Highlights From the Cape Town Conference
A new drug, GRACE for women, and Selzentry
by Jeff Berry
GSK/Shionogiâ€™s integrase inhibitor 572-â€śThe New Kid on the Blockâ€ť
Data was presented on S/GSK1349572 (or 572 for short), a second-generation integrase inhibitor (INI), being developed in a joint venture between GlaxoSmithKline and Shionogi, which demonstrated â€śunprecedented antiviral activityâ€ť with this once-daily unboosted drug. The Phase 2a 10-day dose-ranging study showed a very substantial 2.5 log drop in viral load in those taking 50 mg once daily, which was sustained through day 14 after stopping therapy on day 10 and a 2 log drop (still highly effective) in the 10 mg group. There is no food effect with 572 (it can be taken with or without food). The majority of adverse events were grade 1 (mild) and the drug was generally well tolerated, with four grade 3 events, including migraine. 572 has a unique resistance profile and a potential for a higher genetic barrier to resistance, and is expected to have limited cross-resistance to Merckâ€™s Isentress (raltegravir), the first and only integrase inhibitor currently available, and elvitegravir (Gileadâ€™s integrase inhibitor now in Phase 3 studies). GSK is moving forward with doses ranging from 10 mg to 50 mg in a Phase 2b study in treatment-naĂŻve subjects that is currently underway, with a follow up integrase inhibitor, S/GSK1265744, also in development.
This is probably some of the most exciting information to come from GSK in a while, ever since the disappointing news regarding development of their CCR5 inhibitor (aplaviroc) which was abruptly halted several years ago due to liver toxicity concerns. It should certainly bode well for the new company (whose name had not yet been announced at press time). Newco, as itâ€™s being referred to, is a joint venture between GSK and Pfizer devoted exclusively to HIV, and is expected to launch by the end of 2009 or first quarter of 2010 (visit www.hivfutures.com).
In related news, GSK convened a call with HIV advocates in August after some concern was raised by members of the European AIDS Treatment Group and the AIDS Treatment Activists Coalitionâ€™s (ATAC) Drug Development Committee (DDC) regarding their 572 Phase 2b study design. Advocates expressed concern about the risk of exposing treatment-naĂŻve study participants who have less than 200 CD4s to potentially suboptimal therapy, when they most likely would have other treatment options available under current standard of care. After calls with both groups, GSK agreed to revise the study design and raised the CD4 inclusion criteria from 100 to 200 CD4s. Other companies have struggled, and continue to grapple, with this question when designing clinical trials in HIV, but currently there is no FDA guidance regarding standard CD4 criteria for studies of experimental HIV drugs or unproven drug regimens in treatment-naĂŻve individuals. FDA spokesperson Jeff Murray, M.D., Deputy Director of the Division of Antiviral Products, when asked to comment, said, â€śThe CD4 inclusion criteria of 200 cells is not mentioned in the current version of our HIV guidance document. It sounds like a reasonable inclusion criteria. When we update our guidance, we will consider including this.â€ť
GRACE at IAS
48-week results from GRACE, the largest study in North America to focus on treatment-experienced women, demonstrated that it is possible to recruit large numbers of women, African Americans, and Latinos into U.S.-based HIV-1 treatment studies, but that â€śhigher rates of discontinuation among women highlight the need for investigation into the retention of women in clinical trials,â€ť the study authors noted.
The study, which enrolled 287 women and 142 men, compared gender differences in the efficacy, safety, and tolerability of boosted Prezista (darunavir) and found no statistically significant differences in viral load response rates between treatment-experienced women and men receiving Prezista (600 mg twice daily with 100 mg ritonavir) with an investigator-selected optimized background regimen. The most common adverse events (AEs) were nausea (women, 24.4%; men, 14.1%), diarrhea (women 16.4%; men, 22.5%); upper respiratory tract infection (women 11.1%; men, 7.7%), and vomiting (women 11.5%; men, 6.3%).
A post-hoc analysis was conducted to determine if reasons for discontinuation differed by sex, and it was found that the rate of treatment discontinuation was higher in women (n=94 [32.8%]) compared with men (n=33 [23.2%]), which is a statistically significant difference. The primary reasons for discontinuation of study treatment were loss to follow-up (when participants cannot be reached) and AEs, but there were no trends toward a specific type of AE driving discontinuations in either group.
