By Anthony Giovinazzo, president and CEO, Cynapsus Therapeutics, Inc.
Finding new formulations for approved drugs continues to produce important therapeutics. In recent years, an increasing number of pharmaceutical development programs have focused on this endeavor.
Depending on the amount of existing human exposure data, reformulating an existing drug has the potential either to eliminate preclinical testing and early clinical trials or cut some of the 10 to15 years and the more than $1 billion it can take to bring a new chemical entity to market. Reformulation also reduces the risk of late-stage product failure from unexpected toxicity or efficacy, and it is breathing new confidence into an industry whose research managers have been trained to “fail fast.”
As Fred Olds recently noted in these pages (“Repurposing And Rescuing Pharmaceutical Drugs”, May 2013), about 80% of drug candidates fail in Phase 2 trials because they don’t reach criteria for efficacy. Reformulating marketed drugs offers entrepreneurs the potential to replenish pipelines with reduced risk and time in drug development. Olds also correctly observed that with reformulation, research starts with defined pharmacokinetic data and a compound already proven safe through possibly millions of human exposures. If an apparent safety issue arises, investigators are more likely to approach it as an anomaly rather than to consider dropping the project.
Reformulating drugs is particularly important in the treatment of central nervous system disorders, cardiovascular disease, metabolic disorders, and cancer. Pathological processes in these conditions are carried out by proteins and processes that differ from their normal counterparts only in a subtle way, such as the level or pattern of expression. Sometimes these subtleties are only discovered by anecdotal observations of patients or by patients reporting unexpected therapeutic benefits, and the reformulating activity depends on improving the formulation or optimizing a treatment regimen. In contrast, molecular target-based screening and rational drug design remain the standard for targeting infectious agents (e.g. HIV and hepatitis C viruses) because the pathogen’s targets are either unique or sufficiently different from their human homologues as to increase the likelihood of developing specific inhibitors.
Support For Drug Reformulation
Reflecting the appeal of drug reformulation, 2012 witnessed several conferences for researchers. A few years ago, no such conferences existed. Additionally, initiatives related to drug reformulation are growing. For example, in spring 2012, eight major drug firms joined the National Center for Advancing Translational Sciences (a division of NIH) to create the Discovering New Therapeutic Uses for Existing Molecules program.
Many drug reformulation projects are supported by the FDA’s intention to encourage innovation without creating duplicate work under the 505(b)(2) provision. Filing a new drug application (NDA) under the 505(b)(2) provision allows a sponsor to rely, in part, on the FDA’s earlier findings of safety and/or effectiveness for the previously approved drug, thereby simplifying the drug development pathway, allowing a less expensive development program and faster access to market.
Drug reformulation holds the promise of delivering new forms of treatment for some of the most intractable CNS disorders, cardiovascular disease, metabolic disorders, and cancer. Reformulated drugs can also provide the tools and understanding needed to develop second-generation drugs. Given the stringent demands of managed care for truly differentiated products, drug reformulation is a beacon of hope to developers of drugs for conditions that have not been improved by molecular target-based design.
In addition to the motivations that have been outlined above, drug reformulation can be instrumental in creating new drug-delivery methods that are better for the patient. For example, a drug that is traditionally available only in an inconvenient and painful injectable form might be reformulated into a sublingual thin-film strip. If pharmacokinetic studies reveal that the latter delivers the drug at a concentration and in a time period similar to that offered by the original form, it can help many patients uncomfortable with the prospect of injection.
Ultimately, a great range of patients with a wide range of conditions may benefit from the class of reformulated drugs that have gone through the regulatory approval process at least once and have an abundance of human experience.