We are developing Gimoti, with promotility and anti-emetic effects, for the relief of symptoms associated with acute and recurrent diabetic gastroparesis with diabetes mellitus. Since 1979, metoclopramide tablets and metoclopramide for injection have been the only products approved in the United States to treat gastroparesis. Gimoti is a novel formulation of metoclopramide providing systemic delivery via nasal administration.
We are developing the nasal formulation of metoclopramide to provide the target patient population with acute or recurrent symptoms of diabetic gastroparesis with a product that can be systemically delivered as an alternative to the oral and injection routes of administration. Nasal delivery is possible because the thickness of mucosa of the nasal cavity is a single epithelial cell layer which is well vascularized and allows metoclopramide molecules to be transferred directly to the systemic circulation without ingesting oral tablets. In addition, 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 nasal formulation may also provide an alternative means of delivering metoclopramide in patients with delayed gastric emptying and/or frequent vomiting.
A nasal spray formulation of metoclopramide also has the potential to offer an alternative route of administration for patients receiving the parenteral formulation of metoclopramide. Following hospitalization for treatment with parenteral metoclopramide, a nasal spray formulation could also provide a non-oral option for patients transitioning to outpatient treatment.
New Drug Application (NDA) & Complete Response Letter (CRL)
We submitted our NDA for Gimoti to FDA on June 1, 2018 and received formal acceptance of the NDA for review. The NDA included data from Evoke’s clinical development program for gastroparesis as well as PK data from the comparative bioavailability study. The 505(b)(2) NDA also relies on FDA’s prior findings of safety and efficacy for the reference listed drug, Reglan Tablet.
On April 1, 2019, Evoke received a Complete Response Letter (CRL) from FDA with recommendations for addressing approvability issues in an NDA resubmission related to clinical pharmacology and product quality/device quality. The Agency did not raise any safety concerns.
One approvability issue related to clinical pharmacology was specific to a low Cmax in less than 5% of the total administered Gimoti doses in the comparative bioavailability study. Without the aberrant doses, the analysis shows that the data meet the criteria for bioequivalence for both men and women. The Agency recommended that Evoke conduct a root cause analysis to determine the origin of the variability and provide mitigation strategies to address the issue.
Additionally, FDA requested data from previously planned registration batches of commercial product to be manufactured by the Company. These data will provide additional support for the proposed acceptance criteria of the sprayer device.
FDA did not request additional human clinical trials be completed for resubmission.
New drug Application (NDA) Resubmission
After our type A meeting with FDA on July 25, 2019, we expect to resubmit the New Drug Application for Gimoti in the fourth quarter of 2019. The resubmission will include the root cause analysis as well as previously collected patient use and experience information. We will also provide an analysis of pump performance characteristics of the nasal spray devices used in the comparative bioavailability study and 3-month stability data from commercial scale batches of Gimoti, which were completed in September 2019.
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, there were more reports of nasal irritation (15% versus 5%) and central nervous system effects (14% versus 10%) among patients receiving placebo compared to patients receiving Gimoti. There were no deaths and no reports of tardive dyskinesia.
Comparative Bioavailability Study
In 2017, we completed a comparative bioavailability study with Gimoti and the reference listed drug. 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 internal 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.