By Stephen Benoit, CEO, Metabolic Solutions Development Company
Imitation may be the sincerest form of flattery, but it may also be contributing to suboptimal treatment outcomes for patients. The current pipeline of drugs to treat diabetes offers a case in point.
According to an April 2013 Cowen and Company report, 86 drugs are in the diabetes pipelines of major pharmaceutical companies worldwide, which makes it the third largest therapeutic area (after CNS and oncology/hematology) for drug development activity. The vast majority of these agents treat only the symptoms of diabetes rather than stopping the progression or preventing the condition altogether. Moreover, there is tremendous redundancy across the industry's development pipelines.
This begs an important question: Of the 86 drugs in the industry's diabetes pipeline, how many agents are truly innovative and how many are simply me-toos? One is hard-pressed not to be concerned that the industry may be substituting imitation for innovation.
For example, at least 8 compounds are being developed that block glucose reabsorption by the kidney (SGLT2 inhibitors)--in addition to the two SGLT2s already on the market. Dapagliflozin (Forxiga) has been approved in Europe; canagliflozin (Invokana) in the United States. While these new agents appear to deliver durable glucose control, as well as clinically significant weight loss, the question becomes: Is there a need for the 4th, 5th, or 6th agent (or more) in this therapeutic class?
Don't get me wrong: Many of the therapeutic agents in the development pipeline may offer promise for patients diagnosed with Type 2 diabetes. However, public and private payers around the globe are demanding that pharma companies be prepared to demonstrate substantive added value when it comes to reimbursement and pricing. As that focus sharpens, it is imperative that we innovate--and not just imitate.
Betting on innovation
Admittedly, I come to this discussion with a subjective viewpoint. In making the decision to join Metabolic Solutions Development Company (MSDC) as CEO in 2010, I made a bet on innovation.
Having been among the original researchers in the field of insulin sensitizers, MSDC's founding scientists long questioned the prevailing hypothesis that these therapeutic agents initiate their glucose-lowering pharmacology through a receptor protein primarily responsible for stimulating lipid uptake and producing fat storage cells. Their vision and persistence has led to an innovative new strategy--targeting a recently identified mitochondrial protein complex, called mTOT, through which a new class of compounds, called mTOT modulators, improve insulin sensitivity and restore beta (b)-cell function. Clinical data have shown that mTOT modulators may represent an innovative new tool for the treatment of diabetes.
If at first you don't succeed...
Based on more than 14 years of clinical use, insulin sensitizers are the only drugs shown to be effective in treating both of the core physiological defects associated with Type 2 diabetes: b-cell dysfunction and insulin resistance.
Moreover, insulin sensitizers may be the only therapeutic approach with the potential to reverse the course of the disease, and, if prescribed toward the "prediabetes" end of the diabetes continuum, they could quite possibly prevent the development of this growing threat to public health.
So why then has the industry concentrated its resources on developing drugs directed at treating symptoms, and not the root defects, involved in diabetes?
As my colleagues pointed out in a 2006 editorial in Expert Opinion on Investigational Drugs, the ability to improve insulin sensitivity with synthetic compounds was uncovered by empirical discoveries in the late 1970s. The promise of these new insulin sensitizers included prevention of diabetes as well as the potential to make a significant impact on the incidence and severity of the life-shortening consequences of the disease.
Unfortunately, the first agent to be approved in this category, troglitazone (Rezulin), produced an idiosyncratic and sometimes fatal liver toxicity that necessitated its removal from the marketplace in 2000. The two compounds that followed, rosiglitazone and pioglitazone (Avandia and Actos, respectively), generated annual sales of more than $7 billion at their peak--notwithstanding having side effect profiles that limited their use (severely so, in the case of rosiglitazone after 2010).
Seeking safer insulin sensitizers, pharma invested tens of millions, if not hundreds of millions, of dollars; however, no new insulin sensitizers have been approved since 1999. In response, the industry retrenched, and a mindset seems to have taken hold wherein imitation appears to have overcome innovation.
The status quo should not stand. Patient outcomes shouldn't remain suboptimal simply due to a misguided understanding of the biochemical mechanism of action of insulin sensitizers. And this is just one example in one drug class. The industry needs to try, and try again.
Raising the bar
Yes, MSDC is a small company, making a big bet. As a venture-backed startup, imitation was not an option. But I strongly believe this approach can--and should--drive the industry as a whole. We can't let "me-toos" become our new benchmark--not when it comes to improving care for patients and the need to fill the gaps in today's diabetes therapeutic armamentarium.
Our mantra must be: "Innovate, don't imitate."
Stephen Benoit is CEO of Metabolic Solutions Development Company, a drug discovery and development company investigating novel molecular targets and developing new therapeutics to treat metabolic diseases associated with age-related mitochondrial dysfunction, especially insulin resistance and Type 2 diabetes.