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Unassigned

New Medicines

ZynquistaType 1 diabetes mellitus (adjunct to insulin)

Information

Zynquista
New molecular entity
Lexicon Pharmaceuticals
Lexicon Pharmaceuticals

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Not approved
Mar 21In its latest annual report, Lexicon does not discuss its plans for European launches. Its anticipated 2021 milestones include an NDA filing for sotagliflozin in heart failure and active efforts to secure strategic alliance for sotagliflozin in heart failure. Sotagliflozin is still listed in its pipeline as wholly owned by Lexicon [36].
Jun 20FDA has confirmed its position in denying two appeals of the complete response letter in November 2019 and March 2020. Lexicon is currently evaluating the feedback provided in the most recent response. No plans described for EU commercialisation in latest annual report [34].
Jan 20EU marketing authorisation transferred to Guidehouse Germany GmbH [35].
Dec 19 US FDA issued Complete Response Letter denying appeal in relation to sotagliflozin to use with insulin for type 1 diabetes. The company plan to appeal the decision to the Center for Drug Evaluation and Research in the US.[32]
Apr 19Approved in EU for adjunct to insulin therapy to improve blood sugar (glycemic) control in adults with type 1 diabetes (T1D) mellitus and a body mass index >= 27 kg/m2, who could not achieve adequate glycemic control despite optimal insulin therapy [30].
Mar 19Rejected by US FDA due to concerns regarding the risk of diabetic ketoacidosis [27]
Mar 19Pooled analysis of data from inTandem1 and inTandem2 trials (n=278) shows combined with optimised insulin in type 1 diabetes, sotagliflozin significantly increased glucose time-in-range without increasing risk of hypoglycaemia, thereby improving glycaemic control [26].
Feb 19Recommended for EU approval by CHMP - the full indication is "as an adjunct to insulin therapy to improve glycaemic control in adults with type 1 diabetes mellitus with a Body Mass Index (BMI) ≥ 27 kg/m2, who have failed to achieve adequate glycaemic control despite optimal insulin therapy.” It is proposed that the treatment with the drug be initiated and supervised by physicians experienced in the treatment of type 1 diabetes mellitus. [25].
Jan 19US FDA advisory panel divided over whether to recommend approval due to concerns regarding risk of diabetic ketoacidosis. A final decision is expected by 22/3/19 [24].
Jun 18Has also been filed in US [22].
Mar 18Filed in EU. The submission contains data from the inTandem clinical trial programme, including three PIII trials [21].
Mar 18Filings for T1DM planned for 2018 [20].
May 17Launches expected to be in 2019 for type 1 diabetes, and in 2021 for type 2 diabetes [16].
Nov 15Sanofi is paying Lexicon $300 million up front and promising as much as $1.4 billion in milestone payments for the rights to sotagliflozin. Sanofi obtains an exclusive worldwide license to develop, manufacture and commercialise sotagliflozin. Lexicon will continue to be responsible for all clinical development activities relating to type 1 diabetes and will retain an exclusive option to co-promote and have a significant role, in collaboration with Sanofi, in the commercialisation of sotagliflozin for treatment of type 1 diabetes in the US [8].
Sep 15PIII in UK and Europe [10].
Mar 15Lexicon appears to be pursuing PIII studies in type 1 diabetes and a trial is planned to start this month [6].
May 14In January 2014, the company said it would be concentrating resources on its late-stage development programmes, including LX 4211, and prepare for commercialisation[5].
Jun 12PIII studies planned to start 1H 2013 [4]

Category

Dual sodium-glucose co-transporter (SGLT) 1 / SGLT2 inhibitor; decreases glucose absorption and increases urinary excretion, thus decreasing blood glucose level
Currently, 3.8 million people in the UK are diagnosed with diabetes. Up to 1 million people have type 2 diabetes that is yet to be diagnosed, so the total is estimated to be 4.7 million people at present. This represents 7% of the UK population (1 in every 15 people) having diabetes (diagnosed and undiagnosed). 10% have type 1 diabetes [28]. Incidence is increasing by about 4% each year, particularly in children under five, with a 5% increase each year in this age group [29].
Type 1 diabetes mellitus (adjunct to insulin)
Oral

