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EMERGING TECHNOLOGIES

Vaccines for Emerging Infectious Diseases The Accomplishments of Acambis

Executive summaryDuring the post-9/11 fears of bioterrorism, a small British biotechnology company, Acambis, hit the headlines when it gained a contractto supply the US government with doses of an experimental second-generation smallpox vaccine (ACAM2000) for an emergency-usestockpile. Since that time, Acambis has steadily carved out a name for itself in the vaccines sector, building an impressive pipeline ofvaccines targeting emerging infectious diseases and making deals with the ‘big guns’ of the sector such as Baxter and Sanofi-Synthelabo.ACAM2000 has now been filed for US FDA approval and Acambis is also developing a third-generation smallpox vaccine (MVA3000)for use in people likely to experience adverse effects from older products. However, in mid-November, the company suffered a blowwhen the Department of Health and Human Services eliminated MVA3000 from its tender process. Other key candidates in theAcambis pipeline include vaccines in late-stage clinical development to prevent West Nile disease and Japanese encephalitis, whichare based on the company’s proprietary ChimeriVax™ technology for producing safe and effective recombinant viral vaccines.Although these products will not be blockbusters, analysts are forecasting healthy sales of several hundred million dollars annually. Inaddition, Acambis is developing protein-based vaccines against pandemic flu and an emerging superbug that is becoming a majorproblem in hospitals.

the aftermath of the terrorism scares in the early 2000s,Vaccines are acquiring an increasing strategic value inAcambis was awarded a $US500 million biodefensethe pharmaceutical industry, as indicated by fourcontract to supply the US government with an emergency-significant mergers and acquisitions in the last 18 monthsuse stockpile of an experimental second-generation(table I), and big companies such as GlaxoSmithKline,smallpox vaccine (ACAM2000), as well as to conductNovartis, Baxter, and Sanofi-Synthelabo now possessclinical trials of ACAM2000. Acambis also sellssubstantial programs in the vaccines sector. Notably,Cangene’s vaccinia immunoglobulin (C-VIG) product inBaxter and Sanofi are involved in collaborations withcountries outside the US, Canada and Israel. C-VIG isAcambis, a small UK biotech company that is making adesigned to treat individuals who have experienced seriousbig name for itself in the vaccines sector. Acambis has aadverse reactions following smallpox vaccination.novel technology platform, a pipeline of vaccines in

clinical development and a unique arrangement with theUS government to supply smallpox vaccine for an Pipeline targets emergingemergency-use stockpile in the event of bioterrorism. infectious diseases

A tale of two cities The ACAM2000 vaccine has been filed for US FDAapproval and Acambis is conducting clinical trials with aHeadquartered in Cambridge, England, Acambisfollow-up smallpox vaccine ACAM3000 (MVA3000). Theconducts most of its operations through its US subsidiarycompany’s products in development (table II) include late-based in Cambridge, MA. Acambis is focused onstage vaccines against West Nile virus and Japanesedeveloping vaccines and other biotechnology productsencephalitis based on the company’s ChimeriVax™against infectious diseases of increasing importance. Mostrecombinant virus technology platform (see text box onof the company’s current revenues are derived fromnext page).smallpox vaccine contracts with the US government. In

Table I. Recent mergers and acquisitions in the vaccines sectorAcquirer Target Date Approximate value ($US million)

Novartis Chiron April 2006 5424

Crucell Berna Biotech February 2006 461a

GlaxoSmithKline ID Biomedical September 2005 1400

GlaxoSmithKline Corixa April 2005 300

a Converted from euro price of deal: €349 million.

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Table II. Products in clinical developmentVaccine Disease Technology Development status

ACAM2000 Smallpox Live attenuated vaccinia virus Filed (US)

ChimeriVax-JE Japanese encephalitis ChimeriVax Phase III

ACAM3000 (MVA3000) Smallpox Modified vaccinia ankara (MVA) Phase II

ChimeriVax-West Nile West Nile ChimeriVax Phase II

ChimeriVax-Denguea Dengue fever ChimeriVax Phase II

Clostridium difficile Hospital-acquired infectious Protein (toxoid) Phase Idiarrhea

ACAM-FLU-A Influenza (universal and pandemic) Protein Preclinical

a Out-licensed to Sanofi-Synthelabo.

