Can Biologic Drugs Tackle Antibiotic Resistance?
Antibody-based products present a novel approach to the treatment and prevention of infections, as an alternative to conventional antibiotics. Several companies are developing such agents for a range of indications, but their cost, complex manufacturing methods and mode of administration are restrictive. A high unmet need and well defined target groups are key to commercial success in this market.
Increased interest in the development of antibody-based agents
Historically, serum-derived antibody therapy has been used to treat a wide range of infections, but safety concerns and the increased availability of anti-infective drugs have led to the slow decline of antibody agents over the past five decades. However, advances in technology have improved manufacturing costs and tolerability, leading to a renewed interest in the development of antibody-based agents for prophylaxis (prevention) and the treatment of infectious diseases. A key factor in gaining wider clinical acceptance is the fact that fully human antibody reagents avoid the toxicities associated with traditional human- or animal-derived serum therapy.
The emergence of new pathogens, combined with an increasing prevalence of drug-resistant microorganisms, has compromised the efficacy of existing therapeutic options. Moreover, old pathogens have re-emerged as the difficulties involved in preventing and treating infections in immuno-compromised patients have highlighted the need for adjunctive immunotherapy. Despite the approval of the first monoclonal antibodies more than 20 years ago, only one antibody product has been successfully approved for an infectious disease indication; Medimmune's Synagis, a humanized antibody for the prophylaxis of respiratory syncytial virus. The drug's annual sales are now approaching $1 billion, following its approval in 1998. Its follow-on product, motavizumab, was filed with the FDA in February 2008.
Now, however, several companies, including Genentech, have such products in development for a range of infections. However, the benefits of monoclonal antibodies are still largely offset by their cost, complex manufacturing methods and mode of administration, all of which will restrict their use to the treatment of certain infections. Consequently, a high unmet need, as well as precisely defined target groups, is invaluable if the favorable efficacy and cost-benefit profiles, which are required to convince the regulatory and reimbursement gatekeepers, are to be demonstrated. Antibody-based products that fulfill these criteria have a reasonable probability of commercial and scientific success.
Antiviral antibody development
Substantial progress has been made in the development of novel antiviral therapies over recent years, but the majority of new and existing products only inhibit, rather than curing, the infection. There is still no available vaccine, or other preventative measure, for many viral infections. At the same time, many antivirals are suffering from unfavorable side effect profiles and emerging resistances. Antibody agents in development for viral infections such as HIV and Hepatitis C (HCV) could potentially help in overcoming these issues.
While current HIV and HCV therapies are associated with resistance and toxicity issues, the pressing unmet need lies in disease prevention and cure. Unfortunately, the majority of antibody agents in development are not addressing this issue. Datamonitor forecasts that this factor, combined with their intravenous mode of administration, will seriously restrict their use in these indications.
Antibody agents actually have a bigger role to play in the treatment and post exposure prophylaxis of infections such as rabies, SARS and West Nile virus, for which there are no effective treatments or preventative measures available. Unfortunately, although infected individuals often require immediate protection, the markets for these indications are relatively small and possibly not commercially viable.
Antibody treatments for nosocomial infections
The need for alternative strategies to prevent and treat nosocomial infections has increased owing to a rise in the number of medical procedures and the number of immuno-compromised patients, alongside the growing resistance to conventional antibiotic therapy. Antibody-based products can offer patients fast and immediate protection, and will benefit those unable to mount a sufficient immune response, such as infants, the elderly and immuno-compromised patients.
Ongoing difficulties in identifying suitable targets on bacteria and defining high-risk patient populations are just some of the obstacles that manufacturers face in the development of these agents. Moreover, given antibodies' specificity and cost, their use will be restricted to either prior microbiologic diagnosis of the infection, or a high prevalence rate of the respective pathogen, limiting their use to a small number of patients, in whom the benefits are well defined.
Since MRSA is the most common pathogen causing nosocomial infections, it has formed the most popular target for antibody development. However, despite concerns over resistance, there are still several antibiotics available that can treat multi-drug resistant strains of S. aureus. Because of this, antibodies are likely to have a limited role in the treatment of S. aureus infections in the medium term, but may form effective prophylactic agents.
In the hospital environment, the greater need lies in the shortage of effective treatments for Pseudomonas and fungal infections. The hypervariability of Pseudomonas, however, has made the identification of targets for both antibody and vaccine development extremely difficult. Antifungal antibodies are likely to be more successful commercially, given the persistently high mortality rates associated with candidiasis, and a slowly increasing prevalence of resistance to current antifungals. Severely immuno-compromised patients, who are most at risk from such infections, will benefit most from this immunotherapeutic approach, which augments or replaces the host immune response. As such, anti-candida antibodies would form an attractive adjunct to conventional antifungal therapy.
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