We are developing Gimoti, with promotility and anti-emetic effects, for the relief of symptoms associated with acute and recurrent diabetic gastroparesis in women with diabetes mellitus. Since its approval in 1980, oral and intravenous metoclopramide have been the only products approved in the United States to treat gastroparesis. Gimoti is a novel formulation of metoclopramide offering systemic delivery by intranasal administration.
We are developing the intranasal formulation of metoclopramide to provide our targeted patients with acute or recurrent symptoms of diabetic gastroparesis with a product that can be systemically delivered as an alternative to the oral or intravenous routes of administration. Intranasal delivery is possible because the mucosa of the nasal cavity is single epithelial cell layer which is well vascularized and allows metoclopramide molecules to be transferred directly to the systemic circulation. There is no first pass liver metabolism required prior to onset of action. Since gastroparesis is a disease that blocks or slows the movement of the contents of the stomach to the small intestine, oral drug administration is often compromised. Unlike the oral tablet formulation of metoclopramide, we believe that Gimoti may be tolerated even when patients are experiencing nausea and vomiting. The intranasal formulation may also provide a predictable and consistent means of delivering metoclopramide in patients with delayed gastric emptying and/or frequent vomiting.
We believe that if approved Gimoti could also offer an alternative route of administration for female patients with severe symptoms of diabetic gastroparesis, who typically receive the intravenous formulation of metoclopramide. A nasal spray formulation of metoclopramide could offer an alternative route of administration for female patients with severe symptoms of diabetic gastroparesis receiving the parenteral formulation of metoclopramide. Following hospitalization for intravenous metoclopramide, a nasal spray formulation would also provide a non-oral option for the transition to an outpatient treatment.
Clinical milestones before potential new drug application (NDA) submission
Planned PK trial and timeline to NDA
A comparative exposure pharmacokinetic (PK) trial will be conducted in healthy volunteers to demonstrate the appropriate exposure of Gimoti to the listed drug, Reglan® Tablets. We are preparing to execute and complete the trial during the second half of 2017. Spaulding Clinical Research has been contracted to conduct the trial which is in the latter planning stages. We believe we will be able to submit the new drug application (NDA) for Gimoti by late 2017 or early 2018. After a 505(b)(2) NDA is accepted for review, the timeline for the FDA’s decision on approval is typically 10 months from submission.
Completed Phase 3 clinical trial and recent pre-NDA meetings
In July 2016, we announced results from our Phase 3 clinical trial of Gimoti in female patients with symptoms associated with acute and recurrent diabetic gastroparesis. This was US multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety and population pharmacokinetics, or PK, of Gimoti in adult female subjects with diabetic gastroparesis. Eligible patients received Gimoti or placebo, four times daily for 28 days and completed a daily symptom diary. The primary endpoint was the change in the average symptom severity score prior to starting study drug (baseline) compared to Week 4 on treatment, as measured using a proprietary Patient Reported Outcome, or PRO, instrument.
Although the Phase 3 trial failed to reach its primary endpoint (ITT population was not statistically significant (p=0.881)), Gimoti demonstrated clinically meaningful benefits in patients with moderate to severe symptoms at baseline, which included 105 of the 205 patients (51%) enrolled in the study. This patient population with higher symptom severity at baseline achieved statistically significant clinical benefits with Gimoti compared to those receiving placebo. Importantly, patients receiving Gimoti had clinically and statistically significant improvements in nausea and upper abdominal pain, two of the most debilitating symptoms of gastroparesis, at all four weeks.
Reports of treatment-emergent adverse events were similar in both groups (36% Gimoti and 35% placebo) and most were mild or moderate in severity. Five serious adverse events (SAEs) were reported (3 on Gimoti and 2 on placebo) only one SAE was assessed as related to study drug (anxiety disorder on placebo). The most frequently reported AE was headache (7% on placebo versus 5% on Gimoti). For events of special interest, more reports of nasal irritation (15% versus 5%) and central nervous system effects (14% versus 10%) were reported for patients receiving placebo compared to patients receiving Gimoti. There were no deaths and no reports of tardive dyskinesia.
In pre-NDA meetings with FDA in August 2016 and December 2016, we confirmed various regulatory, chemistry, manufacturing, and control, or CMC, non-clinical and clinical requirements for our potential NDA submission. FDA has agreed that a comparative exposure PK trial is acceptable as a basis for submission of a Gimoti NDA. In March 2017 in a Type A meeting with FDA, we reached agreement on the structure, population and overall design of the comparative exposure PK trial and certain other CMC related items associated with the proposed NDA. After discussing the protocol design with FDA, we agreed with their comments and incorporated the Agency’s recommendations in the final protocol. The comparative exposure PK trial will serve as a portion of the full 505(b)(2) data package which will also include clinical efficacy and safety data developed by us and FDA’s prior findings of safety and efficacy for the listed drug, Reglan Tablets.