Background Analysis: US FDA Advisory Committee to Review Sanofi’s Zynquista (sotagliflozin) for Type 1 Diabetes – JAN 17, 2019 (EMDAC)

Announcement

The US FDA has scheduled an Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting for Thursday, January 17, 2019 to discuss a new drug application (NDA) for Zynquista (sotagliflozin) oral tablet, sponsored by Sanofi-Aventis U.S., LLC (Sanofi), for the proposed indication of use as adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus. Zynquista is being developed in partnership with Lexicon Pharmaceuticals, Inc.

Indication Background

Description of Indication

Diabetes a disease in which the body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood and urine. When untreated, diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease.

Approximately 5 percent of people with diabetes have type 1 diabetes (T1D). T1D is characterized by complete inability of the pancreas to produce insulin. It is typically diagnosed in children and young adults. Because the pancreas does not make insulin in people with T1D, patients must consistently monitor their glucose levels throughout the day and have insulin therapy through injection with a syringe, an insulin pen, or insulin pump to avoid becoming hyperglycemic (high glucose levels). Disease management also includes following a healthy diet and physical activity.

Product Background

Description of Product

Sotagliflozin (a.k.a. LX4211 and SAR439954) is an investigational drug product that inhibits both sodium-glucose cotransporter type 2 (SGLT2), a transporter responsible for most of the glucose reabsorption by the kidney, and sodium-glucose cotransporter type 1 (SGLT1), a transporter responsible for glucose and galactose absorption in the gastrointestinal tract. In clinical trials, sotagliflozin was administered orally at daily doses of 200 mg and 400 mg as an adjunct to insulin in patients with TD1.

Products by Other Sponsors

Tarius did not find publicly available information about other investigational dual SGLT1/2 inhibitors being developed for the treatment of T1D. However, we note that several SGLT2 inhibitors have been FDA-approved for the treatment of Type 2 Diabetes, some of which are being investigated for potential use in the treatment of T1D, including: Pfizer’s Steglatro (ertugliflozin); Boehringer Ingelheim’s Jardiance (empagliflozin); Janssen’s Invokana (canagliflozin); and AstraZeneca’s Farxiga (dapagliflozin). Investigational SGLT2 inhibitors not yet approved by the FDA include: Astellas Pharma’s ipragliflozin; Avolynt, Inc.’s remogliflozin; Taisho Pharmaceutical’s luseogliflozin; and Chugai, Sanofi-Aventis and Kowa’s tofogliflozin.

Drug Class Labeling

FDA class-wide labeling for SGLT2 inhibitors carry key warnings regarding the following: ketoacidosis (high levels of ketones in the blood that can lead to serious infections); kidney problems; dehydration; increased cholesterol; yeast infection; hypersensitivity; and Fournier’s gangrene (a rare, serious infection of the genital area).

Clinical Trials of Proposed Indication

The sotagliflozin NDA is based on data from the inTandem clinical trial program. The program included three Phase 3 clinical trials. Two of these trials evaluated two doses (200 mg and 400 mg oral daily doses) over 24 weeks in patients with T1D, followed by a 28-week extension. Prior to dosing, the participants’ insulin therapy was optimized over a 6week period. The third clinical trial evaluated only the 400 mg oral daily dose in T1D patients over 24 weeks. Participants’ insulin therapy was not optimized prior to dosing in the third trial.

A summary of the outcomes from these trials are presented below, based on information from company press releases. Comprehensive data and detailed analyses by both Sanofi and the FDA will be presented two days prior to the meeting in meeting materials posted by FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

