Status: BLA pending; EU MAA withdrawn in Feb. 2014

Organizations involved:

Rhein Biotech –.R&D; Tech.; Parent

Dynavax Technologies Corp. – Manuf.; R&D; Tech.; World mark.; Parent

Merck & Co., Inc. – Former

Berna Biotech AG – Former

Cross ref.: See the generic entry for Hepatitis B Virus Vaccine Products.

Description: Heplisav is a hepatitis B virus (HBV) vaccine combining recombinant hepatitis B surface antigen (HBsAg) expressed by a Hensensula (yeast) cell line with novel adjuvant, 1018 ISS Adjuvant, composed of an immunostimulatory sequence (ISS; synthetic oligonucelotide) that specifically target (their sequence complements portions of) Toll-like Receptor 9 (TLR9) to stimulate an innate immune response.

This vaccine is a sterile liquid dosage form supplied in 0.5 mL dose vials and contains 20 mcg of HBsAg and 3000 mcg of 1018 ISS Adjuvant given in a 2-dose series over 1 month by intramuscular (IM) injection.

Nomenclature: Hepatitis B Vaccine, rDNA/ISS [BIO]; Heplisav [TR]; hepatitis B virus surface antigen, recombinant with Toll-like Receptor 9 (TLR9) immunostimulatory sequences (ISS) adjuvant [SY]; 1018 ISS Adjuvant [SY for adjuvant]

Biological:

HEPLISAV combines a yeast-derived recombinant hepatitis B surface antigen (rHBsAg) with Dynavax’s 1018 ISS Adjuvant, a Toll-like receptor 9 (TLR9) agonist with an immunostimulatory cytosine phosphoguanosine (CpG) motif. The goal of using 1018 ISS Adjuvant is to increase the immunogenicity of rHBsAg, including increasing the immunogenicity in populations hyporesponsive to the current vaccines. 1018 ISS is a “B-class” ISS, which is effective at inducing PDC maturation, but induces relatively lower levels of proinflammatory cytokines than other classes of ISS.

The 1018 ISS Adjuvant used in HEPLISAV resulted from more than a decade of research on specific immumodulators. Beginning in 1999, Dynavax Technologies conducted preclinical and toxicity studies with 1018 ISS. Acting mechanistically in a very different manner from aluminum-based adjuvants, 1018 ISS stimulates TLR9, predominantly in plasmacytoid dendritic cells (pDCs). The activated pDCs then present the hepatitis B surface antigen (HBsAg) to CD4+ cells, leading to production of HBsAg-specific antibodies (anti-HBs) against the hepatitis B virus. In contrast, alum adjuvants used in the currently licensed hepatitis B vaccines stimulate a more general inflammatory response to mechanical disruption of cell membranes that is not as specific to the production of anti-HBs.

Companies.: In April 2006, Dynavax Technologies Corp. completed acquisiton of Rhein Biotech GmbH, including its Berna Biotech AG subsidiary that had a contract with Dynavx for for supply of hepatitis B surface antigen for use with Heplisav.

In Jan. 2007, Dynvax announced a global license and development collaboration agreement with Merck & Co., Inc., to jointly develop Heplisav. Merck received worldwide exclusive rights to Heplisav, funds future vaccine development, and is responsible for commercialization. Dynavax received an initial payment of $31.5 million, and will be eligible to receive up to $105 million in development and sales milestone payments, and double-digit tiered royalties on global sales. The BLA) and other marketing applications are the joint resposibility of Merck and Dynavax, and will be filed by Merck. Dynavax is responsible for manufacture of the hepatitis B surface antigen component of the vaccine for Merck, which will be produced at Dynavax Europe's Dusseldorf, Germany facility using Dynavax's proprietary technology and later, at a new facility to support expected market needs.

In Dec. 2008, Merck withdrew from its licensing deal concerning Heplisav. A ll rights reverted to Dynavax.

In Dec. 2009, Dynavax received European Union (EU) approval for its (former Rhein Biotech) cGMP manufacturing facility in Duesseldorf, Germany, for the commercial production of hepatitis B surface antigen. The approval came as a result of an upgrade expanding production capacity. This facility is expected to be able to meet the initial commercial production demands for the launch of Heplisav. Dynavax's subsidiary Rhein Biotech has manufactured the hepatitis B surface antigen for Heplisav clinical trials in this facility since 2006.

