PROJECT SUMMARY Managing the complex risk-benefit profile of opioid therapeutics is a significant challenge for today’s physicians. Prescription opioid analgesics provide excellent pain relief but, at the same time, put patients in danger of severe adverse effects, most notably opioid use disorder (OUD). The current opioid crisis in the United States reflects these risks, as over 2.4 million Americans suffer from OUD, and over 50,000 of these patients die each year. Current clinical guidelines urge physicians to minimize opioid doses, but a narrow therapeutic window limits their ability to accomplish this goal in a meaningful way without losing efficacy. Thus, there is a critical unmet need for new technologies that significantly minimize the opioid doses needed for effective relief from moderate to severe pain. Amalgent Therapeutics, LLC is directly addressing this need by developing AMGT-0220, a fixed-dose combination therapeutic for the treatment of pain that utilizes the dopamine D3 receptor agonist pramipexole as a novel adjuvant to morphine. Our preliminary and animal and human data show that pramipexole significantly increases the analgesic properties of morphine, decreasing the opioid dose needed for pain relief compared to the opioid administered alone. Our published work also demonstrates that pramipexole mitigates the reward seeking behavior associated with morphine and restores opioid analgesia in a neuropathic pain model. Importantly, pramipexole is FDA approved to treat Parkinson’s Disease and Restless Legs Syndrome. Combining two approved drugs, pramipexole and morphine, in our first therapeutic allows the use of the 505(b)2 approval pathway and mitigates significant risks to approval compared to a new molecule. Our core objective is to create a first-in-class fixed-dose combination therapeutic for the treatment of pain that provides pain relief at decreased opioid doses and can replace opioid monotherapy. This therapeutic will significantly minimize the quantity of prescribed opioids, reducing the risk of side effects, including addiction. In Direct to Phase 2, we propose to quantify the mitigating effect of pramipexole on morphine abuse liability and to test the combination in a reinstatement model. This work will drive the development as an opioid sparing combination with decreased risk for developing OUD. We also IND enabling safety studies and develop a manufacturing process ready to supply clinical material. After completing these Aims, we will be well-positioned to submit an IND in preparation for our first clinical trial.

NARRATIVE Amalgent Therapeutics, Inc. is developing AMGT-0220, a novel combination drug with decreased abuse potential compared to current opioid analgesics. The work proposed in this application will support critical non- clinical studies needed to bring this product to market.