SmithKline Beecham Biologicals pipeline
Therapeutic vaccine targets
OXFORD - Vaccines for a long time have been considered a low margin business, but with the advent of recombinant technologies and a better understanding of the biology of the immune system, the sector looks poised for dramatic growth.
This is good news for biotech, as the leading pharmaceutical players such as Pasteur Merieux Connaught and SmithKline Beecham appear to be doing much of their discovery and development work in partnership with biotech companies.
This is particularly true with the so-called therapeutic vaccines or pharmaccines. These, unlike conventional vaccines, do not prevent disease from occurring but instead use the immune system to help prolong life.
"We are still mostly focused on prophylactics but it is only logical that as we further understand the mechanisms of the human immune system we should want to develop products that help the immune system fight off diseases such as cancer once they have started," said Pierre Meulien, vice president of R&D at Pasteur Merieux Connaught, the world's leading vaccines company.
"Research has shown that there are a host of tumor-associated antigens - proteins that are displayed on the surface of cancer cells but are rarely found on normal cells," Meulien told BioCentury. "It is these proteins which are our targets. We want to alert the immune system to lock onto the target proteins and kill the cells to which they are attached."
In collaboration with the Canadian government, Pasteur Merieux Connaught (Lyon, France) last year launched a global 10-year program involving private sector partners, universities and hospital research centers. "It is our intention to build up a series of partnerships with others," said Mark Lievonen, senior vice president and general manager of the company's oncology business unit.
"I think it is clear that we have a number of key competencies but that we do not have all the pieces," Lievonen said. "We want to acquire those technologies, intellectual property and access clinical trials to develop successful products. We consider ourselves to be at the hub of this new area. And, if everything works out, therapeutic vaccines could be a significant part of the portfolio." Research into therapeutic vaccines accounts for one-fifth of the vaccines business research budget.
One of the first deals associated with the program was signed in January with Therion Biologics Corp. (Cambridge, Mass.) to develop therapeutic vaccines to treat colorectal and lung cancers and melanoma. Pasteur Merieux will have exclusive worldwide rights to develop and manufacture Therion's melanoma vaccines and carcinoembryonic antigen (CEA)-based vaccines. Therion will have access to pox virus vector technologies owned by Pasteur Merieux and its Virogenetics Corp. affiliate (Troy, N.Y.), which can be used to properly present antigens to the immune system.
According to Lievonen, the deal also is important because Therion has been building a position with its own recombinant pox virus vector technologies and is a close collaborator with the U.S. National Cancer Institute. "We will get access to NCI work and antigens," he said. "In fact, we want to create a series of relationships to get antigens to bolt onto the pox virus technology."
Meulien believes that the pox virus technology is the basis for a platform in therapeutic vaccine development. "These are live viral recombinant vectors, based on the canarypox virus, which have been shown to be safe as they have been used in thousands of patients in clinical trials. We have shown that these vectors have a unique capacity to stimulate cytotoxic T lymphocytes - the very cells that could kill tumor cells or virus-infected cells. We are now looking for antigens to attach to the vectors," he said.
In the cancer field, Lievonen said the goal "is to demonstrate proof of concept by the year 2000. We are working to demonstrate that it is possible to stimulate an active immunization approach which will work in cancer patients."
Pasteur Merieux Connaught is able to dismiss some of the doomsayers who suggest that therapeutic vaccines will never move from concept into the market (see BioCentury, April 27). The company already makes a BCG cancer immunotherapeutic, ImmuCyst, that Lievonen said "is licensed and sold in more than 40 countries, and has been shown to be 83 percent effective in the treatment of superficial bladder cancer." Pasteur Merieux Connaught has also developed a post-exposure immunotherapeutic against rabies.
Among its most advanced cancer therapeutic projects is a collaboration with Aphton Corp. (APHT, Woodland, Calif.) to develop and commercialize APHT's Gastrimmune immunotherapeutic for the treatment of a variety of cancers (see BioCentury Feb. 24, 1997). Gastrimmune works by blocking production of the hormone gastrin 17, which has been linked to several cancers. Gastrimmune is in Phase III trials in gastrointestinal cancers.
Pasteur Merieux Connaught also has established a string of partners in its bid to develop therapeutic vaccines to treat conditions linked to Helicobacter pylori, which include the majority of cases of duodenal and stomach ulcers. The bacterium is also considered to be a major risk factor for stomach cancer.
In a four-way alliance, Pasteur Merieux Connaught and OraVax Inc. (ORVX, Cambridge, Mass.) have entered into a research and licensing agreement with Human Genome Sciences Inc. (HGSI, Rockville, Md.), and MedImmune Inc. (MEDI, Gaithersburg, Md.) to access the complete H. pylori genome sequence to develop vaccines.
The Pasteur Merieux/ORVX joint venture has conducted Phase I and II studies using certain H. pylori antigens. In October 1996, ORVX presented Phase II data showing immune responses and reduced infection in some patients, and the partners said they planned to optimize the vaccine (see BioCentury, Oct. 21, 1996).