Next-generation smallpox vaccines Acambis filed for FDA approval of ACAM2000 in April2006.Routine vaccination against smallpox ended in 1980

when the virus was globally eradicated from the wild. ThisMVA3000means that the current population is susceptible to this

highly contagious virus that historically killed about one- Acambis is also developing a third-generation smallpoxthird of those it infected. Recent fears that some of the vaccine, ACAM3000 (MVA3000), under a contract withfew remaining laboratory stocks of smallpox could find the US National Institute of Allergy and Infectioustheir way into the hands of terrorists has led to efforts to Diseases (NIAID). MVA3000 is a weak smallpox vaccinedevelop stockpiles of vaccine for emergency use – an area based on the Modified Vaccinia Ankara (MVA) strain thatin which Acambis has been leading the way. is intended for use in people likely to experience serious

adverse effects from Dryvax and derived products – e.g.ACAM2000 those with compromised immune systems or the skinACAM2000 is derived from Dryvax® (Wyeth), the allergy atopic dermatitis. Acambis completed delivery of

original – and still the only FDA-licensed – smallpox 500 000 doses of MVA3000 to the NIAID in Decembervaccine. Unlike Dryvax, which is grown from calf lymph, 2005 and finished a phase II safety and immunogenicityACAM2000 is manufactured using modern good trial of MVA3000 in 590 healthy individuals in mid-2006.manufacturing practice cell-culture techniques, producing Phase I trials in patients from target populations had beena well-characterized vaccinia virus product with minimal scheduled.potential for transmitting other infections or causing The Department of Health and Human Services (HHS)anaphylactic reactions. is running a tender process for MVA smallpox vaccines,

Acambis began supplying ACAM2000 to the US under which Acambis and Bavarian Nordic weregovernment in 2002; in September 2006, the company was believed to be the only contenders. However, in mid-awarded an extra contract to supply another 10 million November 2006, for reasons that are unclear but likely todoses of the vaccine to the Centers for Disease Control relate to either the specific properties of the vaccine or theand Prevention (CDC). Acambis has an arrangement with proposed timeline for clinical trials, the HHS informedBaxter for supply of ACAM2000 in the US. In terms of Acambis that MVA3000 was no longer being considered.clinical development, phase III trials are complete, and Acambis has requested a meeting with the HHS to

ChimeriVax platformChimeriVax™ is a technology for producing recombinant viral vaccines against flaviviruses, which cause diseases such as yellowfever, West Nile disease, Japanese encephalitis, dengue fever, and hepatitis C. The technology is based on the yellow fever17D vaccine, a live attenuated viral vaccine notable for its efficacy (one dose confers life-long immunity) and safety that has beenused successfully for over half a century.A ChimeriVax vaccine is an engineered version of the 17D virus in which the genes encoding the yellow fever outer envelopestructural proteins (prM and E) have been replaced with those from another flavivirus. The resulting chimeric virus has the protein coatof the specific flavivirus whose genes have been inserted, triggering protective immune responses against that virus, but replicates inthe host like the yellow fever 17D strain. Thus, vaccination with the ChimeriVax vaccine should offer protection against infection withthe specific flavivirus, with similar safety and efficacy as the 17D vaccine.Acambis acquired the ChimeriVax technology when it took over Boston-based OraVax in 1999, which had licensed the technologyfrom St Louis University where Dr Thomas Chambers had developed it.

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ascertain the reason for the decision, which will guide the this often-fatal infection in the US. The West Nile viruscompany’s development plans for MVA3000. first hit the headlines in 1999 when an outbreak infected

62 people in New York City, killing seven. Since 2003,ChimeriVax vaccines West Nile infections have been reported in 45 states,

killing >100 people every year. Currently, there are noAcambis has three ChimeriVax vaccines invaccines or therapies licensed specifically for West Niledevelopment for viral diseases that are becoming ofdisease.increasing concern – Japanese encephalitis, West Nile

The ChimeriVax-West Nile vaccine is currentlyvirus and dengue fever.undergoing phase II trials to test its safety and

