Dynavax's Hep B Vaccine Finally Clears US FDA With Clean Label But Larger Safety Study

Heplisav-B labeling notes myocardial infarction imbalance in one trial but also apparent absence of a causal relationship; sponsor will conduct a postmarketing safety cohort study involving 50,000 subjects, 10,000 more than initially planned.

After several failed attempts at US regulatory approval, Dynavax Technologies Corp.'s hepatitis B vaccine Heplisav-B will finally enter the market in early 2018 with a relatively clean label but a postmarketing study that is 25% larger than originally proposed.

On Nov. 9, FDA licensed Heplisav-B (hepatitis B vaccine [recombinant] adjuvanted) for prevention of infection caused by all known subtypes of hepatitis B virus in adults ages 18 years and older.

"Heplisav-B is the first new hepatitis B vaccine in the US in more than 25 years and the only two-dose hepatitis B vaccine for adults," Dynavax said in a press release announcing the approval.

With FDA approval finally behind it, Dynavax is now looking ahead to an Advisory Committee for Immunization Practices vote on Heplisav, expected in February.

With FDA approval finally behind it, Dynavax is now looking ahead to the Centers for Disease Control and Prevention Advisory Committee for Immunization Practices' February meeting, at which the panel is expected to vote on adding Heplisav to the adult vaccination schedule.

Dynavax expects to launch the vaccine in the 2018 first quarter and will announce a price closer to the launch. Promotional efforts are expected to highlight the vaccine's robust efficacy as well as dosing advantages relative to currently approved three-dose hepatitis B vaccines for adults: GlaxoSmithKline PLC's Engerix-B, Merck & Co. Inc.'s Recombivax HB, and GSK's hepatitis A/B combination vaccine Twinrix.

Merck is not currently distributing the adult formulation of Recombivax, and the vaccine is not expected to become available until the first half of 2019, according to FDA's website.

Neutral Labeling On CV Safety

For Dynavax, the Heplisav approval caps a more than five-year regulatory odyssey that included two advisory committee reviews, two complete response letters and user fee goal date extensions resulting from safety concerns with the adjuvanted vaccine.

In July, FDA convened its Vaccines and Related Biological Products Advisory Committee to weigh in on the higher rate of major adverse cardiovascular events in one of three pivotal trials, Study DV2-HBV-23. (Also see "Heplisav Vaccine Postmarketing Study Might Overcome FDA Safety Worries At Panel" - Pink Sheet, 26 Jul, 2017.)

Although there was a consensus that the vaccine had demonstrated robust effectiveness, there was still a large degree of uncertainty as to whether myocardial infarctions (MIs) were a safety signal caused by the vaccine. Ultimately, the committee voted overwhelmingly that the available data support the safety of Heplisav when administered to adults 18 years and older.

On a bright note for Dynavax, all of the regulatory hand-wringing around the vaccine's safety is not readily apparent from the product's labeling.

The vaccine is contraindicated in individuals with a history of severe allergic reaction after a previous dose of any hepatitis B vaccine or to any of Heplisav's components, including yeast. The most common local reaction was injection site pain (23%-39%), with the most common systemic reactions listed as fatigue (11%-17%) and headache (8%-17%).

The Adverse Reactions section of labeling describes the imbalance in MIs observed in Study DV2-HBV-23 (called "Study 3" in labeling). This was the largest of three randomized, observer-blinded trials conducted against Engerix. However, labeling states that additional evidence does not support a causal relationship between Heplisav and acute MI. (See box.)

Heplisav-B Labeling: Serious Adverse Events In Study 3

"Acute myocardial infarction (AMI) was reported in 0.25% (n=14) of Heplisav-B recipients and 0.04% (n=1) of Engerix-B recipients. An analysis of serious adverse events likely representing myocardial infarction (MI) was conducted using the standard Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) for MI. This analysis identified a total of 19 Heplisav-B subjects (0.3%) and 3 Engerix-B subjects (0.1%) with events included in the SMQ for MI (these events include the 15 reports of AMI)."