ORVX has a number of on-going Phase II trials testing a variety of antigens, delivery systems and adjuvants.
To build on the HGSI and MEDI data, Pasteur Merieux/ORVX earlier this year acquired an exclusive worldwide option to an attenuated Salmonella typhi oral vaccine delivery system from Peptide Therapeutics Group (LSE:PTE, Cambridge, U.K.) (see BioCentury, May 4). PTE acquired the oral vaccine delivery system from Medeva plc as part of a package of projects and patent rights linked to mucosal vaccine delivery. PTE is incorporating the joint venture's H. pylori antigens into its delivery system, while the joint venture is to fund and conduct preclinical testing of the resulting vaccine.
The fact that Medeva (London, U.K.) sold the mucosal vaccine delivery technology for £1 million plus a further £1 in development funding should not be seen as a signal that Medeva is opting out of the vaccine business. Indeed, CEO Bill Bogie is looking to the vaccines as a potential springboard to growth.
Medeva could be the first to bring a therapeutic vaccine targeted at a major disease to the market. It is developing Hepagene both for vaccination against hepatitis B and the commercially more attractive indication, treatment of chronic hepatitis B.
According to Medeva, Hepagene is the first recombinant HBV vaccine that includes both the S surface antigen and the pre-S1 and pre-S2 epitopes, which together comprise the major part of the viral envelope.
Bogie told BioCentury that the company expects to file for marketing approval this year, first in Europe and then in the U.S.
Clinical trials of Hepagene as an immunotherapeutic for the treatment of chronic hepatitis B are also on schedule, according to Bogie. Interim data on a four dose, double-blind, placebo-controlled study in South East Asia are due at the end of the year. However, he noted that Phase II data showing a 40 percent response came from an eight-dose study, while the Phase II four dose study achieved 10 percent clearance. Thus the results of the pivotal trial using an eight 20 µg dose regimen, due at the end of 1999, will be more important clinically.
"We intend to develop a platform technology based on the core protein of the hepatitis B virus which will form the basis of future immunotherapy products for hepatitis diseases," said Bogie.
He added that a proof of principle study, completed in the first half of 1998, has shown that hybrid hepatitis B cores expressing surface hepatitis B virus components augment the immune response to hepatitis B in a preclinical setting. The vaccine has been moved into exploratory development.
Part of the company's plan is to build its portfolio via partnerships. "We are looking to access products from biotech companies that have reached at least Phase II," Bogie said. "It would be our intention to do all the scale up, clinical filings and even market and sell the products. It is our intention to help biotech companies get their babies into the market."
It will be a slow process, he added, noting that Medeva would want to in-license only two to three technologies or products in the coming two years. Already this year, Medeva has completed the due diligence on three possible arrangements.
Clearly not all arrangements with biotech companies will be successful. Last week the company announced that early results of a Phase I proof of principle trial of an intranasal influenza vaccine being developed with PTE did not meet the immunogenicity criteria for efficacy (see B9). Medeva had hoped that the intranasal version would confer mucosal immunity at a level greater than the systemic immunity stimulated by the injectable form of the vaccine.
Both PTE CEO John Brown and Bogie said they were surprised by the findings in the light of previous preclinical data. After further analysis, Medeva may reformulate the vaccine and put it through extra trials.
Brown was also at pains to point out that the intranasal flu vaccine uses different technology from all its other vaccine projects. "These results have no bearing on other parts of our oral mucosal vaccine program, which is developing vaccines for typhoid and enterotoxigenic Escherichia coli and is the basis for the H. pylori vaccines we are developing with Pasteur Merieux/Oravax," he said.
SmithKline Beecham also is counting on vaccines to boost its earnings, estimating a near doubling of vaccine sales from $1.2 billion to $2.2 billion over the next four to five years. This growth initially will come from conventional prophylactic vaccines such as its Lymerix Lyme disease vaccine, although the company expects that the fledgling pharmaccines business could add a further 50 percent growth in vaccine sales starting in about eight or nine years.
The success of the vaccines business could be important to SmithKline's future as a stand-alone company in the wake of failed merger talks with both American Home Products and Glaxo Wellcome. Britain's second largest pharmaceuticals company reported second quarter pre-tax profits of £362 million (US$595.5 million), up from £347 million a year earlier, but below the £370-£380 million expected by analysts.
CEO Jan Leschley has said that he wants to see two to three new chemical entities and one new vaccine introduced each year. Indeed, in its most recent annual report, the company said that in the next three years it expects to file product registrations in major markets for 10 new chemical entities, six new vaccines and six new combination vaccines.
The vaccines business, SmithKline Beecham Biologicals (Rixensart, Belgium), is almost run as an autonomous business. In fact, rumors periodically circulate suggesting that the Rixensart business may be disposed of via a spinout or merger. But currently, the vaccines portfolio looks like one of the platforms that could achieve substantial growth for SmithKline.
