Funded Projects

Kinoxis has developed a novel small-molecule lead, KNX100, that reduces the severity of opioid withdrawal symptoms in preclinical animal models of opioid use disorder (OUD). KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile and has undergone testing for efficacy signals in two rodents and two non-human primate species. The proposed activity is to progress the development of KNX100 to treat opioid withdrawal in OUD. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA.

In order to address the opioid crisis, this group has developed a candidate heroin/opioid vaccine that induces antibodies that bind heroin/opioid upon injection and subsequently prevent the drug from crossing the blood-brain barrier and interacting with the brain's µ-opioid receptor. They completed pre-clinical testing of the vaccine candidate in mice and rats and demonstrated that the animals were protected from subcutaneous and intravenous heroin challenge. Ongoing durability studies have demonstrated that antibody titer and protective efficacy were maintained 6 months after the last vaccination. This project proposes to advance the development of the vaccine candidate by conducting a Phase I/IIa human clinical trial, by performing vaccine synthesis, nonclinical studies, and then a clinical trial. The supplemental award will allow for testing the efficacy of fentanyl haptens and of the combination heroin–fentanyl vaccine.

Methadone maintenance therapy has been shown to facilitate recovery and prevent deaths from opioid use disorder (OUD). This proposal is for development of a once-weekly oral methadone for maintenance therapy for OUD. Lyndra has developed an oral gastric residence dosage form that has been demonstrated to provide at least seven days of continuous delivery. A once-weekly oral methadone product could lower a major barrier to treatment for many patients, reduce the stigma and socioeconomic impact of medication-assisted therapy, and increase the capacity of methadone treatment centers by reducing the number of patient visits. This study will perform pharmaceutical development and pharmacological characterization of a once-weekly oral methadone dosage form, leading to the selection of a clinical candidate for a first-in-human trial and submission of an IND. Clinical trials will then be performed to evaluate the safety and pharmacokinetics of the once-weekly oral methadone dosage form in subjects with OUD.

Deaths from opioid overdose continue to rise; from 2015 to 2016, there was a 28 percent increase in the number of fatal overdoses. Currently available pharmacotherapies include MOR agonists (e.g., buprenorphine) and antagonists (e.g., naloxone), all of which suffer from specific and clear limitations. To address the main deficits in these treatments, the researchers will develop and optimize medications with longer duration of action that prevent and reverse the effects of opioids in a manner that is not surmounted by increasing doses of agonist. Their pilot studies in monkeys show that the pseudo irreversible MOR selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses—as well as protects against—respiratory depression by heroin, with a single injection being effective for a week or longer. Bringing a medication like this to marketable fruition could significantly improve the treatment of OUD and save lives by providing insurmountable extended protection after rescue from overdose, including from ultra-potent fentanyl analogs.

Naltrexone (NTX) has proven to be an important, safe, and effective therapy for helping patients overcome opioid use disorders (OUD) and for preventing overdose. Unfortunately, the therapeutic potential of NTX has been blunted by poor adherence. To combat this issue, a system must be developed to deliver NTX for longer durations than currently available and with a more patient-friendly format. To address this problem, we will develop a long-acting and bioabsorbable NTX subcutaneous implant for the treatment of OUD. The proposed research will (a) determine the optimal chemical preparation of NTX inside the implant, (b) optimize the composition and porosity of the drug delivery substrate, and (c) refine the surgical procedure and instrumentation to be used during implantation. Once the safety and efficacy of this novel NTX implant is established, we will conduct the necessary clinical trials. The proposed study is highly relevant to and complementary of other efforts, either in consideration or already deployed to stem the tide of the lingering opioid crisis. If successful, this solution has the potential to enhance health, lengthen life, and reduce illness and disability for those suffering from OUD.