One of the largest impediments to capital formation in the biopharmaceutical industry is regulatory uncertainty. Our products are regulated by the Food and Drug Administration (FDA). Success in the development of important new drugs requires the development of a close working relationship with the FDA to minimize regulatory uncertainty, and to elucidate additional benefits of a new drug or address unmet needs in addressing serious diseases.

Migraine is a debilitating disease affecting of 36 million Americans, with hallmark symptoms of headache pain, sensitivity to light (photophobia), sensitivity to sound (phonophobia) and nausea/vomiting. Migraine is more prevalent in women, and patients on average suffer three to eight attacks per month, lasting a few hours to a few days, contributing to disability and lost productivity.

FDA has traditionally demanded the use of low sensitivity measures, or endpoints, to determine the effectiveness of new migraine drugs. This lack of sensitivity of endpoints has driven extremely large trials for migraine drugs approved for over two decades. Furthermore, these endpoints have not measured the most significant benefits of new drugs to the patients who take them. Migraine has been a very “tired” area of drug development with very little innovation. Most acute treatments (triptans) are off patent. The presumed large, long and expensive trials have led investors to avoid investing in migraine companies like the plague.

The FDA is difficult to navigate. Its more than 15,000 rank and file include lawyers, physicians, statisticians and scientists have traded more lucrative careers in private industry for challenging but unglamorous public service. Its review divisions are organized like battalions in the Army – each with its own specific mandate. Migraine is regulated by the Division of Neurology Products (DNP).

 At CoLucid, we developed lasmiditan, with the intention of seeking approval for the first new mechanism of action for the acute treatment of migraine in over 25 years. Lasmiditan works within the brain, unlike triptans which work peripherally by constricting blood vessels. Because lasmiditan has no effect on blood vessels, it may provide additional benefit for migraine patients over the age of 40 who have multiple risk factors for cardiovascular disease (about 75% of diagnosed migraine patients).

We worked closely with the FDA to map out new endpoints and clinical trial designs under a process called Special Protocol Assessment (SPA). SPA is an advanced declaration from the FDA that an uncompleted Phase III clinical trial’s design, clinical endpoints, and statistical analyses are acceptable for FDA approval. This is trailblazing work, not just putting the proverbial “lipstick on a pig.”

We held three in-person meetings with DNP and negotiated the two SPAs for our pivotal clinical trials, SAMURAI and SPARTAN. These SPAs codify the use of a more novel, more sensitive and patient-centric endpoint, the Freedom from the Most Bothersome Symptom of Migraine, a novel statistical analysis plan, and the first use of electronic diaries for patient reported outcomes in a large, pivotal clinical trial for the acute treatment of migraine. We also enriched our trials with patients with CV risk. The SPA for SAMURAI resulted in the FDA issuing a new Draft Guidance for the Development of Acute Treatments for Migraine which guides other sponsors to follow the path that CoLucid has blazed.

This path has not been easy. Negotiations with FDA consumed almost 15 months of time, delaying the potential approval of lasmiditan for two years. During this delay period, the company ran out of money and had to secure a loan to make payroll in December of 2014. However, with the regulatory uncertainty removed from the FDA, CoLucid could move forward.

The SAMURAI SPA provided access to capital markets, attracting $95 million in investment in 2015 to complete the SAMURAI trial. Positive data from the SAMURAI clinical trial drove our stock from $8/share to $20/share overnight. We attracted an additional $75 million in investment to fund the SPARTAN clinical trial.

And in a full circle story, our Board approved the sale of CoLucid to Eli Lilly for $46.50/share, valuing the company at over $960 million in March 2017. Removal of regulatory uncertainty can unlock access to capital markets and shareholder value.

Thomas P. Mathers is the former president and chief executive officer of CoLucid Pharmaceuticals.

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