The InTandem1 Trial

The inTandem1 trial enrolled 793 patients with type 1 diabetes in the US and Canada in a randomized, double-blind, placebo-controlled study of 200 mg and 400 mg once daily doses of sotagliflozin over a 24-week treatment period, followed by a 28-week extension. Insulin therapy was optimized in patients over a 6-week period prior to dosing. The primary efficacy endpoint under evaluation in the trial was the reduction of hemoglobin A1c, or A1C, versus placebo on optimized insulin treatment at 24 weeks, with secondary endpoints that included: percentage of patients achieving A1C levels of less than 7% without experiencing an event of severe hypoglycemia or diabetic ketoacidosis, or DKA; change in meal-time, or bolus, insulin use; body weight; fasting plasma glucose; and patient-reported assessments. Data from the study showed that patients treated with sotagliflozin experienced statistically significant reductions in A1C from baseline of 0.43% for the 200 mg dose (p<0.001) and 0.48% for the 400 mg dose (p<0.001), as compared to a reduction of 0.07% on placebo after 24 weeks of treatment, meeting the study’s primary efficacy endpoint at both dose levels. The A1C benefit achieved with sotagliflozin was sustained, with statistically significant results over the full 52-week duration of the study for both the 200 mg and 400 mg doses. Benefits in all secondary efficacy endpoints were observed in both the 200 mg and 400 mg dose arms compared to placebo, with statistically significant improvements in all secondary efficacy endpoints observed in the 400 mg dose arm and in the percentage of patients achieving A1C levels of less than 7% without any severe hypoglycemia or DKA events and weight loss observed in the 200 mg dose arm. Over the full 52-week treatment period, the incidences of treatment-emergent adverse events in the placebo, 200 mg, and 400 mg dose arms were 80.6%, 81.7%, and 79.8%, respectively; the incidences of serious adverse events were 7.5%, 10.3%, and 11.1%, respectively; and the incidences of discontinuation due to adverse events were 4.1%, 4.9%m\, and 6.5%, respectively. Potential cases of severe hypoglycemia and DKA were reviewed by a blinded adjudication panel, which determined whether such cases met pre-established diagnostic criteria. The number of patients with positively adjudicated severe hypoglycemic events during the full 52-week treatment period was 26 (9.7%), 17 (6.5%), and 17 (6.5%) in the placebo, 200 mg, and 400 mg dose arms, respectively. The number of patients with positively adjudicated DKA events during the full 52-week treatment period was 1 (0.4%), 9 (3.4%), and 11 (4.2%) in the placebo, 200 mg, and 400 mg dose arms, respectively.

The InTandem2 Trial

The inTandem2 trial enrolled 782 patients with type 1 diabetes in Europe and Israel in a randomized, double-blind, placebo-controlled study of 200 mg and 400 mg once daily doses of sotagliflozin over a 24-week treatment period, followed by a 28-week extension. Insulin therapy was optimized in patients over a 6-week period prior to dosing. As with inTandem1, the primary efficacy endpoint under evaluation in the trial was the reduction of A1C versus placebo on optimized insulin treatment at 24 weeks, with secondary endpoints including percentage of patients achieving A1C levels of less than 7% without experiencing a severe hypoglycemia or DKA event, change in bolus insulin use, body weight, fasting plasma glucose, and patient-reported assessments. Data from the study showed that patients treated with sotagliflozin experienced statistically significant reductions in A1C from baseline of 0.39% for the 200 mg dose (p<0.001) and 0.37% for the 400 mg dose (p<0.001), as compared to a reduction of 0.02% on placebo after 24 weeks of treatment, meeting the study’s primary efficacy endpoint at both dose levels. The A1C benefit achieved with sotagliflozin was sustained with statistically significant results over the full 52-week duration of the study for both the 200 mg and 400 mg doses. Statistically significant improvements in all secondary efficacy endpoints were observed in both the 200 mg and 400 mg dose arms compared to placebo. Over the full 52-week treatment period, the incidences of treatment-emergent adverse events in the placebo, 200 mg, and 400 mg dose arms were 61.2%, 68.2%, and 68.8%, respectively; the incidences of serious adverse events were 6.6%, 10.0%, and 8.0%, respectively; and the incidences of discontinuation due to adverse events were 3.5%, 3.8%, and 6.8%, respectively. Potential cases of severe hypoglycemia and DKA were reviewed by a blinded adjudication panel, which determined whether such cases met pre-established diagnostic criteria. The number of patients with positively adjudicated severe hypoglycemic events during the full 52-week treatment period was 13 (5.0%), 13 (5.0%), and 6 (2.3%) in the placebo, 200 mg, and 400 mg dose arms, respectively. The number of patients with positively adjudicated DKA events during the full 52-week treatment period was 0 (0.0%), 6 (2.3%), and 9 (3.4%) in the placebo, 200 mg, and 400 mg dose arms, respectively.

