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.
New Drug Application (NDA) submission, acceptance & PDUFA date
We submitted our 505(b)(2) NDA to FDA on June 1, 2018 and received formal acceptance of the NDA for review. The Agency stated that our application is sufficiently complete to permit a substantive review and set a target goal date under the Prescription Drug User Fee Act (PDUFA) of April 1, 2019. Additionally, the Agency did not indicate they are planning to hold an advisory committee meeting to discuss the NDA.
The NDA included data from our comparative exposure PK trial as well as clinical efficacy and safety data developed by us and FDA’s prior findings of safety and efficacy for the reference listed drug. In addition, our NDA included a proposal for a risk management strategy and a post-approval safety study. We expect to discuss many details of the submission and post-marketing trial with FDA during the NDA review process.
In a separate FDA communication, the Agency has conditionally accepted the proprietary brand name, Gimoti. This conditional acceptance validates that Gimoti is a proprietary name consistent with FDA’s goal of preventing medication errors and potential harm to the public associated with product misidentification or confusion.
Comparative Exposure Pharmacokinetic (PK) Trial
In 2017, we completed a comparative exposure pharmacokinetic trial for Gimoti. The PK study was an open-label, 4-way crossover that enrolled 108 male and female healthy volunteers who each received one Reglan Tablet dose and three different doses of Gimoti. The study successfully identified two doses of Gimoti based on criteria that included a 90% confidence interval for the ratio of area under the plasma concentration curve (AUC), falling within the equivalence range of 80-125% of the reference listed drug. The maximum observed plasma concentration (Cmax) for Gimoti was slightly lower than the bioequivalence range, which had been previously discussed with FDA as a likely outcome given the different route of administration and prior Gimoti PK study results.
Additionally, data showed the AUC and Cmax increased in a dose related manner across all three strengths tested. Relative to safety, all Gimoti doses were well‑tolerated with no clinically significant adverse events reported following any of the doses.
Discovery of Sex-Based Pharmacokinetic Differences
After additional analysis of the PK data, we discovered that there is a statistically significant difference in exposure between men and women at the same dose of metoclopramide. Specifically, there were statistically significantly lower AUCs found in men as compared to women and that this difference was not explicitly attributable to the subject’s body mass index or weight. Similar sex-based differences were observed in a previous healthy volunteer study, irrespective of the route of administration, nasal, oral or IV. This difference may explain part of the efficacy differences we noted in prior phase 2 and phase 3 trials.
Completed Phase 3 clinical trial
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 (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 also agreed that a comparative exposure PK trial would be 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.
In January 2018, we held an additional pre-NDA meeting with FDA to discuss and clarify the Agency’s expectations of items being prepared for inclusion in the NDA based on the discovery of sex-based pharmacokinetic differences for Gimoti.