Further information

Yes

Trial or other data

Dec 19Lexicom report PIII inTandem2 (NCT02421510) study (n=782) met its primary endpoint. Patients had mean HbA1c reductions from baseline of 0.39% on 200mg once daily (p<0.001) and 0.37% on 400mg once daily (p<0.001) vs. 0.03% on placebo after 24 weeks of treatment [14].
Aug 19A 52-week pooled analysis of the inTandem1 and inTandem2 trials (n=1,575) is published; sotagliflozin was associated with favourable effects on clinical biomarkers suggestive of kidney protection at 52 weeks at a 200mg and 400mg dose, similar to those seen with SGLT2 inhibitors in type 2 diabetes [31].
Jun 18Results of PIII inTandem1 study published in Diabetes Care. [23].
Sep 17Lexicon announces that the New England Journal of Medicine (NEJM) published results of the PIII inTandem3 study. The study met its primary endpoint with statistical significance, demonstrating the superiority of sotagliflozin 400 mg compared to placebo in the proportion of patients with A1C <7.0% at Week 24 and no episode of severe hypoglycemia and no episode of DKA after randomization. The responder rate for patients on sotagliflozin was approximately twice the rate as compared to placebo. The difference compared to placebo for patients treated with sotagliflozin was 13.4% (p<0.001). The outcome on every secondary endpoint achieved statistical significance favoring sotagliflozin over placebo, including change from baseline in A1C, body weight, systolic blood pressure (SBP) in patients with baseline SBP ≥130 mm Hg and bolus insulin. Sotagliflozin significantly reduced A1C compared to placebo after 24 weeks of treatment. The least squares (LS) mean reduction in A1C from baseline was 0.79% and 0.33% for sotagliflozin and placebo, respectively. The difference compared to placebo for patients treated with sotagliflozin was 0.46% (p<0.001). Patients taking sotagliflozin experienced an LS mean reduction from baseline in body weight after 24 weeks of treatment of 2.2 kg compared to a mean body weight gain of 0.8 kg for patients on placebo (p<0.001 for sotagliflozin and placebo). The reduction in LS means compared to placebo for patients treated with sotagliflozin was 3.0 kg (p<0.001). Systolic blood pressure in the subset of type 1 diabetic patients in the study with baseline hypertension (SBP ≥130 mm Hg) was reduced by 9.2 mm Hg at Week 16 when treated with sotagliflozin compared to a reduction of 5.7 mm Hg on placebo (p<0.001 for sotagliflozin and placebo). The reduction in LS means compared to placebo for patients treated with sotagliflozin was 3.5 mm Hg (p=0.002). Sotagliflozin significantly reduced the amount of bolus insulin used compared to placebo after 24 weeks of treatment. The reduction in bolus insulin from baseline was 3.9 IU per day and 1.1 IU per day for sotagliflozin and placebo, respectively (p<0.001 and p=0.02, respectively). The reduction in LS means compared to placebo for patients treated with sotagliflozin was 2.8 IU per day (p<0.001) [19].
Aug 17Lexicon announces additional positive data from the pivotal PIII inTandem2 study, showing that the A1C benefit was sustained over 52 weeks as well as achievement of all secondary endpoints for both sotagliflozin doses. These results of the inTandem2 study, conducted primarily in Europe, replicated results previously reported from the inTandem1 study, conducted in North America. Sotagliflozin was generally well tolerated during the 28-week extension period, with rates of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to AEs that were consistent with rates seen in the initial 24-week treatment period [18].
Jun 17Lexicon Pharmaceuticals announces positive data from another PIII trial. The latest trial enrolled 1,402 patients with type 1 diabetes and assessed the proportion of participants in the sotagliflozin and placebo arms whose A1C levels fell to below 7% over 24 weeks of treatment. Sotagliflozin resulted in a statistically-significant improvement in the proportion of patients who met the A1C target [17].
May 17Analysis of key secondary endpoint of PIII inTandem1 (n=793) found sotagliflozin was linked to bigger reduction from baseline in body weight after 24 weeks [-1.6kg; 200mg; -2.7kg; 400mg dose) vs placebo (+ 0.8 kg (p<0.001 both doses)] [15].
