Reductions in Certain Types of HPV-Related Cervical and Non-Cervical Diseases in Women and Men Observed with Real-World Use of Merck's GARDASIL® in Systematic Literature Review of 138 Studies

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today that an updated systematic literature review examining the global impact and effectiveness of HPV vaccination using GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] was published online in the journal Expert Review of Vaccines. This systematic review observed that use of GARDASIL led to reductions in the rates of high-grade (precancerous) and low-grade cervical lesions, as well as reductions in certain non-cervical HPV-related diseases and HPV infection in women and men. The systematic review included 138 peer-reviewed studies, published between March 1, 2016, and March 31, 2020. It details the impact and effectiveness of GARDASIL through immunization programs in 23 countries, across Africa, Asia, Europe, Australia, South America and North America and builds on a prior review of real-world data published in 2016. The previous real-world analysis was based on 58 peer-reviewed studies published between Jan. 1, 2007, and Feb. 29, 2016, across Australia/New Zealand, Europe and North America. Studies examining GARDASIL 9® (Human Papillomavirus 9-valent Vaccine, Recombinant) were not included in this review.

In the U.S., GARDASIL¹ is indicated for use in females 9 through 26 years of age for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. GARDASIL is also approved for use in males 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16 and 18, for the prevention of anal dysplasia and precancerous lesions caused by HPV types 6, 11, 16 and 18, and for the prevention of genital warts caused by HPV types 6 and 11. GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

“Since its first authorization in 2006, GARDASIL has been widely used in national immunization programs all around the world, which has enabled researchers to study the impact of HPV vaccination in a broad range of populations and settings,” said Ravinder Dhawan, vice president, head of center for observational and real-world evidence, Merck Research Laboratories. “These real-world data from more than one hundred published studies show decreases in vaccine-type HPV infections and related diseases and are an important reminder that we need to do more to expand vaccination to males and females as part of the global fight to lessen the incidence of certain HPV-related diseases and cancers.”

¹ GARDASIL is no longer marketed in the United States. GARDASIL 9 was approved in the United States in 2014.

In addition to the inclusion of real-world data from more countries compared to the previous review published in 2016, longer-term effects of HPV vaccination were also observed, including reductions in certain types of cervical high-grade (precancerous) lesions. Studies included in this review reported reductions in vaccine-targeted low-grade and high grade (precancerous) cervical lesions in females. The greatest reductions were observed in younger age groups (14-17 years), with up to 73 percent reduction in CIN3+ (cervical pre-cancerous lesions) among vaccinated females. Consistent with the previous review, declines in the incidence of anogenital warts continue to be observed within vaccine-targeted female age groups, with larger decreases (up to 88%) observed in younger age groups.

Sixteen studies reporting on non-cervical disease endpoints were also evaluated in this review. There is no routinely recommended screening for the detection of non-cervical HPV-related diseases and cancers. Findings in non-cervical disease included:

• Consistent decreases observed in vaccine-type HPV infection rates in females among age groups targeted by national immunization programs, of up to 96%.
• A consistent overall decrease in prevalence of anal infection in men was reported with variability observed by HPV-type. A significant reduction in high-grade anal pre-cancers (AIN) was observed among vaccinated versus unvaccinated men who have sex with men in one study. In years one and two after vaccination, statistical significance in the estimate was observed (HR 0.42 [95% CI: 0.22-0.82, p=0.01] and HR 0.50 [95% CI: 0.26-0.98, p=0.05], respectively). Year three results were not significant, potentially due to loss of follow-up participants in the longer-term study.

About the systematic review

A 2016 review of real-world data previously captured both the effectiveness and impact data of GARDASIL since 2007-2016. This updated systematic literature review identified studies published from March 2016 through March 2020 that met the pre-specified criteria for assessment of the real-world impact of HPV vaccination on HPV-related precancerous and dysplastic cervical lesions, genital warts and HPV infection. The literature search was expanded to include peer-reviewed observational studies between January 2007 and March 2020 on additional endpoints of oral and anal HPV infections, oropharyngeal and anal lesions and recurrent respiratory papillomatosis (RRP). The review identified 138 studies from 23 countries with varying degrees of HPV vaccination coverage, among populations of different ages and used different study methods and disease endpoints. A majority of the countries used GARDASIL; some countries utilized the bivalent HPV vaccine in addition to GARDASIL. Studies reporting only on the bivalent HPV vaccine were excluded.

Indication for GARDASIL and GARDASIL 9

GARDASIL 9 is a vaccine indicated in females 9 through 45 years of age. GARDASIL is a vaccine indicated in females 9 through 26 years of age. GARDASIL 9 is indicated 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; and precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. GARDASIL is indicated for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV Types 16 and 18, and precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, and 18. Both are indicated for the prevention of genital warts caused by HPV Types 6 and 11. GARDASIL 9 is indicated in males 9 through 45 years of age. GARDASIL is indicated in males 9 through 26 years of age. GARDASIL 9 is indicated for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; and precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. GARDASIL is indicated for the prevention of anal cancer caused by HPV Types 16 and 18, and precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, and 18. Both are indicated for the prevention of genital warts caused by HPV Types 6 and 11.

The GARDASIL 9 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.

Indication - Limitations of Use

GARDASIL 9 and GARDASIL do 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 and GARDASIL have 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 and GARDASIL protect only against those vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV types contained in the vaccines.

GARDASIL 9 and GARDASIL are 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 or GARDASIL may not result in protection in all vaccine recipients.

Select Safety Information

GARDASIL 9 and GARDASIL are contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL.

Because vaccinees 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 and GARDASIL have not been established in pregnant women.

For GARDASIL 9, 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. For GARDASIL, the most common (≥1.0%) adverse reactions were headache, fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising.

The duration of immunity of GARDASIL 9 or GARDASIL has not been established.

Dosage and Administration

Administer either GARDASIL 9 or GARDASIL intramuscularly in the deltoid or anterolateral area of the thigh.

For GARDASIL 9, a complete vaccination regimen consists of:

• 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.

For GARDASIL, a complete vaccination regimen for individuals 9 through 26 years of age consists of 3 doses at the following schedule: 0, 2 months, 6 months.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

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Please see Prescribing Information for GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] at https://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf and Patient Information/Medication Guide for GARDASIL at https://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_ppi.pdf.

Please see Prescribing Information for GARDASIL 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) at https://www.merck.com/product/usa/pi_circulars/g/gardasil_9/gardasil_9_pi.pdf and Patient Information/Medication Guide for GARDASIL 9 at https://www.merck.com/product/usa/pi_circulars/g/gardasil_9/gardasil_9_ppi.pdf

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