An advisory committee to the U.S. Food and Drug Administration (FDA) has voted unanimously to recommend the approval of Pfizer's Celsentri® (maraviroc), an HIV entry inhibitor that targets the CCR5 receptor on CD4 cells. Should the FDA follow the recommendations of its Antiviral Drugs Advisory Committee (ADAC), the drug – the first member of a new class of oral HIV drugs in more than a decade – will likely be approved for treatment-experienced patients with "CCR5-tropic" HIV.
Celsentri in Development
In order for HIV to infect a T-cell, researchers have long known that the virus must first bind with a receptor called CD4 on the cell's surface (T-cells expressing the CD4 receptor are known as CD4 cells). Researchers also suspected that HIV requires the use of a second receptor on the surface of CD4 cells, but this elusive "coreceptor" remained a mystery for more than a decade of intense research.
It wasn't until 1996 that research groups in New York, Boston, and Bethesda simultaneously discovered what they were looking for: chemokine (C-C motif) receptor 5 (CCR5). In turn, a more complete picture of HIV "fusion and entry" came into view. While HIV first binds with the CD4 receptor, it must then latch on to a coreceptor, either CCR5 or CXCR4, with CCR5 being the most common of the two.
As research into CCR5 continued, a fascinating picture began to form. It turned out that people born with two defective CCR5 receptor genes (dubbed the CCR5 delta-32 mutation) – one from each parent – are highly resistant to HIV (provided that they are exposed to CCR5-tropic HIV, not CXCR4-tropic HIV). There are also people who inherit a defective CCR5 gene from one parent. While they're still able to contract HIV, studies suggest that they're more likely to experience slower disease progression than those without the genetic defect.
With these important data, along with additional research suggesting that CCR5 is not vital to health or survival, pharmaceutical and biotech companies scrambled to develop therapeutic compounds that block the CCR5 receptor. In effect, Pfizer's Celsentri – which made its research debut in 1997 as UK-427,857 – will likely end up being the first approved treatment for HIV that works by targeting a function of cells in the body, not the virus itself.
The Tests of Efficacy
With respect to effectiveness, the blue-ribbon experts sitting on the April 24 ADAC panel were most interested in the preliminary results from MOTIVATE-1 and MOTIVATE-2, two Phase III clinical trials pitting Celsentri against placebo. While the studies intend to follow patients for a total of 48 weeks, 24-week results indicated that Celsentri, combined with an optimized background regimen (OBR), is associated with greater viral load reductions and CD4 count increases compared to placebo among HIV-positive patients with limited treatment options due to drug resistance.
The ADAC panelists noted that, aside from the necessary 48-week follow-up data and the anticipated results from another Phase III study exploring Celsentri in patients new to HIV treatment, more data are needed regarding the drug's effectiveness in key HIV populations. Approximately 90% of the patients in the MOTIVATE studies were men and 83% were white. If approved, the FDA will likely request additional data involving women and African-Americans, to allow for a more complete evaluation of Celsentri's efficacy and safety in these groups.
As for maraviroc's safety, clinical trial data reviewed by the ADAC panelists suggest that the addition of Celsentri to a combination of other antiretroviral drugs is generally well tolerated. In the MOTIVATE studies, toxicities were similar among the treatment groups, with 84% to 89% of the study participants experiencing at least one mild adverse effect. While discontinuation rates due to side effects were slightly higher in the maraviroc groups compared to the placebo groups, the differences were not statistically significant.
The most common side effects, during the first 24 weeks of the MOTIVATE studies, were diarrhea, nausea, headache, fatigue, cough, fevers, Fuzeon-related injection site reactions, decreased hemoglobin and neutrophil levels, and elevated liver enzymes and bilirubin levels.
The ADAC panelists noted that rates of upper respiratory infections, herpes simplex virus infections, and cardiac problems were slightly more common among patients taking Celsentri compared to placebo. However, these events were consistent with rates observed in the general population of treatment-experienced HIV-positive people.
ADAC panelists representing the FDA noted that additional short- and long-term safety data regarding cancer rates and liver toxicity will likely be needed. This is due to concerns raised in clinical trials of other CCR5 inhibitors, notably Schering-Plough's vicriviroc and GlaxoSmithKline's aplaviroc.
In one Phase II study, four cases of lymphoma – all of them among patients receiving vicriviroc – were reported in March 2006 by Schering-Plough. However, a causal relationship between the vicriviroc use and the lymphoma occurrences has not been confirmed. And while lymphomas have been documented in the ongoing and completed Celsentri studies, they do not appear to be any more common among those receiving the CCR5 inhibitor.
In October 2005, GlaxoSmithKline reported that approximately 4% of patients receiving its CCR5 inhibitor aplaviroc experienced a phenomenon called Hy's law – a sharp increase in three liver function test parameters (ALT, AST, and bilirubin) – that can potentially damage the liver permanently. In turn, the aplaviroc's development was discontinued. Rates of Hy's law have been significantly lower in the Celsentri Phase II/III studies.
The Trouble with Tropism
Celsentri will only be effective against CCR5-tropic HIV. It will not be effective against virus targeting CXCR4 (and will have a limited effect against HIV with the ability to target both receptors). Because "CXCR4-tropic" and "dual-tropic" HIV is more common in people who have been infected with HIV for several years – the people who are most likely going to be using Celsentri – a new laboratory test, Monogram Bioscience's Trofile® tropism assay, will be necessary before Celsentri is used, to determine if treatment with the drug will be useful.
Even among patients who begin Celsentri treatment with CCR5-tropic HIV, there is the possibility that their virus will switch to the CXCR4 receptor during therapy, meaning that the addition of Celsentri will no longer have any significant benefit. Much like drug-resistance testing, tropism testing can be ordered by a healthcare provider if Celsentri treatment failure is suspected.
What's more, because CXCR4-tropic HIV is usually seen in people who have advanced infection, experts have speculated that the emergence of CXCR4-tropic virus during entry inhibitor therapy would result in more rapid disease progression. In another Phase III study, however, patients who experienced a "switch" to CXCR4-tropic virus while taking Celsentri actually ended up with significantly greater CD4 cell counts. In other words, while therapy with a CCR5 inhibitor may not be virologically effective in patients who experience a switch to CXCR4-tropic HIV, it does not appear to be harmful.
Pfizer is committed to providing the FDA with long-term follow-up data from its ongoing clinical trials, as well as pediatric research and a patient registry, to help settle lingering questions and concerns. For its part, the FDA did not specify when it would issue an agency decision regarding the approval of Celsentri, but official word is expected in the coming weeks.