Merck to Seek FDA Approval of Gardasil for Men Who Have Sex With Men

Nick Mulcahy

March 29, 2010

March 29, 2010 — Merck will submit data from a study of its human papillomavirus (HPV) quadrivalent vaccine (Gardasil) in young men who have sex with men (MSM) to the US Food and Drug Administration, the company told Medscape Oncology. However, the company is not disclosing exactly what indication it is seeking for the vaccine in MSM.

Currently, Gardasil is approved in the United States for use in males 9 to 26 years of age for the prevention of genital warts (condylomata acuminata) caused by HPV types 6 and 11. The vaccine was first approved for use in females to prevent cervical cancer.

The new data on Gardasil in MSM comes from a trial known as protocol 020, which involves 602 MSM (aged 16 to 26) and 3463 young heterosexual men.

The trial was designed to evaluate the effectiveness of Gardasil in preventing genital lesions related to HPV 6/11/16/18 in both heterosexual men and MSM and its effectiveness in preventing anal lesions related to HPV 6/11/16/18 in MSM.

Medscape Oncology has also learned that clinicians involved with this industry-sponsored multicenter trial have been recalling the recipients of placebo to give them Gardasil.

The planned 3-year trial was completed a bit earlier than originally planned, Elizabeth Garner, MD, associate director of clinical research at Merck, told Medscape Oncology. The median follow-up for all participants in protocol 020 was 35 months, close to the planned timeframe.

Target end points were met for both genital and anal lesions, she noted. On the strength of the efficacy data against genital warts, Merck, in consultation with the study's Data Safety Monitoring Board, compressed the time schedule of the "last few follow-up visits" to accelerate study completion.

A long-term extension study will follow all of the men in protocol 020 for 10 years from enrollment and will examine the long-term safety, effectiveness, and immunogenicity of Gardasil, a Merck spokesperson said.

However, the 10-year extension study is not placebo controlled.

A longer placebo-controlled study would have been helpful in more definitively answering an important question about the efficacy of Gardasil in MSM, suggested a prominent HPV expert not involved in the study.

The findings from protocol 020 do not robustly prove the vaccine's efficacy against precancerous anal lesions (high-grade lesions caused by HPV 16 and 18), said Diane M. Harper, MD, professor of medicine in the Departments of Community and Family Medicine, Obstetrics/Gynecology, and Informatic Medicine and Personalized Health at the University of Missouri-Kansas City School of Medicine in Kansas City, in an email to Medscape Oncology. Dr. Harper has been involved in clinical trials with HPV vaccines in women, and has been vocal in discussing the place of such vaccines in preventing cervical cancer.

The study would have to continue for a couple more years.

"The study would have to continue for a couple more years before the placebo arm accumulates enough cases to be able to tell if there is truly any prevention of cancer precursors, and hence cancer, in this group," Dr. Harper told Medscape Oncology.

However, an investigator in the study said that the data are "strongly suggestive" of cancer prevention and that Gardasil has proven effectiveness against warts, which is a protection that is highly meaningful to MSM.

All indications are that it will prevent cancer.

"Gardasil will prevent both external genital warts and anal warts, and all indications are that it will prevent cancer with the 2 most important cancer causing types, HPV 16 and 18," Joel M. Palefsky, MD, professor of medicine at the University of California at San Francisco, told Medscape Oncology. The "indications" that Dr. Palefsky refers to are efficacy data related to both biopsy-proven lesions and swab-detected persistent infections.

Data on the effectiveness of Gardasil against both anal lesions and infections were first presented at a European conference in February 2010, and the following week were presented at the federal Advisory Committee on Immunization Practices (ACIP).

According to Merck, the annual incidence of anal cancer among males in the United States is about 2000 cases; between 80% and 90% of cases are HPV-related and 73% of all anal tumors are associated with HPV 16.

Anal cancer is a rare disease but is much more common in MSM, noted Dr. Palefsky. "Men who have sex with men have a 17-times higher rate of anal cancer than the general population," he said.

Results in MSM from EUROGIN

Results in MSM from protocol 020 were reported recently at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) conference in Monte Carlo, Monaco. They show that Gardasil is effective in preventing anal lesions, or anal intraepithelial neoplasia (AIN), related to HPV 6/11/16/18 in young MSM, as reported by Medscape Oncology.

Gardasil was 77.5% effective against biopsy-proven AIN associated with HPV 6/11/16/18 in the 402 MSM who met protocol 020 study requirements, according to Dr. Palefsky, who presented the results at the meeting.

Specifically, there were 5 cases of an AIN (any grade) related to at least 1 of the vaccine's 4 HPV types among the vaccinated men, and 24 cases among the men randomized to placebo. This efficacy was statistically significant (95% confidence interval [CI], 39.6% - 93.3%; P < .0001). There was a median follow-up of 2.5 years.

Dr. Palefsky also presented data at EUROGIN that showed, among MSM, the effectiveness of Gardasil against external genital lesions caused by HPV 6/11/16/18 was 79.0% (95% CI, 87.9 - 99.6), with 5 placebo cases and 1 vaccine case in the study.

But it is the data on anal lesions in MSM that concern Dr. Harper, who attended Dr. Palefsky's presentations at EUROGIN.

Dr. Harper suggested that the study's end point in MSM — the combined incidence of HPV 6/11/16/18–related AIN — is a case of mixing apples and oranges.

