The New Quad on the Block: Gilead's Four-Drug, Fixed-Dose Combination With a Novel Booster Sails Through Phase 2 Trials
A Blog Entry From CROI 2010
For those of you who last used the word "quad" to describe that dorm you went to in college where you got totally wasted, it's time to update your vocabulary.
Calvin Cohen, M.D., unveiled new 24-week data on Wednesday from an intriguing pair of phase 2 trials. One of them pits the current U.S. standard of care in initial antiretroviral therapy, efavirenz/tenofovir/emtricitabine (Atripla), against a fixed-dose combination drug in development known as the "quad" tablet, which is comprised of tenofovir/emtricitabine (Truvada), the investigational integrase inhibitor elvitegravir and a novel booster drug in development, GS 9350. The other looks at GS 9350 itself -- specifically, how well it holds up against ritonavir (Norvir) as a pharmacokinetic booster when either is administered alongside atazanavir (Reyataz) and tenofovir/emtricitabine.
We'll follow up with more data soon, but in a nutshell, there were two key takeaways from these studies:
- The quad tablet was non-inferior to efavirenz/tenofovir/emtricitabine in terms of viral load suppression to less than 50 copies/mL (90% versus 83%, respectively). The quad pill also exhibited a roughly similar adverse effect profile, with one key exception (more on that in a moment).
- GS 9350 exhibited similar efficacy, safety and tolerability to ritonavir.
Aside from the inclusion of GS 9350, the primary difference between efavirenz/tenofovir/emtricitabine and the quad pill is, of course, the exchange of efavirenz for elvitegravir. The goal here is ultimately to provide another first-line option to people who can't tolerate efavirenz, likely due to central nervous system (CNS) side effects (particularly dizziness and the crazy dreams that, for many people with HIV, are the stuff of legend). And therein lies the only noteworthy difference in adverse events that Dr. Cohen reported in his presentation: Overall, 35% of patients in the quad arm had some kind of adverse event related to a study drug, versus 57% of patients in the efavirenz/tenofovir/emtricitabine arm. That entire difference can basically be accounted for by CNS events, which impacted 10% of quad patients versus 48% of efavirenz/tenofovir/emtricitabine patients. (Lipid data were similar across both arms of the study, incidentally.)
Much has been made, in parsing the results of earlier studies involving GS 9350, about the potential for the drug to negatively impact serum creatinine levels, which raised fears about the potential for renal issues with the drug. In response to those concerns, Dr. Cohen devoted four of his 18 slides to a discussion of GS 9350's impact on creatinine, all of which appear to support his conclusion that the drug is no worse on the kidneys than cimetidine, an over-the-counter acid blocker known by the brand name Tagamet.
Cohen's central assertion was that the modest impact of GS 9350 on serum creatinine (which increased 0.14 mg/dL among quad patients, versus an increase of 0.04 mg/dL among efavirenz/tenofovir/emtricitabine patients -- and notably, the increase among quad patients was not cumulative over time, but rather remained stable through 24 weeks), coupled with what appeared to be no real impact on the actual glomerular filtration rate, indicated that GS 9350's impact on creatinine was an issue of tubular secretion, not drug-related glomerular filtration. Presumably, a phase 3 trial that enrolls many more patients (only 71 were involved in the quad phase 2 study) will flesh this issue out even further if needed.
Based on these results, both the quad pill and GS 9350 will sail through to phase 3 trials. GS 9350 has also been given a graduation present -- a generic name, and a sufficiently hard-to-pronounce one at that: cobicistat (that's koe-bih-SIH-stat).
It's difficult to decide what the bigger story is here. It is certainly exciting and encouraging that the quad pill could potentially provide a viable alternative to efavirenz/tenofovir/emtricitabine for the not-insignificant number of people who currently take the drug because it's convenient but then have to deal with CNS issues that damage their quality of life. But there is also an undeniable allure to the potential for cobicistat to finally break ritonavir's rock-solid hold on the antiretroviral booster market. Judging by the criticism ritonavir has received over its toxicity profile and price level (not to mention the F that ritonavir distributor Abbott Laboratories got last year from the AIDS Treatment Activists Coalition), it appears a large cross-section of the HIV/AIDS clinical and advocacy communities likely agree with that sentiment.