Most obvious on the radar screen is the Lyme disease vaccine, currently being evaluated at FDA. A prophylactic genital herpes vaccine is in Phase III trials in 10,000 patients, while prophylactics to prevent malaria and diseases caused by rotavirus and respiratory syncytial virus are in Phase II.
Although in the short term the emerging products are prophylactic vaccines, Jean Stephenne, senior vice president and general manager at SmithKline Biologicals, expects pharmaccines to emerge as an important business.
"We are developing immunotherapeutics, or pharmaccines as we call them, to tackle three therapeutic classes - chronic infectious diseases, cancers and allergies," said Thierry Plouvier, vice president of immunotherapeutics.
While pharmaccines have only had limited success in the past, Plouvier said, "we now believe that with the new adjuvants and a better understanding of the antigens associated with illness the whole area has moved on. We now have adjuvant technologies that enable us to boost the TH-1 response and that when combined with therapeutic proteins can produce potent products."
Adjuvants appear to be key to SmithKline's prospects in pharmaccines, and SBAS2, a combination of two adjuvants, seems to have a pivotal position in these efforts. SBAS2 is a cocktail of a lipopolysaccharide endotoxin from a Gram negative bacterium, monophosphoryl lipid A (MPL) immunomodulator, the QS-21 adjuvant derived from saponins from the bark of Quillaja saponaria tree; and an oil-in-water emulsion. SmithKline licensed MPL from Ribi ImmunoChem Research Inc. (RIBI, Hamilton, Mont.) for a number of specific indications and the QS-21 adjuvant from Aquila Biopharmaceuticals Inc. (AQLA, Worcester, Mass.).
Interestingly, the adjuvants being developed for therapeutic vaccine use may not require as benign a safety profile as those used in prophylactic vaccines. "As prophylactic vaccines are going into healthy people, that safety profile is essential," said John Roberts, medical director of Cantab Pharmaceuticals plc (LSE:CTB, CNTBY, Cambridge, U.K.). "However, the therapeutic vaccines are going to be given to people who are very sick and so it is likely that the acceptable risk:benefit profile will shift to allow cancer adjuvants that may have been considered too toxic before."
According to Roberts, CTB was attracted to SmithKline as a partner because of the strength of its adjuvant program. "Adjuvants are going to be very important, as our products will need to elicit the right immune response," he said.
CTB's human papillomavirus-based pharmaccine to treat genital warts is one of SmithKline's most advanced products. According to Plouvier, a Phase IIa trial demonstrated that 63 percent of patients (12/19) with recurrent warts completely cleared, with recurrence seen in only 17 percent. In cases with new warts, 10/10 cleared their warts with a recurrence of only 3/10.
Roberts said that the next stage will involve a switch from using alum as the adjuvant to proprietary adjuvants that are likely to be more efficacious.
Most of SmithKline's late stage pharmaccines owe a great deal to the company's ability to do deals with the biotech industry and academia. Plouvier reckons he spends about a quarter to a third of his time looking for new products and technologies to license. Plouvier cites PTE in allergy and Corixa Corp. (CRXA, Seattle, Wash.) in cancer as examples of potentially fruitful alliances.
"The deal with PTE is very important to our allergy ambitions because their approach is non-allergen specific and this enables us to focus on controlling several steps in allergic reactions," said Plouvier. PTE has already demonstrated efficacy in food allergies and hay fever and SmithKline is extending Phase II feasibility trials in a range of allergic indications.
According to PTE's Brown, other uses for the allergy vaccine include juvenile asthma and anaphylaxis.
SmithKline's deal with CRXA provides the vaccines developer with an array of antigens associated with prostate and breast cancer. SmithKline is providing CRXA with research funding, milestone payments and royalties on future products in return for worldwide rights to antigens discovered in the research and options to license additional CRXA vaccine technology in related fields.
SmithKline also is developing a pharmaccine against malignant melanoma in collaboration with Thierry Boon at the Ludwig Institute for Cancer Research, (Brussels, Belgium), and the European Organization for Research and Treatment of Cancer (Brussels). The pharma company has demonstrated proof of concept by vaccinating patients with a peptide derived from melanoma-associated antigen plus a proprietary adjuvant. The trial involved 39 patients of whom 25 had advanced melanoma; Plouvier said there were 3 complete responses and 4 partial responses.
In June, SmithKline entered into a deal covering use of APHT's Gonadimmune anti-gonadotropin releasing hormone vaccines for a variety of GrRH-related cancers. The companies have chosen prostate cancer as the first indication and plan to start a Phase I/II trial in the U.K. shortly.
While most of the pharmaccines portfolio is based on in-licensed technologies, SmithKline's most advanced pharmaccines project is an in-house product to treat chronic hepatitis B. Phase II trials are underway and Plouvier expects Phase III to start in the fourth quarter.
Data from trials so far indicate that it is ineffective in interferon-resistant patients although sero-conversion in interferon responders was observed in 3 out of 4 patients.