By Nelson Vergel
Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2) of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.
Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.
All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76 for 50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for 50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated: mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.
Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations. 46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort. Longer-term (24 weeks) assessments in this phase 2b study are ongoing.
The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent. Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved. I will write about this project in future articles.
DTG will also be tested in naïve patients in head-to-head with raltegravir in phase 3 studies (using a background of Epzicom (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.
This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii. This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).
The development of Trii for approval as a first line treatment seemed risky to me due to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV. These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients. So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?
Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation, the US Food and Drug Administration (FDA) presented a surprising poster on March 2 that reported no evidence of an association between abacavir and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug. The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.
It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines. Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills. Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.
As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.
DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB