An Oral Long-Acting Doxycycline for Onchocerciasis Eradication: Process Improvement for Small Batch Manufacturing

Period of Performance: 08/01/2016 - 07/31/2017

$300K

Phase 1 SBIR

Recipient Firm

Lyndra, Inc.
BOSTON, MA 02210
Principal Investigator

Abstract

An Oral Long-Acting Doxycycline for Onchocerciasis Eradication:Process Improvement for Small Batch ManufacturingProject SummaryPatients with Onchocerciasis (African River Blindness) are currently treated with microfilaricidal therapiessuch as ivermectin. To achieve Onchocerciasis eradication, however, will require addition of a macrofilaricidalto current mass drug administration campaigns. Doxycycline, which has been shown to reduce macrofilarialife expectancy and embryogenesis in phase II clinical trials, is an emerging candidate. The barrier to a massdrug administration strategy, however, is significant patient nonadherence that limits effectiveness andincreases cost. Development of once-weekly long-acting oral regimens would substantially improve theefficacy of Onchocerciasis eradication campaigns. No existing oral delivery system can achieve therapeuticserum levels for small molecules therapeutics beyond 12-24 hours. We have developed prototype oralcapsules based on Lyndra's Gastric Residence technology that can achieve a week or beyond of sustainedtherapeutic doxycycline levels in a pig model. The goal of this grant is to achieve a reproducible, scalablemanufacturing capability that will lead to GMP production of clinical specimens for a phase 1 humanpharmacokinetic (PK) study of a novel long-acting oral formulation of doxycycline. This capability is criticalbefore performing toxicology studies and filing an IND. Process optimization will focus on the following aims:Aim 1: Small-scale hot-melt extrusion of the gastric residence polymer matrix. Uniformity of drugcompounding is critical to dosage form performance (doxycycline release rate, mechanical strength) and tomeeting regulatory requirements. Our efforts will focus on optimizing methods of efficient and homogeneouscompounding of doxycycline into Lyndra's polymeric matrix using a scalable hot-melt extrusion approach.Aim 2: Reproducible and scalable assembly of the multicomponent gastric residence dosage forms. A workplan for sequential linear assembly compatible with GMP production has been developed and custom-builttooling will be engineered and optimized.Aim 3: Quality control assays to evaluate the small batch manufacturing capability. Analytical chemical,mechanical, and geometric validated quality control assays will be developed to provide bridging capabilityfor future improvements.The successful completion of the Phase I aims would lead to a Phase II SBIR for GMP production of clinicalspecimens for a phase 1 human PK study, including assembly automation tooling to facilitate productionscale-up, in-line quality control techniques, long-term stability testing, and IND-enabling toxicology.