Buprenorphine (BUP) is an FDA-approved medication-assisted therapy (MAT) for that improves outcomes and saves lives in patients with opioid use disorder (OUD). It is available in multiple dosage forms and routes of administration, including daily sublingual (SL) and buccal tablets and films, a monthly subcutaneous (SC) injectable, and a 6-month SC implant; however, these forms leave many patients untreated or undertreated. No oral BUP product is currently available, nor do non-parenteral BUP products exist that are administered less frequently than once per day. NIDA, as well as the federal government, have called for new treatment strategies for OUD to help address the current opioid crisis, including new formulations of existing medications to improve access and compliance and reduce diversion. This proposal is for development of a once-weekly oral BUP dosage form for maintenance therapy for OUD. A long-acting oral BUP may address important limitations of current MATs by providing improved PK with less euphoria than SL, a patient- and provider- preferred route of administration, and an optimal dosing interval for improved patient adherence with the potential for cost-effective direct observed therapy. The oral bioavailability of BUP is lower than SL but may be high enough to achieve therapeutic plasma concentrations if delivered continuously to the upper GI tract. Lyndra has developed an oral gastric residence dosage form that provides at least 7 days of continuous drug delivery. Lyndra's technology has been validated in multiple large animal models and through a clinical partnership with Allergan for Alzheimer's Disease. Lyndra's lead product has been manufactured under cGMP and approved by a stringent regulatory authority for Phase 1 trials which are ongoing. The UG3 phase of this proposal is for two years of pharmacological characterization of continuous gastric delivery of BUP, pharmaceutical development of a clinical candidate dosage form, and submission of an IND for a first-in- human trial.
Aim 1 will evaluate the pharmacology of continuous oral administration of BUP and feasibility of gastric delivery in a well-characterized rhesus monkey model.
In Aim 2, dosage form development and optimization will be pursued to achieve target values for drug load, release kinetics and PK profile. Naloxone (NAL) will be co-encapsulated with BUP in a polymer matrix via hot melt extrusion to deter diversion and misuse.
Aim 2 culminates in the election of a lead formulation for clinical development.
Aim 3 will focus on activities leading to submission of an IND for a first-in-human clinical trial of a once-weekly BUP/NAL dosage form, including process development and scale-up, shelf life studies, clinical manufacturing and GLP toxicity studies. The UH3 phase of the proposal includes a first-in-human clinical trial to evaluate the safety and PK of a once-weekly oral BUP/NAL dosage form in individuals with OUD, as well as a POC single ascending dose and multiple dose study demonstrating safe and consistent delivery of therapeutic BUP plasma concentrations. The gating milestone for advancement to the UH3 phase is acceptance of the IND by the FDA. Lyndra Inc Confidential Page 1
Improved pharmacologic options for medication-assisted therapy (MAT) of opioid use disorder are needed. The goal of the proposed program is the preclinical development and clinical proof of concept of an oral once-weekly therapy for opioid use disorder incorporating buprenorphine and naloxone into a Lyndra dosage form. Successful completion of this grant would yield clinical data demonstrating a novel MAT with improved pharmacokinetics, a patient- and provider- preferred route of administration, and an optimal dosing interval for patient adherence with the potential for cost-effective directly observed therapy.