The study authors noted that, overall, the data suggest that boosted Prezista can be used in women and men with similar safety and efficacy outcomes, but that â€śdiscontinuations due to loss of follow-up, relocation, and withdrawal of consent reflect challenges that may be unique to women with respect to clinical trials.â€ť They concluded by stating that â€śGRACE provides insight for the development and design of future clinical trials,â€ť and pointed out that â€śsetting a requirement of enrolling three women to one man appears to be an effective method of increasing the enrollment of women.â€ť
A planned immunology sub-study of GRACE showed â€śimprovements in the function and quantity of T-lymphocyte immune cells at 48 weeks,â€ť according to study authors. â€śThis immunology sub-study is interesting in that it evaluates not only the quantity of CD4 cell increases in treatment-experienced patients, but also the improvement in function of those cells,â€ť said Chris Tsoukas, M.D., Professor, McGill University Health Centre in Montreal, Quebec.
According to a Tibotec press release, most previous studies of immune recovery have been conducted primarily in Caucasian males and have not prospectively assessed in vitro (in the test tube) immune function. The analysis evaluated 19 men and 13 women, 15 of whom were African American, 10 Latino, and 7 Caucasian. Mean baseline viral load was 4.74 log10 (around 55,000) copies and mean baseline CD4 cell count was 183. At 48 weeks, the number of CD4 cells â€śsignificantly increased from baseline an average of 164 cellsâ€ť overall (n=32) and 195 cells in responders (n=19) [those achieving undetectable viral load less than 50]. Both immune phenotype and function of CD4+ and CD8+ cells were significantly improved â€śas evidenced by positive changes in the capacity to proliferate and the expression of intracellular cytokines by CD4+ cells,â€ť concluded study authors, adding that â€śresults from this sub-study validate that virologic suppression with highly-active ART not only leads to increased CD4+ cell counts, but also improves immune function.â€ť Additional studies will be needed to demonstrate the benefits of Prezista in improving immune cell function.
Selzentry at 96 weeks
96-week data was presented on a post-hoc analysis of the MERIT registrational study of Selzentry (maraviroc) using the Trofile ES (enhanced sensitivity) tropism assay. The analysis of the treatment-naĂŻve study, which compared Selzentry (the only FDA-approved oral CCR5 entry inhibitor) to Sustiva, both in combination with Combivir (lamivudine/zidovudine), showed a similar percentage of patients on Selzentry and Sustiva achieved a viral load of less than 50 at week 96.
Using the enhanced test, the researchers went back and screened out patients who had dual or mixed tropic virus (and whose virus thus would likely not respond to Selzentry) but were missed with the original, less sensitive Trofile test, and then reanalyzed the data. The baseline characteristics of those patients included in the re-analysis were similar to those in the original MERIT analysis. The enhanced Trofile test was not available at the time of the study, and is now the only version currently available.
The 96-week data also showed fewer discontinuations due to adverse events (AEs) in those taking Selzentry (6.1%) versus Sustiva (15.5%), but a greater number of discontinuations due to insufficient clinical response for those in the Selzentry group (12.5%) versus the Sustiva group (5.9%).
Of much interest were the safety results from the full study population, with fewer malignancies seen in those taking Selzentry (1.1%) versus those on Sustiva (2.8%). Selzentry also demonstrated a more favorable impact on lipids than Sustiva.
As this issue went to press, the FDA Advisory Committee reviewed data and accepted public comment regarding the proposed treatment-naĂŻve indication for Selzentry, and the committee voted to support approval. The FDA is not obligated to, but almost always does, follow the committeeâ€™s recommendations.
Screening for tropism
An oral presentation was given by Richard Harrigan on a study seeking to determine the ability of V3 loop genotyping and the older, less sensitive Trofile tropism assay to predict response to Selzentry in treatment-experienced patients.
Determinants of tropism are primarily, though perhaps not exclusively, located in the V3 region (the part which binds to a chemokine receptor, such as CCR5 or CXCR4) of the HIV Env (a viral protein that serves to form the viral envelope used to help viruses enter host cells). Genetic tropism testing has advantages in terms of cost ($80 for the genetic test vs. $1,960 for the Trofile), turnaround time (days versus weeks), convenience, and availability.
The study found that V3 genotype and Trofile tests were comparable in predicting antiviral responses to Selzentry in treatment-experienced patients, and responses were maintained over 24 weeks. Study authors concluded that V3 genotype is an â€śattractive optionâ€ť for tropism screening.â€‚