On September 5, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported new, 10-year long-term follow-up (LTFU) data published in the peer reviewed journal, Pediatrics, for girls and boys who received a three-dose regimen of GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) at 9-15 years old (Press release, Merck & Co, SEP 5, 2023, View Source [SID1234634900]). The LTFU study was conducted from 2009 through 2021 across 13 countries and five continents.
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"These data highlight the importance of GARDASIL 9 in prevention of certain HPV-related cancers and diseases later in life," said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. "HPV-related cancers and diseases are a significant public health issue. These strong study results serve as a reminder that we need to do everything we can to expand and recover vaccination rates globally to help protect all eligible people from certain HPV-related cancers."
In the U.S., GARDASIL 9 is indicated for use in females 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; cervical, vulvar, vaginal, and anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11. GARDASIL 9 is also indicated for use in males 9 through 45 years of age for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11. The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The confirmatory trial is ongoing. GARDASIL 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant].
GARDASIL 9 targets HPV types that cause approximately 80% of cervical cancers. Additionally, HPV is responsible for causing genital warts and certain types of vulvar, vaginal, and anal cancers. For most people, HPV clears on its own, but for those who don’t clear the virus it could lead to certain cancers and other diseases.
As part of the primary objective of immunogenicity, data showed sustained HPV-antibody responses at 10 years after the third dose in boys and girls. Across GARDASIL 9-targeted HPV types, antibody assessments evaluated through geometric mean titers peaked at Month 7 and decreased thereafter through 126 months. The vast majority of study participants remained seropositive at the end of the study period; 99.6% to 100% of study participants were seropositive for the targeted HPV types at Month 7 based on HPV-9 competitive Luminex immunoassay (cLIA), and 81.3% to 97.7% remained seropositive at Month 126 depending on the HPV type. Based on the HPV-9 immunoglobulin G Luminex immunoassay (IgG-LIA), 94.9% to 100% of participants were seropositive at Month 126.
In accordance with the study’s secondary objective, incidence of persistent infection and disease related to vaccine-targeted HPV types was assessed in the per-protocol population in both female and male participants. Female participants were followed up to 11.0 years post the third dose (median 10.0 years), and male participants were followed up to 10.6 years post the third dose (median 9.9 years).
Among girls, there were no cases of vaccine-targeted HPV type high-grade disease – cervical intraepithelial neoplasia (CIN) 2/3, adenocarcinoma in-situ (AIS), vulval intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN) – certain cancers (cervical, vulvar, vaginal), or external genital warts observed;
One case of CIN1 tested positive for HPV 16, 39 and 59 was observed at Month 84. Cervical cytology results were negative at subsequent visits;
In boys, there were no cases of vaccine-targeted HPV type disease (penile intraepithelial neoplasia (PIN)), certain studied cancers (penile, perineal, perianal) or external genital warts observed. GARDASIL 9 is not approved for the prevention of HPV-related PIN, penile, perineal or perianal cancers.
No GARDASIL 9-related serious adverse events or deaths were reported throughout the LTFU study. The most common reasons for discontinuations from the LTFU study were due to participant withdrawal or loss to follow-up.
HPV will infect most sexually active males and females in their lifetime. For most people, HPV clears on its own, but for those who don’t clear the virus it could lead to certain cancers and other diseases. In the United States, the CDC estimated that tens of thousands of people were diagnosed with certain HPV-related cancers each year from 2015-2019. And worldwide, cervical cancer is the fourth most common cancer in women. There is no way to know which people who have HPV will develop cancer or other health problems. With the exception of cervical cancer, there is no routinely recommended screening for the detection of HPV-related cancers.
About the study
The Phase 3 immunogenicity study for GARDASIL 9 in boys and girls aged 9–15 years was extended to a LTFU study to assess immunogenicity through 10 years after the last GARDASIL 9 vaccine dose. The LTFU study was conducted at 40 sites across 13 countries: Belgium, Brazil, Colombia, Costa Rica, Peru, Poland, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand and USA. There were 1,272 participants (971 girls, 301 boys) enrolled in the LTFU study. Analysis of the per-protocol population included 872 girls and 262 boys who completed the GARDASIL 9 vaccination series within one year, were seronegative to the relevant HPV type at initiation of the vaccination series and had not initiated sexual activity prior to receiving the third dose of GARDASIL 9.
The primary objective of the LTFU study was to evaluate anti-HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 antibody responses through 10 years post the third dose of GARDASIL 9. Secondary objectives were to estimate the long-term incidence of the composite endpoint of HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58-related persistent infection (≥6 months duration ±1 month visit window) and disease. Safety assessments during the LTFU study included reporting of all deaths and vaccine-related serious adverse events.
Indication for GARDASIL 9
GARDASIL 9 is a vaccine indicated in females 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by human papillomavirus (HPV) Types 16, 18, 31, 33, 45, 52, and 58; cervical, vulvar, vaginal, and anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.
GARDASIL 9 is indicated in males 9 through 45 years of age for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.
The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
GARDASIL 9 does not eliminate the necessity for vaccine recipients to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended by a health care provider.
GARDASIL 9 has not been demonstrated to provide protection against diseases caused by:
HPV types not covered by the vaccine
HPV types to which a person has previously been exposed through sexual activity
Not all vulvar, vaginal, anal, oropharyngeal and other head and neck cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58.
GARDASIL 9 is not a treatment for external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; or cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial neoplasia (AIN).
Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.
Select Safety Information
GARDASIL 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant].
Because vaccines may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following HPV vaccination. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.
Safety and effectiveness of GARDASIL 9 have not been established in pregnant women.
The most common (≥10%) local and systemic adverse reactions in females were injection-site pain, swelling, erythema, and headache. The most common (≥10%) local and systemic reactions in males were injection-site pain, swelling, and erythema.
The duration of immunity of a 2-dose schedule of GARDASIL 9 has not been established.
Dosage and Administration
GARDASIL 9 should be administered intramuscularly in the deltoid or anterolateral area of the thigh.
For individuals 9 through 14 years of age, GARDASIL 9 can be administered using a 2-dose or 3-dose schedule. For the 2-dose schedule, the second dose should be administered 6–12 months after the first dose. If the second dose is administered less than 5 months after the first dose, a third dose should be given at least 4 months after the second dose. For the 3-dose schedule, GARDASIL 9 should be administered at 0, 2 months, and 6 months.
For individuals 15 through 45 years of age, GARDASIL 9 is administered using a 3-dose schedule at 0, 2 months, and 6 months.