Aspire BioScience: Using endocannabinoids to mimic the body’s natural pain relief network

December 1, 2017 By Applied Innovation

The market for managing acute and post-operative pain relief is estimated at $18 billion by 2017 (GlobalData Healthcare, GBI Research) and another $35.1 billion by 2017 (GBI Research) for chronic pain. But there is no painkiller that does it all: is effective, non-addictive, and doesn’t cause undesirable side effects. Currently, two classes of drugs are used to manage postoperative pain: opiates and non-steroidal anti-inflammatory drugs (NSAIDs). Opiates are highly addictive for most people. NSAIDs cannot effectively relieve moderate and severe pain and, used long term, can cause gastrointestinal damage. These drug classes can cause side effects ranging from vomiting, nausea, bleeding, constipation, to respiratory depression.

Aspire Bioscience is developing synthetic, small molecule endocannabinoid-boosting drugs, called FAAH inhibitors, that could offer better and safer relief of pain after surgery, and difficult-to-treat psychiatric conditions like PTSD and addiction.

FAAH inhibitors block fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, an endocannabinoid molecule in the central nervous system (CNS) that regulates response to pain. Aspire BioScience’s FAAH inhibitors were developed by company co-founder Daniele Piomelli, Ph.D., M.D., UCI professor in the departments of anatomy, neurobiology, pharmacology and biological chemistry.

Tapping into the body’s pain-relief network

FAAH inhibitors offer a way to tap into the human endogenous cannabinoid system of receptors ─ so called, because they also respond to tetrahydrocannabinol (THC), the primary active ingredient in cannabis. Dispersed throughout the CNS and the body, this natural network of endocannabinoid receptors helps regulate pain and stress.

Well-studied since the 1960’s, mostly in animal models, the endocannabinoid network also affects learning, appetite, and emotions such as fear and anxiety. Which means that, any analgesic, or painkiller that attempts to modulate this network has to be both global and specific. According to Piomelli, where you interrupt pain signaling in the network matters as pain signals travel to the brain from the periphery of the body where an injury occurs.

Aspire Biosciences has two lead compounds; URB937, a peripheral FAAH inhibitor, targeted for management of acute postoperative pain, and the global FAAH inhibitor URB597, for treatment of post traumatic stress disorder (PTSD) and opioid addiction in the pipeline. It also has some newer URB597 analogs waiting in the wings.

URB937 blocks pain by stimulating cannabinoid signaling in the periphery of the body. In multiple animal studies by blocking anandamide degradation in the periphery but not in the CNS, URB937 activates cannabinoid receptors to relieve pain. URB937 is at the pre-IND stage being developed for acute pain, and investigational new drug (IND) approval is targeted for 2018. The IND program is supported by a Phase II NIH Small Business Technology Transfer (STTR) grant covering the preclinical safety and pharmacology testing. “That is our crown jewel,” said Soren Mogelsvang, Ph.D., Aspire CEO. “This is the one that really got us excited about FAAH inhibitors and led us to contact the UCI tech transfer people. But what is neat about 937 is that it is not global. It is peripherally restricted from the central nervous system and the brain. It turns out that it works much better for pain management.” According to Mogelsvang, peripherally blocking FAAH can manage pain in animal models and URB937 is effective for different types of pain, including neuropathic pain. “Opioids have a lot of unfortunate side effects.” Mogelsvang said. “This is a really strong alternative to opioids.”

AspireBio’s other lead molecule, URB597, developed by Piomelli ten years ago, enters the brain. According to Mogelsvang, URB597 is specific, and the preclinical workup showed no undesirable side effects. As the drug distributes globally throughout the body, it lends itself to treatment of CNS conditions like PTSD, substance-use disorders, anxiety, and depression. Some studies showed that this class of drugs can wean animals off opioids. Evidence, including a study at Yale that showed FAAH inhibitors succeeded at weaning people from cannabis.

Giving FAAH inhibitors another chance

In 2016, a disastrous first-in-human (FIH) trial of a FAAH inhibitor called BIA 10-2474 was conducted in France, in which one volunteer died and four others were hospitalized with neurological damage. Regulatory agencies castigated Bial, a Portuguese drug developer and its contract research organization, for negligence and for withholding preclinical information such as animal deaths. “They had an unidentified toxicity that they were unaware of,” said Mogelsvang. “They didn’t run their trial, their protocol right. They upped their dosage before they understood the toxicities.” The molecule was “very unselective” according to Piomelli, and the drug company and CRO had botched both the preclinical and clinical trial. The upshot is that big pharma put their FAAH inhibitor programs on hold. The FDA cleared FAAH inhibitors later that year, saying that, “10-2474 exhibits a unique toxicity that does not extend to other drugs in the class.”

Diamonds in the Rough

Piomelli’s portfolio of molecules was optioned from UCI Applied Innovation by a group of Vancouver, Canada investors led by Mogelsvang, who incorporated Aspire Bioscience in Boulder, Colorado. “It was a great opportunity for us,” said Mogelsvang. “It was just sitting on the shelf.” The investors were attracted to FAAH inhibitors, according to Mogelsvang, because FAAH inhibitors are again a hot topic; they can address a large market– URB597 already has non diluted grant funding and so much work has been done already in de-risking it. “They are diamonds in the rough,” said Mogelsvang. URB597 received a CTA, the Canadian equivalent of an IND. The preclinical package on it was completed and it was approved for a Phase I trial. “That is a really interesting asset from company point of view because when a company goes from a development stage to a clinical stage, you have a different valuation, you are at different maturity.” said Mogelsvang. “You can have a different dialogue with pharmaceutical companies and potential suitors.”

Because 597 is an older molecule, the patent life is shorter. “We do have some activities to extend the patent life,” Mogelsvang said. “Our thinking is to get into the clinic with 597, then step back and go into the clinic with other FAAH molecules. The newer molecules would be considered new drugs. But if you had a proof of concept with the older version you would feel a lot more comfortable investing money and taking these through that path.” The newer generation of global FAAH inhibitors have patent coverage to 2035.

Aspire operates virtually, using advisors, IP counsel, and contract research organizations (CROs) for its good laboratory practice (GLP) activities. The company is currently raising capital and

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