Oct 16Lexicon announces data for the inTandem4 PII trial that found that both doses, 200 mg and 400 mg once daily, had significant reductions in A1C relative to placebo. The mean A1C reductions from baseline were 0.60%, 0.84% and 0.73% for the 75-mg, 200-mg and 400-mg doses, respectively, after 12 weeks of treatment. The mean placebo reduction was 0.35% [13].
Sep 16Lexicon announces topline results from NCT02384941 (inTandem1), reporting that the study met its primary endpoint [11]. The results showed a ´statistically significant and clinically meaningful´ improvement in A1C from baseline after 24-weeks (0.43% for 200 mg, 0,49% for 400 mg), with no increase in severe hypoglycaemia: the study continues with a further 28-week double-blind extension. Topline results from the other two on-going PIII studies (NCT02421510, inTandem2; NCT02531035, inTandem3) are expected late 2016 and in Spring 2017 [12].
Sep 15NCT02531035 is a PIII trial to evaluate the net clinical benefit of sotagliflozin as an adjunct to insulin therapy in patients with TIDM. The proportion of patients with glycosalyted haemaglobin (A1C) < 7% at week 24 will be evaluated as primary endpoint measure of this trial. Recruitment of ~ 1400 patients is underway and the study is due to complete in March 17 [10].
Jul 15NCT02459899 is a PIIb trial to evaluate the efficacy of sotagliflozin in patients with type 1 diabetes mellitus who have inadequate glycaemic control with insulin therapy, compared with placebo. The primary endpoint is change in haemoglobin A1C, assessed at week 12 from baseline. The study is due to complete in July 16 [10].
May 15NCT02421510 is a PIII study intended to demonstrate superiority of either sotagliflozin high dose or low dose versus placebo on glycosylated hemoglobin A1C (A1C) reduction at Week 24 when used as an adjunct in adult patients with type 1 diabetes mellitus (T1D) who have inadequate glycemic control with insulin therapy. The study is expected to complete Sep 16 [10].
Mar 15NCT02384941 is a PIII, randomized, double-blind, placebo-controlled, multicentre study of LX4211 (high and low dose) as adjunct therapy in 750 adult patients with type 1 diabetes mellitus who have inadequate glycaemic control with insulin therapy. It is expected to start Mar 15 and to complete Sep 16 [7].
Jul 12Results of two initial clinical trials published in Clinical Pharmacology & Therapeutics (2012); advance online publication 27 June 2012. doi:10.1038/clpt.2012.58
Jun 12Top-line data from the PIIb study show that patients in the LX4211 treatment arms had mean HbA1C reductions from baseline to week 12 of 0.43, 0.52, 0.79 and 0.95% (for the 75mg od, 200mg od, 200mg bd, 400mg od doses, respectively) vs an HbA1C decrease of 0.09% in the placebo arm (p<0.001 for all treatment arms). LX4211 also produced significant reductions in body weight and blood pressure. Adverse events were generally mild to moderate, and the overall incidence was similar to placebo [4].
Jun 11Phase IIb randomised, double-blind, placebo-controlled study of LX 4211 in about 285 adult patients (18 to 75 years) with type II diabetes who are not adequately controlled on metformin monotherapy. Treatment: LX 4211 75mg od, 200mg od, 200mg bd, 400mg od or placebo. Main outcome is the change from baseline in HbA1c at Week 12. Secondary outcomes will include % of patients achieving HbA1c <7%, and changes in fasting plasma glucose, three-hour glucose tolerance test, weight, blood pressure, and triglycerides. [3]
Jun 11Data from mechanistic study of LX 4211: single dose significantly increased circulating levels of GLP-1 (active and total) and PYY. [2]
Jan 10Positive Phase II, randomised, double-blind, placebo-controlled trial results from a recently completed study of LX 4211 in 36 patients with type II diabetes mellitus. Patients were randomised to receive either placebo (n=12) or LX 4211 n=150 mg) or 300 mg (n=12), once daily for 28 days. Results: Marked decrease in fasting plasma glucose throughout the treatment period in both dose groups, with significant reductions at week four of 53.4 mg/dl (150mg) and 65.9 mg/dl (300mg) vs. 15.1 mg/dl (placebo). 42% of patients in the 300 mg dose group achieved fasting plasma glucose levels of <105 mg/dl at week four of dosing vs. placebo. Average % haemoglobin A1c (HbA1c), was significantly reduced by 1.15 (150 mg)and by 1.25 (300 mg) vs. 0.49 (placebo). (1)

