Merck and HVTN Halt Trials of HIV Vaccine Candidate V520 Due to Disappointing Preliminary Results

By Liz Highleyman

Last Friday, September 21, Merck and the National Institutes of Allergy and Infectious Disease Health HIV Vaccine Trials Network (HVTN) announced that they were discontinuing development of the HIV vaccine candidate V520, also known as MRKAd5, due to study data showing that it did not lower the risk of infection or disease progression.

Among the several HIV vaccine candidates under development, some are preventive vaccines intended to keep people from becoming infected with the virus, while others are therapeutic vaccines designed to stimulate the body's immune response to the virus and lessen disease progression in people after they become infected.

V520, a trivalent vaccine containing three recombinant HIV genes carried by an adenovirus vector, was being studied as both a preventive and a therapeutic candidate, and it was one of the furthest along in clinical trials. The international STEP study, begun in 2004, enrolled 3000 HIV negative individuals who were considered at high risk for infection, including gay men in San Francisco and female sex workers.

A review of preliminary data from the Phase II trial led the study's Data Safety and Monitoring Board (DSMB) to recommend that the trial not proceed due to lack of efficacy. After about 1 year of follow-up, volunteers who received 1 dose of V520 did not appear to be at less risk of infection than those who received a placebo injection. In both arms, about 3% became infected, and response rates did not improve significantly among those who received a second booster injection in what was intended to be a 3-shot series.

V520 also did not appear to promote stronger immune responses in people who were newly infected, since viral load rose to comparable levels among those who received the active vaccine and the placebo. The disappointing data were unexpected, since V520 appeared to stimulate a robust immune response against HIV in earlier studies.

Although no new subjects will be vaccinated, researchers plan to continue follow-up of participants already enrolled in the STEP study. Another V520 trial in South African, known as Phambili, is on hold while the DSMB reviews early data.

Below are excerpts from announcements from HVTN and Merck concerning the recent developments:

NIAID Statement: Immunizations Are Discontinued in Two HIV Vaccine Trials

An independent Data and Safety Monitoring Board (DSMB) met this week to review interim data from a large, international HIV vaccine clinical trial known as the STEP study - also referred to as the HVTN 502 or Merck V520-023 study. The clinical trial, which began enrolling volunteers in December 2004, is co-sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Inc., which also developed and supplied the candidate vaccine. Based on a review of interim data, the DSMB concluded that the vaccine cannot be shown in this trial to prevent HIV infection or affect the course of the disease in those who become infected with HIV as a result of their own behaviors that expose them to the virus. Therefore, Merck and NIAID instructed all study sites to cease administering the investigational vaccine but continue scheduled follow-up visits with all volunteers until the data can be more thoroughly evaluated and a course of action is developed.

The STEP study, which enrolled 3,000 participants, was conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN) and Merck. Volunteers were enrolled at sites in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, and the United States. The Phase IIb "test-of-concept" study was designed to test Merck's candidate HIV vaccine, the MRKAd5 trivalent vaccine, which aimed to stimulate production of immune system T cells that can kill HIV-infected cells. The goal of the study was to determine if the vaccine could prevent HIV infection, reduce the amount of HIV in those who do become infected, or both.

Based on its first evaluation of interim efficacy data, the DSMB found 24 cases of HIV infection among the 741 volunteers who received at least one dose of the investigational vaccine compared with 21 cases of HIV infection among the 762 volunteers who were vaccinated with placebo. In volunteers who received at least two vaccinations, the DSMB found 19 cases of HIV infection among the 672 volunteers who received the investigational vaccine and 11 instances of HIV infection among the 691 volunteers who received the placebo. The trial partners will fully evaluate the trial data, provide additional instructions to the STEP trial sites, and provide a detailed scientific analysis of the study results in the near future.

The same Merck candidate HIV vaccine is also being tested in South Africa by the HVTN and the South African AIDS Vaccine Initiative in a separate NIAID-sponsored clinical trial known as HVTN 503 or the "Phambili" study. This study was initiated in February 2007 and has enrolled 799 individuals. Immunizations and enrollment in the Phambili study have now been paused. This allows the independent DSMB that oversees the Phambili trial to review all available HVTN 503 and STEP interim findings to determine next steps. In contrast to the STEP study where the interim analysis was almost exclusively based on results in volunteers who were men who have sex with men, the Phambili study has primarily enrolled heterosexuals at high risk for HIV.

The study investigators at each site for both the STEP (HVTN 502/ Merck V520-023) and Phambili (HVTN 503) vaccine trials have been informed of the decision to cease immunizations and are contacting study volunteers to inform them of the developments.

For additional information about the HVTN 502 and HVTN 503 trials, see http://www3.niaid.nih.gov/news/QA/step_qa.htm.

Merck Statement: Vaccination and Enrollment Are Discontinued in Phase II Trials of Merck's Investigational HIV Vaccine Candidate

Interim Analysis of STEP Study Shows Vaccine was not Effective

WHITEHOUSE STATION, N.J., and Seattle, Sept. 21, 2007 - Vaccination in a phase II clinical trial of Merck & Co., Inc.'s investigational HIV vaccine (V520) is being discontinued because the vaccine was not effective. The announcement was made today by the co-sponsors of this clinical trial, Merck & Co., Inc., and the HIV Vaccine Trials Network (HVTN), which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health.