FDA class: BLA Biologic

Status: A BLA filing for chronic kidney disease is planned for the third quarter of 2011, about 6 months ahead of prior plans, due to accelerated enrollment and immunization of subjects for the safety and consistency study of Heplasav. Two doses protected 100% of the dialysis and pre-dialysis patients measured at week 24.

In Sept. 2009, FDA lifted an 15-month clinical hold on testing in patients with chronic kidney disease, and Dynavx resumed its Phase III study of Heplisav. The company started another Phase III lot-to-lot consistency trial in adults over 40 years in early 2010.

In Oct. 2011, FDA concurred with Dynavax's plan to submit a BLA for Heplisav for persons over 40 years of age, followed by a supplemental BLA for licensure of a specific regimen for vaccinating chronic kidney disease (CKD) patients against hepatitis B infection at the time the initial application is approved. Dynavax expected to file the BLA in the first quarter of 2012.

In Oct. 2011, European Medicines Agency (EMA) advised Dynavax it could submit primary endpoint immunogenicity data and associated safety data for the over-40 population as well as the CKD indication as part of its initial Marketing Authorization Application (MAA) and that the outstanding CKD data could be submitted in the course of the application's review. Dynavax confirmed its plan to submit the MAA for European approval after the submission of its BLA in the U.S.

In July 2011, manufacturing test lots showed product inconsistencies. One of three test lots showed a higher antibody response at 8 weeks than the other two lots. The company performed another test run, as requested by FDA.

In July 2011, data were also submitted to FDA supporting the consistency of three consecutively manufactured lots of HEPLISAV. On July 29, 2011, FDA told Dynavax, "CBER agrees that clinical consistency of three consecutively manufactured lots of HEPLISAV has been demonstrated. Although lot consistency criteria were not met at the pre-specified time point of 4 weeks PLD (post last dose), lot consistency criteria were met 8 weeks PLD, the time point corresponding to the primary immunogenicity endpoint, as well as at several other time points." This removed obstacles to filing a BLA.

On June 26, 2012, FDA accepted the BLA for Heplisav for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 through 70 years of age. Upon approval of the BLA, Dynavax plans to submit a supplemental BLA for an indication in patients with chronic kidney disease.

On Aug. 22, 2012, the EU accepted for filing the MAA or Heplisav for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 through 70 years of age and in patients with chronic kidney disease.

In Feb. 2014, Dynavax withdrew its EU MAA after the regulatory agency said more safety data was needed. EMA told Dynavax the safety database it presented to support the application was too small to rule out the risk of less common adverse events. In response, Dynavax withdrew the application while it works to generate the necessary clinical data. As noted below, the company was then starting a new large trial

: The proposed BLA indication for HEPLISAV is for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 through 70 years old. For this indication, Dynavax enrolled 5870 subjects in 9 completed clinical trials of HEPLISAV, including 4425 adult subjects who received HEPLISAV and 1420 adult subjects who received the comparator vaccine, Engerix-B, manufactured by GlaxoSmithKline.

In the briefing provided to the VRBPAC in Nov. 2012, FDA concluded:
"The HEPLISAV clinical program demonstrated the safety and immunogenicity of HEPLISAV compared with Engerix-B®, the most widely used hepatitis B vaccine in the United States. The 2 pivotal phase 3 trials both met their primary endpoints, demonstrating that seroprotection with HEPLISAV is noninferior to that of Engerix-B. The trials showed that the HEPLISAV seroprotection is higher than that of Engerix-B across all subpopulations, including those with a diminished response to the currently available vaccines. HEPLISAV’s 2-dose, 1-month regimen has the potential to improve adherence over the 3-dose, 6-month regimen of the current vaccines. The combination of the higher immunogenicity and potential to improve adherence should result in higher effective seroprotection rates in actual use across all populations at risk for hepatitis B infection."
"The safety of HEPLISAV has been demonstrated in an integrated analysis of the clinical trials. The trials showed that HEPLISAV has a safety profile similar to that of Engerix-B. There were 2 unexpected findings of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, 1 case of cytoplasmic staining anti-neutrophil cytoplasmic antibody (c-ANCA) vasculitis in the HEPLISAV group and 1 case of perinuclear staining anti-neutrophil cytoplasmic antibody (p-ANCA) vasculitis in the Engerix-B group. A comprehensive analysis of autoimmune events showed similar rates of events in the HEPLISAV and Engerix-B treatment groups. Other AEs occurred at similar rates in both treatment groups."

