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The pace of medical innovation
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Although the rate of appearance of new antidiabetic therapies seems to have slowed to a crawl, much slower even than the explosion of new cases of diabetes in America, a rational examination of the recent history of innovations in diabetes therapy suggests otherwise.
Dating from the 1950s, sulfonylureas were long dominant in the field of oral antidiabetic therapies, despite some occasional usage of biguanides before and after the forced withdrawal of phenformin from the US marketplace in 1977. Finally, metformin was approved in 1994 and marketed the following year in the US. However, its use was rather limited until the results of the United Kingdom Prospective Diabetes Study (UKPDS) were published in 1998. These data showed that metformin was highly effective and may have had a unique cardiovascular benefit for overweight or obese patients in the UKPDS study. Perhaps of equal importance to the rapidly expanding use of metformin was its freedom from weight gain and low risk for hypoglycemia. Both of these were viewed as objectionable characteristics of sulfonylureas and their absence therefore made metformin highly desirable when it was tolerated by patients.
Explosion of drug development
However, development of antidiabetic therapies did not stop there. Perhaps because of the explosive growth of the diabetic population, the development of drugs for this epidemic became a major focus for virtually every major pharmaceutical company worldwide.
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A little known observation from 1986 became the origin for the development of an entirely new class of therapeutic compounds for diabetes management, namely the incretin class of agents. In that year, Michael A. Nauck, MD, and Werner Creutzfeld, MD, published their observations that the incretin effect on insulin secretion was greatly reduced in patients with diabetes as compared with patients without diabetes. From this single observation, the next 20 years saw the rapid investigation and exploitation of the newly discovered entero-insular axis for the development of multiple antidiabetic agents, including the DPP-IV inhibitors sitagliptin (Januvia, Merck), vildagliptin (Galvus, Novartis), saxagliptin (Onglyza, Bristol-Myers Squibb), alogliptin (Takeda) and linagliptin (Tradjenta, Boehringer Ingelheim) and the glucagon-like peptide 1 receptor agonists exenatide (Byetta, Amylin) and liraglutide (Victoza, Novo Nordisk).
Considering the safety and regulatory hurdles to be overcome in drug development, especially in the US, as well as the need for assessments of adequate efficacy, this short span of 20 years — one generation — seems to be remarkably brief. When compared with the time required for scientific breakthroughs in other arenas, the history of diabetes drug development is marked by stunning advances being made shortly after the fundamental discovery that initiated the field. Rapid exploitation of scientific discoveries has always characterized the pharmaceutical industry, especially in the diabetes arena. Consider the rapid commercialization of insulin after its discovery for example.
Looking ahead
Will such rapid rates of drug discovery and development be possible today and in the future? I think not.
One has only to consider the fate of dapagliflozin (Bristol-Myers Squibb, AstraZeneca) at the recent FDA Endocrinologic and Metabolic Drugs Advisory Committee hearing on July 19 (Read more on page 4). This agent has been a decade in development. It is a first-in-class therapeutic agent with a novel mechanism of action. It had no toxicity or carcinogenicity findings in the preclinical development phase. Yet, in phase 2 and largely phase 3 studies, “imbalances” were detected in cases of breast and bladder cancers on drug as compared with placebo or other active treatments. Statistical evaluation of the data showed that these imbalances were not statistically significantly different from comparator arms. However, these imbalances together with a single case of probable drug-induced liver injury (Hy’s Law criteria) in the thousands of patients exposed to dapagliflozin came to dominate the advisory committee deliberations. The committee struggled with the interpretation of the imbalances in cancer events and the risk for liver injury. Ultimately, these imbalances became so great as to prevent the members from recommending approval for this new and otherwise potentially attractive agent. Interestingly enough, off-target adverse events such as cancer and liver disease clouded even the discussions of toxicities and adverse effects associated with the mechanism of drug action such as the potentials for genitourinary infections and the important possible long-term complication of metabolic bone disease resulting from chronic calciuria. These rare and difficult to evaluate findings of a possible signal for cancer may precipitate the need for a massive trial or study involving 30,000 to 100,000 patients and may preclude approval until such a study is completed. To evaluate 16 excess cancers and one case of probable liver toxicity may require years of further study, the further exposure of many patients to a large number of study years of drug and the expenditure of millions of additional dollars.
Thus, in the name of assuring zero risk for therapies for diseases with large quantifiable risks if poorly treated, we may never again see another rapid deployment of therapies arising following basic discoveries as we have seen in the incretin therapy class ever again. Worse, the expanding commitments for pre- and post-marketing safety and CV studies are consuming all the available research dollars from each drug, leaving little for interesting and novel research into new diabetes treatment strategies.
Alan J. Garber, MD, PhD, is the Chief Medical Editor of Endocrine Today.
Disclosure: Dr. Garber is a consultant/advisory board member and on the speakers’ bureau for GlaxoSmithKline, Merck, Novo Nordisk and Daiichi Sankyo.