Evidence based evaluations

ZynquistaHeart failure in patients with type 2 diabetes mellitus

Information

Zynquista
Licence extension / variation
Lexicon Pharmaceuticals
Lexicon Pharmaceuticals

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Pre-registration (Filed)
Jul 22FDA accepts NDA for review with a PDUFA date in May 2023. Lexicon is seeking that sotagliflozin be indicated to: reduce the risk of cardiovascular death, hospitalisation for heart failure, and urgent heart failure visit in adults with heart failure, including those with acute or worsening heart failure and to reduce the risk of cardiovascular death, hospitalisation for heart failure, urgent heart failure visit, nonfatal myocardial infarction, and nonfatal stroke in adults with type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors, including a history of heart failure [12].
Feb 22Lexicon announces voluntary withdrawal and planned near-term resubmission of the NDA to the U.S. FDA to correct a technical issue with the submission recently identified by the company [11].
Dec 21Lexicon announces it has submitted a New Drug Application to the U.S. FDA seeking approval for sotagliflozin to reduce the risk of cardiovascular death, hospitalisation for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure irrespective of left ventricular ejection fraction. The FDA has a 60-day filing review period to determine whether the NDA is complete and acceptable for filing [10].
Aug 21Lexicon plans to file in US by the end of 2021 [9].
Jan 21US FDA advises results of PIII SOLOIST-WHF and SCORED trials can support a NDA submission for an indication to reduce risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with T2D with either worsening heart failure or additional risk factors for heart failure [7].
Jul 19 Although disappointed in the position taken by Sanofi, Lexicon is confident in the strength of the data in the type 2 diabetes program and is optimistic about achieving continued success in the balance of the core PIII program, which is expected to complete in the coming months [4].
Jul 19Following disappointing results in two trials in patients with CKD (SOTA-CKD3 and SOTA-CKD4), Sanofi provided notice to Lexicon that it is terminating the collaboration to develop, manufacture, and commercialize Zynquista in all ongoing global type 1 and type 2 diabetes programs. Sanofi has removed sotagliflozin from its pipeline. Lexicon disputes the Sanofi decision, accusing it of breach of contract. Sanofi has acknowledged this and said the ongoing PIII trials will continue with no immediate changes, and it remains committed to working and supporting the investigators and patients enrolled in the studies while next steps are discussed with Lexicon [4,5].
Jul 18Filings planned for 2021 [2].

Category

Dual sodium-glucose co-transporter (SGLT) 1 / SGLT2 inhibitor; decreases glucose absorption and increases urinary excretion, thus decreasing blood glucose level
1-2% of the adult population in developed countries have heart failure, with the prevalence rising to 10% in patients 70 years of age or older. Coronary heart disease and hypertension are the most common causes of heart failure in the UK; diabetes is another cause [1].
Heart failure in patients with type 2 diabetes mellitus
Oral

Trial or other data

Apr 22Results presented at an American College of Cardiology (ACC) meeting in Washington from the SCORED trial of sotagliflozin in T2D and kidney disease patients (NCT03315143) showed sotagliflozin reduced heart failure by 26% and provided a reduction in the risk of heart attack and stroke (as result not previously seen with SGLT2 inhibitors). Follow-up analysis of the trial revealed consistent reductions in major adverse cardiovascular events (MACE) in two subgroups—a 21% reduction in MACE in patients with CVD and a 26% reduction in MACE in those without CVD. [11].
Aug 21Lexicon announce data from analyses from two PIII studies. In SOLOIST (n=1,222) the drug achieved a 33% ARR for the combined endpoint of cardiovascular deat and hospitalisation or urgent office visits for HF, with benefits within 1 month. In SCORED (n=10,584) sotagliflozin achieved a 26% RR on the same composite endpoint with benefits within 3 months [9].
Jun 21PIII SOLOIST-WHF RCT (n=1222) found for every 100 days of follow-up, patients on SGLT2-inhibitor, sotagliflozin, were alive and out of hospital for 3% or 2.9 more days than those on placebo (91.8 vs. 88.9 days); reflecting 2.6-day difference in days dead and 0.3-day difference in days in hospital [8].
Nov 20PIII SOLOIST-WHF RCT (n=1222) reports sotagliflozin resulted in significantly lower composite of total number of deaths from cardiovascular causes and hospitalisations for heart failure vs. placebo (51.0 vs. 76.3; hazard ratio, 0.67; 95% CI, 0.52 to 0.85; P<0.001) [6].
May 18PIII SOLOIST-WHF global trial to study the effect of sotagliflozin on cardiovascular events in patients with type II diabetes post worsening heart failure starts (NCT03521934). 4000 patients will be recruited. Primary outcome is time to first occurrence of either cardiovascular (CV) death or hospitalisation for heart failure (HHF), in the total population and also patients with left ventricular ejection fraction (LVEF) <50%. Collection of these data is due to complete Jan 21 [3].

ZynquistaType 2 diabetes mellitus

Information

Zynquista
Licence extension / variation
Lexicon Pharmaceuticals
Lexicon Pharmaceuticals

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Apr 22Development of sotagliflozin listed in company pipeline for two indications - type 1 diabetes and heart failure. Presume development for type 2 diabetes has been discontinued [16].

Category

Dual sodium-glucose co-transporter (SGLT) 1 / SGLT2 inhibitor; decreases glucose absorption and increases urinary excretion, thus decreasing blood glucose level
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [11].
Type 2 diabetes mellitus
Oral

Further information

Yes

Evidence based evaluations