa's AVX754 (formerly SPD754), Pharmasset's racivir and Achillion's elvucitabine.
Why did 3TC and FTC prevent elevated lipase levels?
A statement on the Incyte website regarding the safety of DFC following the results of Study 203 noted: "In the absence of ddI, there is a modest increased incidence of asymptomatic hyperlipasaemia meaning there were not cases of clinical pancreatitis attributed to DFC in DFC-treated patients. While longer term safety data will be needed to determine if DFC causes pancreatitis, based on the data to date, we are optimistic that such cases, if any, would be relatively rare."
In last week's conference call Dr Friedman reiterated that they had only seen a 2% incidence of grade 4 hyperlipasaemia in Study 203, and that 3TC and FTC had masked, or ameliorated, this side-effect.
Commenting on possible mechanisms, Dr Levy noted that DFC, 3TC and FTC are all cytidine analogues, and potentially compete with each other for the requisite activation processes that occur in cells to produce the active triphosphates that bind to and inhibit HIV's reverse transcriptase enzyme. "The data are very suggestive that if triphosphates provide the antiviral activity, then this competition...might [also] mean that [the] lower triphosphate levels induced by 3TC and FTC were ameliorating DFC's effects on the pancreas," he said.