Global Insight Perspective | |
Significance | Merck's investigational V520 vaccine failed to prevent HIV infection or boost the body's ability to delay the onset of AIDS in a 3,000-patient trial. Meanwhile, the European Commission cleared Pfizer's Celsentri for marketing in the European Union (EU). |
Implications | The termination of V520 trials due to lack of effectiveness deals a serious blow to the efforts to find an HIV vaccine and sheds doubts on the whole theory that vaccination could stop infection with a virus such as HIV. |
Outlook | As the HIV research community digests the vaccination failure implications, hopes will shift again to treatments for already-infected individuals. Pfizer's Celsentri which prevents HIV from entering cells—albeit only in a subset of patients—holds significant potential. |
HIV Vaccine Hopes Dashed…
Merck & Co. and its research partner, the HIV Vaccine Trials Network (funded by the U.S. National Institutes of Health—NIH), have terminated trials of a Phase II investigational HIV vaccine V520 because of a lack of effectiveness. The so-called STEP trial was an international Phase II test of concept trials in some 3,000 uninfected volunteers (aged 18-45, at high risk of contracting HIV). The primary endpoints were prevention in HIV infection and reduction of viral load in those who developed infection. V520 failed to show effectiveness with regard to both:
- In volunteers receiving at least one dose of the three-dose vaccine series, there were 24 cases of HIV infection among 741 volunteers compared with 21 cases of HIV infection among the 762 placebo recipients.
- In the subgroup that received at least two vaccinations and who were HIV-negative for at least the first 12 weeks of the trial, there were 19 cases of HIV among the 672 volunteers compared with 11 cases among the 691 placebo recipients.
- HIV RNA levels (measuring the amount of virus in the blood stream) approximately 8-12 weeks after diagnosis were similar in the vaccine and placebo arms.
- The geometric means of HIV RNA levels (standard measures of ongoing HIV replication) were 40,000 copies/mL in the vaccine group compared with 37,000 copies/mL in the placebo group.
… While Celsentri Gains European Approval
As the scientific community struggles to come to terms with the HIV vaccination failure, Pfizer has announced positive news. Its HIV drug Celsentri (known as Selzentri in the United States) received marketing clearance by the European Commission. The European approval comes just a month after the U.S. FDA gave final clearance to market the drug in the United States (see United States: 20 July 2007: CHMP Recommends Approval of Pfizer's Celsentri).
The drug, known generically as maraviroc, is the first HIV drug in a new class to gain approval for the past 10 years. Unlike the majority of treatments that interfere with HIV's ability to replicate, maraviroc works by blocking the virus from entering healthy cells. It is the first-approved CCR5 antagonist and the only oral-entry inhibitor. However, it has a major shortfall: the drug only works in a subgroup of people infected with only CCR5-tropic HIV-1 virus detectable. The approval—both in Europe and the United States—is for adult patients with this specific subtype of the virus who have grown resistant to other HIV treatments.
Outlook and Implications
The failure of Merck's HIV vaccine to demonstrate effectiveness in preventing HIV infection or at least slowing down the replication of HIV once individuals are infected casts doubts on the potential of vaccination altogether. The vaccine has been 10 years in development and was the first one to make it as far as Phase II trials. Standard vaccines work by stimulating the body to produce specific antibodies to fight a given virus. With HIV where there are multiple HIV strains, it would be difficult to stimulate a response to all potential strains; thus, researchers have chosen to focus on stimulating the body's T-cells to destroy cells that are infected with HIV. The theory behind Merck's V520 was that by including HIV genes in the vaccine, the body would be stimulated into generating an HIV-specific immune response through its own CD8 T-cells. The validity of this theory and of Merck's approach has now been thrown into doubt following the V520 failure in trials. The setback is huge—not so much for Merck, which has other HIV drugs in its portfolio, but for people at risk of contracting HIV globally.
There are other vaccines in development, but none as advanced as Merck's V520 and they are developed based on the same—potentially faulty—premise. With vaccination hopes dashed for the time being, focus will shift on treatments for those already infected. Pfizer's CCR5 inhibitor has significant theoretical potential in that field, but in reality its marketing aspirations remain limited. Peak sales of maraviroc are estimated at around US$500 million because it is only approved for treatment-experienced patients due to side-effect concerns. The CCR5 receptor, which the drug targets, provides the less-common entry route for HIV in treatment-experienced patients compared with patients in the early stages of HIV. In the United States, less than half of the 40,000 HIV patients that have grown resistant to HIV therapy would be suitable candidates for treatment with maraviroc. Pfizer could succeed in eventually securing approval for treatment-naive patients as well, but longer-term safety data will be required to achieve that. In the meantime, another first-in-class HIV drug, Merck's Isentress (raltegravir), recently recommended for approval in the United States, is likely to emerge as the main new hope for treatment-resistant HIV sufferers regardless of HIV subtype (see United States: 6 September 2007: FDA Advisory Committee Recommends Accelerated Approval of Isentress).