Status: marketed in Europe

Organizations involved:

GlaxoSmithKline Biologicals S.A. – Manuf.; R&D; Tech.

GlaxoSmithKline Inc. – USA mark.

Corixa Corp. – Manuf. other; R&D; Tech.; Former

GlaxoSmithKline plc – Intl. mark.; Parent

SmithKline Beecham Biologicals S.A. – R&D; Tech.; Former

Ribi ImmunoChem Res., Inc. – R&D; Tech.; Former

Cross ref.: See the entries concerning components of this vaccine — Engerix B (hepatitis B vaccine); Monophosphoryl Lipid A [3-deacylated monophosphoryl lipid A (MPL) plus aluminum adjuvant); and Aluminum-based Vaccine Adjuvants].

Description: Fendrix is an aqueous formulation essentially combining the same antigen as in Engerix-B, recombinant yeast-expressed hepatitis B virus surface (s) antigen (HBsAg) vaccine from GlaxoSmithKline, with a novel adjuvant system [AS(04); AS04], a combination of 3-deacylated monophosphoryl lipid A (MPL) plus aluminum potassium sulfate (alum). Thus, Fendrix is recombinant nonglycosylated hepatitis B virus surface antigen (HBsAg) from hepatitis B virus subtype adw2 produced by transformed Saccharomyces cerevisiae (yeast) strain DC5 (RT4376) formulated with adjuvant AS04 (SBAS04) composed of 3-deacylated monophosphoryl lipid A (MPL) plus aluminum potassium sulfate (alum). Each 0.5 mL dose of Fendrix contains 20 µg of HBsAg, 50 µg of 3-deacylated monophosphoryl lipid A (MPL), and 500 mg aluminum potassium sulfate (alum). Fendrix is supplied as a sterile suspension ready for intramuscular injection.

The most novel aspect of Fendrix is its MPL-based adjuvant, with Fendrix being the first vaccine to receive approval in a major market containing MPL. Fendrix with AS04 was originally developed as a hepatitis B vaccine with increased potency (immunogenicity) for use in patients who are low or nonresponders to recombinant HBsAg vaccines (in the U.S., Engerix-B from GlaxoSmithKline and Recombivax from Merck & Co). The vaccine’s original approval (European Union) involves use in pre-hemodialysis and hemodialysis patients, a group likely to be immune compromised and respond poorly to prior hepatitis B vaccines. The vaccine’s increased potency may eventually allow it to be used in a two-dose vaccination regimen (unlike prior hepatitis B vaccines, which involve a three-dose regimen).

Biological.: As discussed in the Monophosphoryl Lipid A entry, MPL adjuvants increase immune responses to vaccine immunogens, particularly strong TH1-type of cellular immune responses.

Nomenclature: Hepatitis B vaccine/AS04, rDNA [BIO]; Fendrix [TR]; Hepatitis B Vaccine (Recombinant) [FDA; likely FDA proper name upon approval]; hepatitis B vaccine (recombinant) with 3-deacylated monophosphoryl lipid A (MPL) plus aluminum adjuvant [SY]; HB-AS04 [SY]; RC-529 [SY]

Companies.: Fendrix (like Engerix-B) was originally developed by SmithKline Beecham Biologicals S.A. (now GlaxoSmithKline Biologicals S.A.), a subsidiary of GlaxoSmithKline plc (GSK). Development was continued and the vaccine is manufactured by GlaxoSmithKline Biologicals S.A.. The vaccine is marketed in the European Union and other countries (upon approval) by GlaxoSmithKline plc and affiliates, and will be marketed in the U.S (upon approval) by GlaxoSmithKline Inc.

The MPL component of GSK’s AS04 adjuvant was originally developed by Ribi ImmunoChem Research Inc., which was acquired in mid-1999 by Corixa Corp., which was acquired by GlaxoSmithKline plc in April 2005. In Dec.1992, Ribi co-exclusively licensed MPL for adjuvant use in various pediatric and other vaccines to to SmithKline Beecham (SKB; now GSK) and Lederle Praxis Biologicals (now Wyeth). As discussed in the MPL entry, in July 2004, Corixa entered into a manufacturing agreement with GSK to provide MPL through 2012; and Corixa (now owned by GSK) was to receive unspecified royalties on sales of vaccines containing MPL.

Status: On Feb. 8, 2005, Fendrix received European Union approval for prophylaxis against hepatitis B virus infection in patients with renal insufficiency including specific high-risk groups such as pre-hemodialysis and hemodialysis patients, from 15 years of age onwards.

No plans for FDA BLA filing have been announced (yet). GSK already markets Engerix-B (without MPL) in the U.S. (see related entry).

Trials: Results from an an open-label randomized study comparing a 2-dose regimen (months 0 and 6) of Engerix-B formulated with AS04 (Fendrix) with a standard 3-dose regimen (months 0, 1 and 6) of Engerix-B were reported in the Scandinavian Journal of Infectious Diseases (Aug. 2002, Vol. 34, issue 8, p. 610-6). Immunogenicity and reactogenicity were compared in healthy subjects aged between 15 and 40 years. This trial demonstrated both higher antibody responses in Fendrix recipients and the feasibility of a two- rather than three-dose vaccination regimen. At 1 and 6 months, there was a 100% seroprotection rate (anti-HBs ≥10 mIU/ml) with Fendrix, compared with a 99% response rate with Engerix-B. The corresponding geometric mean titres were significantly higher for Fendrix compared to Engerix-B: 15,468 and 2,745 mIU/mL at Months 7 and 12 vs. 6,274 and 1,883 mIU/mL, respectively. There was a higher prevalence of local symptoms with Fendrix (90% of doses) than with Engerix-B (48% of doses). However, these symptoms (pain, swelling and redness) were predominantly of mild-to-moderate intensity and resolved rapidly without treatment. A 2-dose regimen of the new HBsAg/AS04 adjuvant vaccine was concluded to compare favorably to the standard Engerix-B regimen in healthy young adults, with this improving compliance and reducing costs.

Tech. transfer: See the entries for Engerix-B, involving technology licensed by GSK from Biogen (Biogen Idec), Genentech and Chiron Corp.; and Monophosphoryl Lipid A (MPL), involving MPL/AS(04) technology licensed by GSK from Corixa (acquired by GSK in April 2005).

Market: The author’s rough guess for annual sales, primarily in Europe, is $20-$60 million, with Fendrix approved for a rather small market.