In June 2013, Dynavax reported feedback from a meeting with FDA. The meeting with FDA resulted in the following messages: The safety database does indeed need additional subjects; VRBPAC's strong endorsement of HEPLISAV's demonstrated immunogenicity was acknowledged; and analyzing the benefit/risk of HEPLISAV's use in discrete patient populations did not fundamentally address the shortfall in the safety database. It was concluded that to do so would unnecessarily restrict the patient population that could benefit from HEPLISAV's approval; The additional safety data collected would facilitate review for an indication in adults 18-70 years of age. With this news that new clinical data or even new trial(s) are apparently required, Dynavax stock price plunged over 33%.

In earl 2014, with its EU MAA then withdrawn (see above), the company was preparing to start s 8,000-subject clinical trial designed to gather additional safety data. Dynavax will use the results to ease the EMA's concerns, as well as to work through its issues with the FDA. Safety concerns had prompted FDA to reject the BLA. Dynavax had hoped to quickly refile and win approval for use in a restricted population, but the FDA subsequently asked the biotech to run a new safety study.

Tech. transfer: The Hansenula Expression Platform, a method for making proteins in Hansenula yeast, was developed by Rhein Biotech. A key patent is "DNA-molecules coding for FMDH control regions and structured gene for a protein having FMDH- activity and their uses" (U.Sl. 5,389,525; EPO299108, priority date 1987, published in 1994). The patent describes the generation of production strains for manufacturing of recombinant biopharmaceuticals, and forms the basis of Heplisav.

Biogen (Biogen Idex) key patents concerning recombinant hepatitis B virus surface antigen (HBsAg; see Recombivax HB and Engerix B entries) will have expired by the time applications are filed in the U.S., EU and other major markets.

Trials: In clinical trials to date, Heplisav has conferred immunogenicity after only two doses while retaining tolerability comparable to a currently marketed hepatitis B vaccine (Recombivax HB). In this context, some will likely label Heplisav as a follow-on biologics, biosimilar, etc. version of prior recombinant HBsAg vaccines.

In March 2010, it was reported that, "The safety profile of Heplisav was comparable to that of Engerix-B, one of two currently licensed vaccines for the prevention of hepatitis B infection, and there is no difference in autoimmune adverse events or laboratory markers of autoimmunity between subjects vaccinated with Heplisav and Engerix-B.

In April 2010, a Phase II trial confirmed immunogenicity and rapid protection in patients with chronic kidney disease.

In Sept. 2010, the Data Safety Monitoring Board (DSMB) established for Dynavax's two ongoing Phase III trials for Heplisavhas completed the third of its planned safety assessments. The DSMB determined that the studies may continue without protocol modification. The Phase 3 lot-to-lot consistency trial was fully enrolled in May 2010; the Phase 3 chronic kidney disease study is expected to complete enrollment within the next few months.

In Oct. 2010, Dynavax reported that Heplisav given as two doses over four weeks demonstrated superior seroprotection in persons with diabetes mellitus compared to Engerix-B given as three doses over 24 weeks. Dynavax's Phase III Heplisav Short-regimen Trial (PHAST), a previously reported multicenter study evaluating adults with diabetes, showed that at 12 weeks 84% of adult diabetics treated with Heplisav achieved seroprotection as compared to 0% of adult diabetics treated with Engerix-B. At week 28, 93% of the Heplisav-treated group versus 35% in the Engerix-B group achieved seroprotection. Heplisav's significantly higher rate of seroprotection was achieved without further immunization past four weeks while the Engerix-B group received a third immunisation at 24 weeks. The seroprotection rate of the Heplisav-treated group was 95% at week 12 and 81% at week 28 in the Engerix-B group is an indication of non-inferiority/superiority of Heplisav over Engerix-B.

In fall 2010, Heplisav was being evaluated in two ongoing multi-center Phase III trials evaluating HEPLISAV, the first a lot-to-lot trial in adults 40 years and older to demonstrate the lot-to-lot consistency of commercial vaccine and to complete the safety database, and the second a trial in chronic kidney disease patients at multiple centers in the U.S., Canada and Germany. This later trial seeks to show that Heplisav is just as good as Engerix-B eight weeks after the last active dose. The other trial is designed to show lot-to-lot consistency for immune response four weeks after the last dosing among three lots of Heplisav consecutively manufactured at (what was then) Dynavax’s facility in Düsseldorf, Germany. Patient enrollment and immunization has been completed for the lot-to-lot consistency trial, and the trial is expected to complete in May 2011.

