Interview with Doug Raines
Founder of Annovation BioPharma, an anesthesiologist at MGH, and the Edward Mallinckrodt Jr. Professor of Anaesthesia in the Field of Pharmacology and Innovationat Harvard Medical School.
Not far from the Ether Dome where William Morton demonstrated the first public surgery using ether as an anesthetic in 1846, Doug Raines has run an NIH-funded laboratory for 25 years, focused on understanding the mechanism of action of anesthetics. We have come a long way in 172 years, but as Doug noted, we still have a long way to go.
Adverse effects from anesthetics can include respiratory and cardiovascular depression which significantly limits the therapeutic window of the drugs. “A lethal dose is not that far from an anesthetic dosage.” Doug explains, “Once we understand the mechanism of anesthetics, we are then able to improve upon it. So, we took a stab at making a better drug.”
Etomidate is a potent anesthetic product intended to be as a safer alternative to the most widely administered IV agent, Propofol. It enhances GABAA receptor function to induce sedation, but it also inhibits the adrenal synthesis of cortisol, which is detrimental in critically ill patients who depend on cortisol for restoring and maintaining homeostasis. The research began by making a soft analog of the existing drug to avoid cortical suppression and creating a rapidly acting agent that can be turned “on and off like a light switch,” Doug said candidly. This was a discovery that could solve an unmet clinical need. The new drug offers precise control of sedation to the anesthetist without the adverse effects of adrenal suppression or depression of breathing and blood pressure.
When Doug first approached the Partners Innovation Fund (PIF), this was merely a concept with limited scientific data and proof of concept to back it up.
“The difficulty for scientists and doctors is that we often have no real business background. We don’t know business plans, or LLC’s versus C-Corp’s, and ask ourselves - why is everything in Delaware? It’s incredibly daunting… but this is an environment that provides you with resources. PIF does lots of the heavy lift.” The Partners Innovation Fund quickly assisted Doug in assembling his team. “PIF gave us credibility, they provided mentoring, and they also helped identify a CEO,” said Doug.
The next task was to attract their first round of funding. Doug and his CEO partner pitched to ten venture capital funds as well as Mass Medical Angels, an organized group of seed investors. Carl Berke, a partner at Partners Innovation Fund, attended most of the meetings to coach the company and indicated to investors that Partners was willing to go beyond licensing and commit its own funds to the effort.
Meanwhile, a Japanese pharmaceutical company had read Doug’s scientific papers and reached out to Partners for a potential license. “When the Japanese pharma first approached us, I was initially very excited,” as this was a validation of the work. We had a choice. We could go down the start-up route or go with licensing. We chose to go the riskier but potentially more rewarding venture route.
In this case, the pharma company balked at the venture option, and the team moved ahead with forming Annovation BioPharma Inc. in 2009. “The institution doesn’t like to separate the baby from the mother,” said Carl Berke. Looking back, Doug states that if he were to do it again, he would make the same decision.
“I’ve learned a lot from the process, and I’ve met a lot of interesting people that I would have never met otherwise.” He continued, “and from a career point of view, it was quite valuable. It’s relatively unusual for a scientific investigator to spin out technology into a commercially viable product. Going through this is a one-in-a-thousand type of thing even if you are in Boston or Silicon Valley.”
By 2011, PIF and Atlas Venture collaborated on a $750,000 seed round to do some initial de-risking before making a more substantial investment. During that period, Doug discovered that their lead drug candidate, MOC-etomidate, was too rapidly metabolized to move into clinical trials. For Doug and his team, there was no such thing as failure, only feedback. Partners’ Carl Berke imparted some sage advice, “All successful projects suffer three near-death experiences.”
“PIF was extremely accommodating, and they were willing to sit at the table to help figure out what went wrong,” Doug said. Annovation had to respond quickly to new options that looked promising. “We went back to the lab, and we started making new compounds based on our previous chemistry experience with this compound. The principle worked but needed some fine tuning, so we designed a dozen new related molecules. In just four months we had the next lead compound in hand which was more potent and with a more optimal half-life.”
All of the initial investors came back for the $7,000,000 Series A funding, with Atlas taking the lead. Atlas also recruited The Medicines Company, a mid-sized pharmaceutical company, as a strategic investor. They invested with an option to acquire the company for a pre-determined price on the condition that they achieved clinical proof of concept. Annovation successfully demonstrated drug safety and efficacy in a human study. In January 2015, the Medicines Company acquired Annovation and continued the development program.
In 2017, The Medicines Company announced a significant reorganization, laid off 90% of staff and terminated all but one of their development programs including Annovation’s effort. The patent rights were returned to Partners and Doug is leading an effort to resume development in a to-be-created new venture with PIF. As Doug likes to say, “It’s important to enjoy the road because if you don’t enjoy the road, there might not be anything at the end of the road.”