The trial, called STEP, was an international phase II "test of concept" trial in uninfected volunteers at high risk for acquiring HIV infection. The independent Data Safety Monitoring Board (DSMB) for STEP reviewed safety data and results of an interim efficacy analysis of the study, and recommended that vaccination be discontinued because the STEP trial will not meet its efficacy endpoints. Study investigators have been instructed to discontinue vaccinating volunteers in this study and to monitor them in accordance with the study protocol. Enrollment and vaccination in a second Phase II trial of this vaccine being conducted by the HVTN in South Africa called Phambili, and two additional Phase I trials, have been discontinued. The DSMB for the Phambili trial will evaluate the available data.

The Merck vaccine candidate is a mixture of three components, each made with a weakened version of a common virus (adenovirus type 5), that serves as a carrier, or delivery vector, along with three synthetically produced HIV genes known as gag, pol and nef.

The STEP study (HVTN 502, Merck V520 Protocol 023) was a multicenter, randomized, double-blind, placebo-controlled phase II test-of-concept clinical trial. The trial enrolled 3,000 HIV-negative volunteers from diverse backgrounds between 18 and 45 years of age at high risk of HIV infection.

The study evaluated two primary efficacy endpoints: whether the vaccine prevented HIV infection and whether the vaccine reduced the amount of virus in those who developed infection. As planned, an interim efficacy analysis was conducted in the approximately 1,500 volunteers expected to have the best response to the vaccine because they had low levels of pre-existing immunity to adenovirus 5.

The vaccine did not prevent infection: in volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed in the 741 volunteers who received vaccine and 21 cases of HIV infection were observed in the 762 participants in the placebo group. In the subgroup who had received at least two vaccinations and who were HIV negative for at least the first 12 weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers who received vaccine and 11 cases were observed in the 691 volunteers who received placebo. In addition, the vaccine did not reduce the amount of virus in the bloodstream of those who became infected; HIV RNA levels approximately 8 to 12 weeks after diagnosis of infection were similar in the vaccine and the placebo arms. The geometric means of the HIV RNA levels in the blood of infected individuals, the standard measure of ongoing HIV replication, were approximately 40,000 copies/mL in the vaccine group and approximately 37,000 copies/mL in the placebo group. Additional analyses will be conducted on the entire study population and will be shared with the scientific community.

Study volunteers were followed for approximately 13 months. Overall adverse event rates were generally similar among the two groups, except for a higher rate of local injection-site related reactions in the vaccine group.

"We share in the disappointment of the research and HIV communities today. Sadly, developing an effective AIDS vaccine remains one of the most challenging tasks facing modern medicine," said Peter S. Kim, PhD, president, Merck Research Laboratories. "Merck's 20-year HIV research program has led to improved scientific understanding of HIV and to true breakthrough medicines. We are committed to studying the data closely and sharing it with the scientific community to inform the on-going search for an effective HIV vaccine."

"HVTN is a global network of scientists, staff and community members whose mission is to speed the rapid development of a safe and effective preventative HIV vaccine," said Larry Corey, M.D., principal investigator of the HVTN. "This trial was the first test of concept trial that provided us information on this vaccine more quickly and efficiently than with a traditional Phase III design.

While we are very disappointed that this vaccine candidate did not demonstrate protection, the data from this trial will provide critical insights into this disease and future vaccine development."

"This is a huge disappointment for all of us who have been involved in the search for an HIV vaccine," said Glenda Gray, MD, principal investigator of the HVTN sponsored Phambili trial. "HIV is ravaging our communities, and all the scientists, participants and communities involved in HIV vaccine studies have been affected by this epidemic. The scientific community must continue the race to find a vaccine to help secure an HIV free generation for the future."

The Merck adenovirus-based vaccine used a cell-mediated immune response approach; it was hypothesized that the HIV genes in the vaccine would stimulate the body to generate an HIV-specific immune response through the body's own CD8 T-cells, which become programmed to recognize and kill HIV infected cells.

Adenoviruses are among the causes of common cold; the type 5 adenovirus used in this investigational vaccine had been modified so that it was unable to replicate and could not cause a cold. Also, because the vaccine did not contain live HIV and contained only three HIV genes, volunteers could not become infected with HIV from the vaccination. This vaccine had previously been tested in several smaller clinical trials and was found to be generally well tolerated and capable of inducing significant levels of HIV-specific cell-mediated immune responses.

STEP included multiple clinical trial sites in North and South America, the Caribbean and Australia, where HIV subtype B, the subtype of HIV from which the HIV genes included in the vaccine, is predominant. Half the study participants received three doses of the vaccine over six months, while the other half were given three doses of a placebo. The first volunteer enrolled in the study in December 2004, and enrollment was completed in March 2007.

The second phase II trial of this vaccine candidate, the Phambili trial, (HVTN 503, Merck V520 Protocol 026) was begun in 2007 in South Africa by the HVTN to explore whether Merck's vaccine would be effective at preventing infection, reducing viral levels, or both, from HIV subtype C, which is more common in southern Africa.

09/25/09

Sources

NIAID. Immunizations Are Discontinued in Two HIV Vaccine Trials. Press release. September 21, 2007.

Merck & Co. Vaccination and Enrollment Are Discontinued in Phase II Trials of Merck's Investigational HIV Vaccine Candidate. Press release. September 21, 2007.