Japanese encephalitis immunogenicity. In September 2006, Acambis reportedpositive results from the first phase II trial of a single doseTransmitted by mosquito bite, infection with theof the vaccine in healthy individuals aged 18–40 years. AJapanese encephalitis virus can seriously damage thesecond phase II study will involve healthy adults agednervous system, causing brain inflammation (encephalitis)>40 years – the likely target population. At the completionthat is fatal in 30% of cases. The virus is endemic to mostof the phase II program, Acambis intends to seek a partnerparts of Asia and Australia, putting approximatelyfor further development of the vaccine. Lehman analysts3 billion people at risk of infection. The CDC estimateshave predicted that ChimeriVax-West Nile could recordthat at least 30 000–50 000 cases of Japanese encephalitis$US125 million in peak annual sales, assuming marketoccur annually. The only Japanese encephalitis vaccinelaunch by the end of 2009 and that the product will becurrently licensed is JE-VAX® (Sanofi/Biken), which issold only in the US.administered in a three-dose schedule. Acambis is

developing a more convenient, single-dose vaccineDengue fever(ChimeriVax-JE) to protect inhabitants of endemic regions

as well as travelers to those regions. Dengue fever is a viral infection transmitted byA phase III safety trial of ChimeriVax-JE in mosquito bite that can cause potentially fatal hemorrhagic

approximately 2000 volunteers in Australia and the US disease. At the present time, there are no specific antiviralhas been completed with no serious concerns, and positive drugs or vaccines available to prevent or treat the disease.interim results from a phase III efficacy trial in the same The global prevalence of dengue fever has growncountries comparing ChimeriVax-JE and JE-VAX in dramatically in recent decades and the virus is now816 individuals were released in October. Final efficacy endemic in more than 100 countries (including thedata are expected in Q1 2007. The main competitor in Americas), putting not only their 2.5 billion inhabitants atdevelopment is the purified inactivated viral vaccine IC51 risk but also travelers to those regions.from the German company Intercell, which has Acambis developed a tetravalent ChimeriVax vaccineundergone phase III trials in the US and Europe– its target against the four disease-causing types of dengue virusmarkets where it would be used by travelers to endemic through to the end of phase I trials. In Q1 2005, Sanoficountries. licensed global rights to further development and

By contrast, Acambis is targeting ChimeriVax-JE commercialization. The terms of the license includetowards endemic countries (including Australia), and will development milestone payments to Acambis, as well asprobably need to conduct additional trials for registration royalties on future sales. Sanofi began phase II trials ofin the US and Europe. Intercell anticipates filing for FDA the tetravalent vaccine in late 2005.approval of IC51 in the near future, while LehmanBrothers analysts expect Acambis to file for approval of Vaccines for hospital superbug, universalChimeriVax-JE in Australia in the first half of 2007. protection from fluAcambis is seeking a partner for commercialization of thevaccine. The Lehman analysts forecast the global market In a departure from its focus on viral diseases, Acambisfor Japanese encephalitis vaccines to grow from its current is developing a vaccine against the Clostridium difficile$US125 million to >$US400 million by 2013, driven by bacterium, a cause of hospital-acquired infectious diarrheasales of ChimeriVax-JE and IC51. that is becoming increasingly common. The vaccine is an

injected formulation of inactivated toxins A and B fromWest Nile virus this bacterium, and is intended for use in healthy elderlyAcambis is developing a ChimeriVax vaccine against individuals (aged ≥65 years). Phase I trials have been

the West Nile virus, to combat the recent emergence of completed successfully.

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Acambis is also developing a protein-based vaccine Looking aheadagainst influenza, ACAM-FLU-A, designed to elicit Elimination of MVA3000 from the HHS tender forimmune responses that protect against all strains of smallpox MVA vaccines was a definite blow to Acambis.influenza A – i.e. a so-called universal flu vaccine. The However, in most other areas, things look positive goingadvantage of this approach is that – unlike current flu forward. The company received an extension of contractvaccines – ACAM-FLU-A would not have to be adjusted for its ACAM2000 smallpox vaccine and approval fromevery year to match the circulating flu strains. In addition, the FDA may be forthcoming in the near future. AcambisACAM-FLU-A has the potential for use during is also receiving ongoing payments from Sanofi for thepandemics, as influenza A strains were responsible for all ChimeriVax-Dengue vaccine. In addition, the Japanesethe historical flu pandemics. A phase I trial of ACAM- encephalitis and West Nile virus ChimeriVax vaccines areFLU-A is scheduled to begin in the US in early 2007. progressing well through late stages of clinical

development and another key product, the universalinfluenza vaccine, looks set to enter clinical developmentin the very near future.

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