Glaxosmithkline’s pipeline cull yesterday drew attention away from a potential problem with a key near-term growth driver, one of its HIV doublets. A case of resistance in a small investigator-led study of dolutegravir plus lamivudine has put investors on the alert ahead of two big readouts next year.
Glaxo executives played down the issue, but the company’s HIV rival Gilead will surely seize on any advantage it is given. The UK company will have to deliver a clean safety profile in the ongoing phase III Gemini trials if it wants to keep increasing its market share in HIV.
Glaxo does not seem too worried yet. John Pottage, chief scientific and medical officer of the group’s ViiV unit, said during yesterday’s conference call that the patient who developed resistance was “chaotically non-adherent” to the medication, which would have increased the risk of the virus multiplying and mutating.
He added that the 120-patient ACTG A5353 study, presented at this week’s International Aids Society (IAS) meeting in Paris, showed “pretty spectacular” efficacy, with 90% of patients having their viral load fully suppressed at 24 weeks.
However, Leerink analysts noted that poorly compliant patients represent the real-world population. “If this pattern of failure, and resistance development, can occur in a relatively small trial, then it is likely to be even more common and concerning in a post-marketing setting,” they wrote.
While the event should not be enough to put the brakes on Glaxo’s doublet, it will no doubt lead to closer scrutiny of the 700-patient Gemini 1 and 2 studies, due to be completed next April. The trials are designed to show non-inferiority to a regimen containing dolutegravir, tenofovir and emtricitabine in treatment-naive patients.
However, Glaxo has another doublet, comprising dolutegravir and Johnson & Johnson’s Edurant, already filed with the FDA; it expects a decision by the end of the year (Snippet roundup: Shire's Lialda goes generic and Novartis whets CAR-T appetites, June 9, 2017).
Doublets could improve the side-effect profile of HIV therapy, which is becoming more important as drugs transform the disease into a chronic, long-term condition. “You now have to deal with all the comorbidities of aging like diabetes and hypertension that require other medicines,” Mr Pottage said. “So we also have a real need to develop medicines that have no interactions.”
However, the latest finding will do nothing to assuage fears that the risk of resistance with a doublet is higher than that with triple-drug therapies.
This plays into the hands of Gilead, which has a triplet, bictegravir/F/TAF, under review at the FDA. This regimen recently showed non-inferiority to triplets containing dolutegravir; more detailed results presented at the IAS meeting suggest that Gilead’s asset has a better side-effect profile than Glaxo’s Triumeq, comprising dolutegravir, abacavir and lamivudine. Abacavir is thought to be the weak link, which would explain why Glaxo is moving away from it with the doublet.
EvaluatePharma shows consensus sales of both Triumeq and Gilead’s triplet both growing out to 2022, but any edge on adverse events would be a boost for the latter.
|Head to head: Glaxo and Gilead’s triplets|
|Sales forecasts ($m)|
After a tough time of late, things are looking up for Gilead: its second-quarter saw sales of its hepatitis C products beat expectations – although they still fell 27% – and HIV revenues grew strongly.
Investors remain fixated on the chances of Gilead doing an acquisition, but until a deal emerges the company will remain reliant on its HIV franchise for growth. Glaxo’s resistance news might have just handed its rival a lifeline.
|ACTG A5353||NCT02582684||Reported at IAS 2017|
|Gemini 1||NCT02831673||Due April 2018|
|Gemini 2||NCT02831764||Due April 2018|