AIN caused by HPV 6 and 11 is not considered precancerous or carcinogenic, whereas AIN 2 and AIN 3 caused by HPV 16 and 18 are precancerous, she explained.

"AIN caused by HPV 6 or 11 is immaterial, as this is never carcinogenic," said Dr. Harper.

Dr. Harper stated that the study's primary end point is "a composite end point that hides the true efficacy."

Dr. Harper noted that, of the 5 cases of AIN found in the vaccinated men, 3 infections were related to HPV 6 and 2 were related to HPV 16. Only by combining the noncancerous and precancerous anal lesions did the investigators achieve statistical significance, compared with placebo, with this efficacy finding, she explained.

Dr. Palefsky disagreed with Dr. Harper about AIN caused by HPV 6 or 11, noting that "about 8% of anal cancers have HPV 11 in them," and citing a study on the subject (Int J Cancer. 2009;124:2375-2383).

He also noted that he and the other Gardasil investigators "are reporting on the results of a prespecified outcome, which was AIN associated with HPV 6/11/16/18."

Data Presented at ACIP Show Efficacy Against Precancerous Anal Lesions

As is the case with Gardasil and cervical cancer, there is no proof to date that the HPV vaccine prevents anal cancer. This is expected, said Dr. Palefsky.

"Reductions in cancer among [HPV] vaccinees will not be seen for a long time, perhaps decades, given the long period of time that it takes to develop cancer," he said.

However, Dr. Palefsky noted that "we believe high-grade AIN is the precursor to anal cancer." He also expects that the "prevention of high-grade AIN will likely lead to a reduction in the incidence of anal cancer over time."

Gardasil efficacy against high-grade AIN lesions (AIN grade 2 or 3) related to HPV 6/11/16/18 was 74.9% (95% CI, 8.8%  95.4%) in the per-protocol population, Dr. Palefsky reported at EUROGIN.

But the composite end point using the noncancerous and cancerous HPV types confuses the true known effectiveness of Gardasil, Dr. Harper countered in reference to the presentation at EUROGIN on high-grade anal lesions in MSM.

"It is not revealed just how many of the high-grade AINs were due to the carcinogenic HPV 16 and 18, and how many were due to the noncarcinogenic HPV 6 and 11," she said.

However, a week after the EUROGIN conference, Merck presented data on MSM that addressed Dr. Harper's criticism.

In a presentation to the ACIP in Atlanta, Georgia, Merck provided a breakdown of high-grade AINs related to HPV 16/18.

Merck showed that the point estimate of efficacy of Gardasil against AIN 2/3 caused by HPV 16/18 was 86.6% (95% CI, 0.013% - 100.000%). Dr. Harper described this as "evidence, but rather weak evidence" of the effectiveness of Gardasil against these lesions.

This study has not reported whether any of the anal lesions detected were associated with more than 1 HPV type, as is often the case for cancer precursors, said Dr. Harper

In short, Dr. Harper said that more data are needed to strongly prove that Gardasil is effective against high-grade precancerous anal lesions (AIN grade 2 or 3) caused by the 2 most common cancer-causing HPV types — 16 and 18.

Data on Persistent Infections Support Likely Anticancer Effect, Says Investigator

The study included data on Gardasil efficacy against persistent anal infection among MSM in the per-protocol population, which was a secondary outcome in the study.

Collecting data on persistent infections represents an "effort to distinguish true infection from a carrier state or fleeting infection," said Dr. Palefsky. He explained that persistence was defined as an infection found at 2 consecutive clinic visits 6 or more months apart.

Persistent infections, which are DNA-detected with a swab or found in biopsy tissue, are distinguished from AIN, which is strictly biopsy-detected, he added.

Gardasil efficacy against persistent infections caused by HPV 6/11/16/18 was 94.9% (95% CI, 80.4 - 99.4), with 39 placebo cases and 2 vaccine cases, according to a presentation by Dr. Palefsky at EUROGIN.

Notably, the efficacy against persistent infections caused by HPV 16 was 93.8% (95% CI, 60,0 - 99.9), with 16 placebo cases and 1 vaccine case, and by HPV 18 was 100% (95% CI, 51.5 - 100.0), with 10 placebo cases and 0 vaccine cases.

"Showing this level of prevention of persistent HPV 16 and 18 infection doesn't prove cancer prevention, but is consistent with it," said Dr. Palefsky.

Persistent HPV infection is the most important risk factor for developing cancers.

"Persistent HPV infection is the most important risk factor for developing cancers," Dr. Palefsky also said, explaining that infections that do not persist cannot develop into cancer.

"It is true that persistent infection is different from disease, but it is highly significant," he added.

Dr. Harper agrees that efficacy against persistent infection is a good first step, but noted that evidence supporting the prevention of persistent infection is just that, and is not evidence of the prevention of precancer or cancer.

"This means that Gardasil will prevent HPV 16 and 18 infections from lasting 6 months. This is a very different claim than preventing anal cancers or precancers," she said.

Dr. Palefsky reports research grant support from Merck. Dr. Harper reports research grant support from Merck and GSK.

Gardasil Update: Efficacy Against Intra-Anal Infections and Disease. Advisory Committee on Immunization Practices. Presented February 24, 2010.

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