Pooled Continuous Glucose Monitoring in inTandem1 and 2 Trials

Pooled continuous glucose monitoring (CGM) showed that the percentage of time during the initial 24-week treatment period spent inside the target range for CGM glucose (70-180 mg/dL) increased from 52.2% to 57.8% in patients treated with 200 mg of sotagliflozin and from 50.7% to 64.1% in patients treated with 400 mg of sotagliflozin, with no relevant change observed in patients receiving placebo. The differences from placebo were clinically significant for both the 200 mg and 400 mg dose groups (p=0.026 and p<0.001, respectively). The increase in time spent in range by both sotagliflozin dose groups was a result of significantly reduced time spent above 180 mg/dL, while the time spent below 70 mg/dL was not increased. These results translate into an additional 1.41 hours and 3.02 hours that a patient would spend within the 70-180 mg/dL target range in a 24-hour period, for the 200 mg and 400 mg dose groups, respectively.

The InTandem3 Trial

The inTandem3 trial enrolled 1,405 patients with type 1 diabetes in the US and Europe in a randomized, double-blind, placebo-controlled study of a 400 mg once daily dose of sotagliflozin over a 24-week treatment period. Insulin therapy was not optimized in patients, and eligibility criteria included any background insulin therapy. The primary efficacy endpoint under evaluation in the trial was the proportion of patients achieving A1C levels of less than 7% at 24 weeks without experiencing a severe hypoglycemic or DKA event, with secondary endpoints including the change from baseline in A1C, body weight, systolic blood pressure, and bolus insulin use. Data from the study showed statistically significant superiority of sotagliflozin (28.6%) compared to placebo (15.2%) in the proportion of patients achieving A1C levels of less than 7% without experiencing a severe hypoglycemic or DKA event (p<0.001), meeting the study’s primary endpoint. Patients treated with sotagliflozin also experienced statistically significant improvements in all secondary efficacy endpoints compared to placebo. The incidences of treatment-emergent adverse events in the placebo and 400 mg dose arms were 52.5% and 55.1%, respectively; the incidences of serious adverse events were 3.3% and 6.9%, respectively; and the incidences of discontinuation due to adverse events were 2.3% and 6.3%, respectively. Potential cases of severe hypoglycemia and DKA were reviewed by a blinded adjudication panel, which determined whether such cases met pre-established diagnostic criteria. The number of patients with positively adjudicated severe hypoglycemic events during the 24-week treatment period was 17 (2.4%) and 21 (3.0%) in the placebo and 400 mg dose arms, respectively. The number of patients with positively adjudicated DKA events during the 24-week treatment period was 4 (0.6%) and 21 (3.0%) in the placebo and 400 mg dose arms, respectively. Results from the inTandem3 trial were published in the New England Journal of Medicine in September 2017.

Regulatory Background

US Regulatory Background

March 22, 2019 – PDUFA date

May 22, 2018 – NDA (NDA 210934) acceptance date

March 26, 2018 – Sanofi announced the NDA submission of sotagliflozin for TD1. In the same announcement, the company stated they have also submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the same proposed use.

Ex-US Regulatory Background

March 26, 2018 – Sanofi announced an MAA submission of sotagliflozin for TD1. In the same announcement, the company stated they have also submitted a US NDA for the same proposed use.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Sanofi, Lexicon Pharmaceuticals Drug Name: sotagliflozin Drug Class: dual SGLT1/2 inhibitor Indication: type 1 diabetes

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.