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Background Analysis: US FDA Advisory Committee to Review Shingles Vaccine Proposed by GlaxoSmithKline – SEP 13, 2017 (VRBPAC)

Announcement

The US FDA has scheduled a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting for Wednesday, September 13, 2017 to discuss and make recommendations on the safety and effectiveness of Zoster Vaccine Recombinant, Adjuvanted, manufactured by GlaxoSmithKline Biologicals (GSK). The proposed trade name is Shingrix.

Indication Background

Description of Indication

Herpes zoster, a.k.a. shingles, is a painful disease that affects 1 million people a year in the US. It is caused by the reactivation of latent chickenpox virus, in particular as the immune system weakens with age. The most common complication from shingles is post-herpetic neuralgia (PHN), defined as a localized pain of significant intensity persisting at least 90 days after the appearance of the acute shingles rash. Other complications of shingles include ophthalmologic, neurological and cutaneous disease, which can result in severe disability.

Product Background

Description of Product

GSK is seeking approval of Shingrix (a.k.a. GSK1437173A) for the prevention of shingles in people aged 50 years or over. The candidate vaccine is a non-live, recombinant vaccine to help prevent shingles and its complications and combines glycoprotein E, a protein found on the varicella zoster virus with an adjuvant system, AS01B, which is intended to enhance the immunological response to the antigen.

Products by Other Sponsors

Currently, Merck & Co.’s Zostavax is the only US-licensed shingles vaccine. Its indication is as follows:

ZOSTAVAX is a live attenuated virus vaccine indicated for prevention of herpes zoster (shingles) in individuals 50 years of age and older.

Limitations of Use of ZOSTAVAX:

·      ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia (PHN)

·      ZOSTAVAX is not indicated for prevention of primary varicella infection (Chickenpox)

The FDA describes the outcomes of the Zostavax clinical program at an FDA “Questions and Answers” website as follows (accessed on August 17, 2017).

For people 50-59 years of age, approximately 22,000 people were studied; half received Zostavax and half received a placebo. Study participants were then monitored for at least one year to see if they developed shingles. Compared with placebo, Zostavax reduced the risk of developing shingles by approximately 70 percent.

For people 60 years of age and older, the studies for Zostavax enrolled approximately 38,000 people throughout the United States; approximately half received Zostavax and half received placebo. Study participants were followed on average for about three years to see if they developed shingles and if they did, how long the pain lasted.

At the conclusion of the studies, researchers found that overall (in persons age 60 years and older) the vaccine reduced the occurrence of herpes zoster (shingles) by about 50%. The vaccine effect was highest at 64% in people between the ages 60-69, but its effectiveness declined with increasing age; to 41% for the 70-79 age group, and 18% for those 80 years of age and older.

In those who were vaccinated with Zostavax, but still developed shingles, the duration of pain was a bit shorter for them versus those who received a placebo. Specifically, the pain of those in the Zostavax group lasted on average for 20 days and for those who received placebo, it lasted for about 22 days. The severity of the pain did not appear to differ among the two groups.

Although the FDA-licensed use includes individuals aged 50 years and older, the US Centers For Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) currently recommends that Zostavax only be routinely recommended for adults 60 years of age and older. Their recommendation states (in part) as follows:

Because the protection offered by the herpes zoster vaccine wanes within the first 5 years after vaccination, and duration of protection beyond 5 years is uncertain, it is unknown to what extent persons vaccinated before age 60 years will be protected as they age and their risk for herpes zoster and its complications increases. Because duration of protection offered by the vaccine is uncertain, the need for revaccination is not clear. Assuming waning of vaccination protection according to currently available studies, the cost-effectiveness model projects a substantially greater reduction of disease burden, health care utilization, and costs with vaccination of older adults who have higher incidence of herpes zoster and related complications. Considering that the burden of herpes zoster and its complications increases with age and that the duration of vaccine protection in persons aged ≥60 years is uncertain, ACIP maintained its current recommendation that herpes zoster vaccine be routinely recommended for adults aged ≥60 years.

Zoster Vaccine Market

In 2015, sales of Zostavax were $746 million. Some analysts project that Shingrix sales could reach $1 billion by 2021. They emphasize two key points, as follows:

·      In their view, Shingrix appears to have demonstrated better efficacy in the population of people aged 50-60 years compared to Zostavax; and

·      Shingrex is a non-live vaccine, whereas Zostavax is a live attenuated vaccine. This potentially expands Shingrex’s use to immune-compromised patients and lessens global manufacturing constraints.

Clinical Trials of Proposed Indication

The biologics license application (BLA) for Shingrix is based primarily on 2 phase 3 clinical trials, named ZOE-50 and ZOE-70. Study methods and results were published in the New England Journal of Medicine, as follows.

ZOE-50 (ClinicalTrials.Gov ID: NCT01165177)

ZOE-50 was a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of Shingrix in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults.

A total of 15,411 participants who could be evaluated received either the vaccine (7,698 participants) or placebo (7,713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1,000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups.

ZOE-70 (ClinicalTrials.Gov ID: NCT01165229)

ZOE-70 was randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of Shingrix or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.

In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either Shingrix (6,950 participants) or placebo (6,950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 Shingrix recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1,000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%).

Pooled Analyses of ZOE-50 and ZOE-70

In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among Singrix recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups.

ZOSTER-048

At the time of the BLA filing, GSK noted that a clinical study was also underway to evaluate revaccination in subjects who have previously been vaccinated against shingles with Merck’s Zostavax (NCT02581410). Top-line results from this trial were announced by GSK on June 21, 2017. These results were announced in conjunction with the company’s presentation of the data at the CDC’s ACIP that same day.

ZOSTER-048, an ongoing study of 430 adults aged 65 years and older, was designed as a prospective, group-matched, non-randomized, open-label trial in those previously vaccinated with Zostavax at least 5 years earlier and in previously unvaccinated subjects. According to GSK, the study met its primary objective of demonstrating non-inferior immune response (i.e. antibody concentrations).

Other Trials

GSK says that additional trials are underway in solid and hematological cancer patients, hematological stem cell and renal transplant recipients and HIV-infected people. These studies will provide additional information on the candidate vaccine’s safety and ability to stimulate immune responses in populations at high risk of shingles because of the weakening of their immune system.

Regulatory Background

US Regulatory Background

October 2017 – PDUFA date (estimated)

November 25, 2016 – BLA submission date

EU Regulatory Background

November 25, 2016 – Marketing Authorization Application (MAA) Filing date

Japan Regulatory Background

April 18, 2017 – NDA submission date

Canadian Regulatory Background

November 21, 2016 – New Drug Submission (NDS) date

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: GlaxoSmithKline Biologicals Drug Name: Zoster Vaccine Recombinant, Adjuvanted Drug Class: vaccine Indication: varicella zoster virus


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.