"Additional evidence, including information on temporal relationship and baseline risk factors, does not support a causal relationship between Heplisav-B administration and AMI. Among the 19 events identified as MI in Heplisav-B recipients, three occurred within 14 days, nine occurred within 53-180 days, and seven occurred more than 180 days following any dose of Heplisav-B. Among the three events identified as MI in Engerix-B recipients, one each occurred 13, 115, and 203 days following any dose. All 19 Heplisav-B recipients and 3 Engerix-B recipients reported one or more baseline risk factors for cardiovascular disease."

On the efficacy side, labeling states that the seroprotection rates induced by Heplisav were shown to be noninferior to Engerix in all three trials. In Study DV2-HBV-23, Heplisav demonstrated a statistically significantly higher rate of seroprotection compared to Engerix in the total study population (95% vs. 81%) and in a subpopulation of patients with type 2 diabetes (90% vs. 65%).

During the conference call, CEO Eddie Gray said the company did not originally anticipate the immunogenicity data for diabetes patients would be included in initial labeling. "However, through the review process, the agency has determined to include the data for this population presented in the BLA, which provides important information for physicians," he said.

Postmarketing Study Grows By 10K Subjects

Dynavax's proposed postmarketing safety study has grown in size, but narrowed in scope, in the interval between the July advisory committee meeting and FDA's approval.

At the panel review, Dynavax proposed a retrospective cohort study consisting of 20,000 Heplisav recipients and 20,000 patients given another other hepatitis B vaccine, with follow-up 13 months after the first dose of the vaccine.

The study would have compared the incidence rates for the composite endpoint of major adverse CV events (MACE) and its individual components – CV death, nonfatal MI, nonfatal stroke – as well as rates for pre-specified immune-mediated events and herpes zoster. The study would enroll patients at Kaiser Permanente Northern California.

Dynavax asserted the sample size of 20,000 patients per group would provide more than 99% power to rule out a two-fold increase in the incidence of MACE if the background rate were six per 1,000 person-years. The company said that depending upon the rate of vaccine uptake, the first interim analysis from the study could be conducted 12 months after initiation.

However, many advisory committee members said the postmarketing study proposal was not good enough. Some said it would not sufficiently answer questions about a causal link to myocardial infarctions and should, instead, be more focused on that particular adverse event. Panelists also raised concerns about studying the vaccine in patients at high risk of CV events. (Also see "Heplisav Seems Headed For Approval, But With More Robust Postmarketing Study" - Pink Sheet, 30 Jul, 2017.)

The study size for the MI analysis was increased "based on the expected event rates in the specific sites within the Kaiser system that were ultimately selected and the desire to obtain meaningful interim and final analyses in the shortest time frame that is feasible." – CMO Janssen

In August, Dynavax announced that FDA had extended the user fee date by three months to iron out details around the postmarketing study. (Also see "Heplisav Postmarketing Worries Push PDUFA Date Back; FDA Seeks More Details" - Pink Sheet, 4 Aug, 2017.)

During the conference call announcing approval, Gray said Dynavax will conduct an observational postmarketing surveillance study focused specifically on acute MIs and immune-mediated diseases. The study will be conducted in the Kaiser Permanente system in California.

To evaluate the risk of AMIs, the study will enroll 25,000 Heplisav subjects and 25,000 Engerix subjects over approximately 10 months and follow them for one year after vaccination, Gray said. "Ongoing review of the patient accrual and AMIs will be performed throughout the study. Interim analyses will be conducted during the study, and we anticipate having final analysis available in about 2.5 years."

Chief Medical Officer Robert Janssen later told the Pink Sheet that the study size for the MI analysis was increased "based on the expected event rates in the specific sites within the Kaiser system that were ultimately selected and the desire to obtain meaningful interim and final analyses in the shortest timeframe that is feasible. The general study design was not changed."

In addition, the company will evaluate the rate of immune-mediated events in this same group of 50,000 patients, plus an additional 5,000 recipients each of Heplisav and Engerix. Results will be available in roughly the same timeframe as those for MIs.

The MI study is a postmarketing requirement, whereas the immune-mediated study, which also will look at herpes zoster and anaphylaxis, is a postmarketing commitment. Dynavax also has a postmarketing commitment for a pregnancy registry, Janssen said.

The postmarketing studies are expected to cost approximately $10m, Gray said.