Great summary of the issues and history of these failed CCR5 antagonists. But it isn't just CCR5 antagonists... Many drugs fail on human testing due to CYP450 conflicts. Everyone should give that a read, especially any doctors promoting small molecule CCR5 antagonists as treatments for active Covid-19 infection or long haulers:.
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who haven't been following the CCR5 antagonist saga should know the background for this unwelcome bomblet. Clinical trials of Pfizer's maraviroc, Glaxo's aplaviroc, and Schering's vicriviroc had been sailing along with few ill winds of late. Most concern focused on two questions:
- Would drugs that smother the CCR5 coreceptor on CD4 cells prod the protean virus to shift coreceptor allegiance and start hooking onto CXCR4, the coreceptor that arises in about half of people with late-stage HIV infection?
- Would virus resistant to one CCR5 antagonist prove cross-resistant to the others?
HIV's vexing capacity to do the right thing for itself and the wrong thing for patients suggests the answers could be yes, though evidence of "coreceptor switching" has been sparse in the limited clinical trials to date.
Then Glaxo put a chill on warm hopes for aplaviroc when severe hepatotoxicity arose in a few antiretroviral-naive people taking the drug. The company promptly shut down that trial and looked hard for sick liver signals in treatment-experienced people taking aplaviroc. Glaxo found exactly what everyone hoped it wouldn't—the same kind of liver toxicity in experienced people taking aplaviroc with other antiretrovirals for salvage.
What sunk aplaviroc
Why would a bare handful of liver problems—four, as it turned out—bring a megabucks clinical trial juggernaut to a clanging halt? Because, Glaxo's Steel explained, liver experts figure that the specific type of toxicity they saw will kill 10% to 50% of those who have it.
No one in the Glaxo trials died, and the toxicity always resolved when they stopped aplaviroc. When researchers rechallenged one of these people with aplaviroc and Combivir (AZT/3TC), signals of hepatic distress arose again.
All four people had elevated alanine aminotransferase (ALT)—sometimes sky-high ALT—plus simultaneously soaring bilirubins. The FDA lists an ALT more than 3 times the upper limit of normal (ULN) plus total bilirubin more than 1.5 times ULN as a "cause for concern."
The trial enrollee who alerted Glaxo to the liver threat had an ALT 70 times ULN and a bilirubin 5 times ULN after taking aplaviroc and Combivir for 59 days. He did not have HBV or HCV coinfection and started the trial with a normal ALT, aspartate aminotransferase (AST), and bilirubin. Nothing else in his medical history suggested why his ALT might suddenly spike to nosebleed heights. Liver biopsy showed a chronic inflammatory infiltrate "consistent with drug-induced hepatotoxicity."
Scouring the central lab database on aplaviroc for similar cases, Glaxo found three it could attribute to the CCR5 antagonist, including one with an ALT 24 times ULN, one with an ALT 12 times ULN, and one with an ALT and AST 9 times ULN.
Although only four of 308 aplaviroc trial enrollees met the criterion of simultaneous high ALT and bilirubin, that was four too many. Glaxo had no choice but to pull the plug on aplaviroc.
What's up with maraviroc?
Pfizer says it wants to alert trial participants and investigators to the single liver toxicity case it found before disseminating the findings publicly. NATAP will report full details as soon as they become available.
That even one such case arose came as a rude surprise since DSMBs for maraviroc trials had just finished a hair-splitting scrutiny of ongoing trials and found nothing that encouraged them even to tinker with the trial protocols.
Liver readings did jog out of line in 5 of 12 healthy volunteers taking maraviroc for 8 days with tipranavir/ritonavir in a pharmacokinetic study [1]. Pfizer planned this study to address the concern that inhibitors or inducers cytochrome P450 (CYP) enzymes—the enzymes responsible for metabolizing so many drugs—affect maraviroc concentrations.
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