In July 2011,top-line data from its Phase III trial comparing HEPLISAV to a currently marketed HBV vaccine, Engerix-B, demonstrated non-inferiority, superiority and the safety of HEPLISAV. The study evaluated a two-dose regimen of HEPLISAV administered at 0 and 1 month compared to a three-dose regimen of Engerix-B administered at 0, 1 and 6 months. The trial studied 2,449 healthy adults 40 to 70 years of age, randomized to HEPLISAV or Engerix-B in a 4:1 ratio. Immunogenicity data demonstrated that at the primary endpoint, 8 weeks post the last dose of vaccine, 12 weeks for HEPLISAV and 32 weeks for Engerix-B, the seroprotection rate (SPR) was 90% for HEPLISAV and 70% for Engerix-B, demonstrating the non-inferiority and superiority of HEPLISAV to Engerix-B. The peak SPR for HEPLISAV occurred at 24 weeks and was 95%. The peak SPR for Engerix-B occurred at 28 weeks and was 73%. At the final visit, week 52, 48 weeks after the last dose of HEPLISAV and 28 weeks after the last dose of Engerix-B, the SPRs were 92% for HEPLISAV and 59% for Engerix-B. 50% of HEPLISAV subjects and 53% of Engerix-B subjects experienced an adverse event and 7% of HEPLISAV subjects and 6% of Engerix-B subjects experienced possibly related adverse events. By Geometric Mean Antibody Concentration (GMC), the results met the pre-specified consistency criteria at 12, 18, 24 and 28 weeks, but not at 8 weeks, the pre-specified primary endpoint. The GMC of one HEPLISAV lot was slightly higher than the other two lots, which resulted in not meeting the consistency criteria at week 8. By SPR, the results met the pre-specified consistency criteria at 12, 18, 24 and 28 weeks, but not at 8 weeks. At all of these timepoints, each lot of HEPLISAV was superior to Engerix-B.

Near the end of the first pivotal trial (DV2-HBV-10), a rare autoimmune event of Wegener’s granulomatosis (granulomatosis with polyangiitis) was reported as a possibly related serious adverse event, leading to a clinical hold by FDA on the HEPLISAV development program. After a thorough safety investigation and analysis of autoimmune events, the clinical hold was lifted and the second phase 3 pivotal trial (DV2-HBV-16) was conducted. Following additional safety measures in DV2-HBV-16, HEPLISAV was found to have a safety profile similar to Engerix-B.

Overall, the immunogenicity of HEPLISAV has been established in 2 pivotal trials, both of which met their primary endpoints, demonstrating that the rates of seroprotection with HEPLISAV were noninferior to seroprotection achieved with Engerix-B. The immunogenicity of HEPLISAV was consistently higher across all subpopulations, including subpopulations hyporesponsive to the currently available vaccines.

Disease: The chronic kidney disease market is large, growing rapidly, and is widely recommended for hepatitie B vaccination. There are approximately 750,000 end-stage renal disease (ESRD) patients in the U.S. and the 5 major European markets and approximately 150,000 new patients annually. Approximately 35% of these immunocompromised ESRD patients do not respond to vaccination and 20% require boosters. As vaccination for these patients occurs regularly at dialysis centers, this is a highly concentrated, renewable market that can be served by cost-effective, targeted sales distribution networks.

Market: DynaVax reports, " Our global strategy is to develop Heplisav for populations that are less responsive to current licensed vaccines, including adults over 40 years of age, individuals with chronic kidney disease, and others." While children are now routinely vaccinated for hepatitis B, many adults have not been, and this is a large target market for Heplisav. The vaccine requires two injections instead of the three required for the existing vaccines, with people are more likely to complete their course of vaccination. Heplisav also appears to provide better protection in older people and others tending to have weaker immune systems. Heplisav might also be targeted for development for use in adults under 40 years of age who need rapid protection, a group that includes emergency personnel, healthcare workers and international travelers.

The total worldwide market for adult hepatitis B vaccines is estimated at well over $500 million annually. Current vaccines leave unmet needs for more rapid and increased protection, particularly for less responsive, underserved populations..

In early 2014, GlobalData predicted Heplisav will generate peak sales of $85 million, leaving Sanofi, GlaxoSmithKline and Merck as the dominant players.