Diabetes Mellitus, Type 1

August 21, 2017

Lexicon Pharmaceuticals released results of a phase III study of sotagliflozin for type 1 diabetes. The study, known as inTandem2, was a double-blind, placebo-controlled, multicenter study of 782 patients in Europe and Israel with type 1 diabetes on insulin pump or multiple daily injection therapy who had an A1C level entering the study between 7.0% and 11.0%. The three-arm study evaluated two doses of sotagliflozin, 200mg and 400mg, each taken once daily before the first meal of the day, against placebo. Prior to randomization, insulin was optimized for all patients over a six-week period, with the objective of improving glycemic control using insulin alone. After completion of this optimization period, patients were maintained on optimized insulin and randomized to one of two doses of sotagliflozin or placebo, and their baseline, post-optimization A1C was measured. The mean baseline A1C levels after the six-week optimization period were 7.79%, 7.74% and 7.71% for patients randomized to the placebo, 200mg and 400mg arms, respectively. The primary endpoint of the study was a change in A1C from baseline after a 24-week period of treatment. The trial had a double-blind long-term extension of 28 weeks, with a total treatment duration of 52 weeks. There were 258 patients in the placebo arm, 261 patients in the 200mg dose arm and 263 patients in the 400mg dose arm. The overall mean placebo-adjusted A1C reduction at week 24 was 0.37% in the 200mg dose arm (p<0.001) and 0.35% in the 400mg dose arm (p<0.001). The A1C benefit achieved with sotagliflozin was sustained with statistically-significant results over the full 52-week duration of the study for both the 200mg and 400mg doses. Sotagliflozin was generally well-tolerated during the study. Across all three dose arms (placebo, 200mg, 400mg), over the full 52 weeks of treatment, the incidences of AEs were 61.2%, 68.2% and 68.8%, respectively; the incidences of SAEs were 6.6%, 10.0% and 8.0%, respectively; and discontinuations due to AEs were 3.5%, 3.8% and 6.8%, respectively. There were two deaths in the study in the placebo arm and no deaths in either sotagliflozin arm.

June 19, 2017

Lexicon Pharmaceuticals reported results of two phase III sotagliflozin studies for type 1 diabetes. Collectively, 24-week data from the two pivotal inTandem1 and inTandem2 studies for sotagliflozin in patients with type 1 diabetes demonstrated the following: Sotagliflozin 200mg and 400mg on top of optimized insulin significantly reduced A1C compared to placebo (p<0.001 in both studies). Sotagliflozin was generally well-tolerated. In both studies, there was a low rate of severe hypoglycemia, which occurred less frequently on sotagliflozin than placebo in three of four arms across the two studies. In both studies, there was a low diabetic ketoacidosis (DKA) rate (0.4% to 3.1% over 24 weeks) that was higher for patients on insulin pump versus multiple dose injections (MDI).

June 27, 2016

Novo Nordisk is reporting that new phase IIIa findings showed that faster-acting insulin aspart demonstrated a statistically significant reduction in HbA1c in type 1 diabetes, compared with NovoLog (insulin aspart [rDNA origin] injection), a comparable HbA1c reduction in type 2 diabetes versus NovoLog and improved post-meal or postprandial glucose (PPG) control in type 1 and type 2 diabetes. Results from the onset 1 and onset 2 treat-to-target trials comparing faster-acting insulin aspart with NovoLog were presented at the 76th annual Scientific Sessions of the American Diabetes Association (ADA) in New Orleans, LA. In onset 1, after 26 weeks of randomised therapy, faster-acting insulin aspart showed statistically significantly greater HbA1c reduction versus NovoLog in adults with type 1 diabetes when dosed at mealtime ([95% confidence interval (CI)] -0.15 [-0.23; -0.07]). Faster-acting insulin aspart also showed comparable HbA1c reduction when dosed 20 minutes after starting a meal, compared with NovoLog dosed at mealtime ([95% CI] 0.04 [-0.04; 0.12]).[1] Trial results for onset 1 also showed superior reduction in 2-hour PPG increment ([95% CI] -0.67 [-1.29; -0.04] mmol/L) versus NovoLog. The change in 1-hour PPG increment, a secondary supportive endpoint, was also reduced ([95% CI] -1.18 [-1.65; -0.71] mmol/L). In onset 2, faster-acting insulin aspart demonstrated non-inferiority in HbA1c reduction compared with NovoLog® ([95% CI] -0.02 [-0.15; 0.10]) in adults with type 2 diabetes. Trial results could not confirm a statistically significant reduction in 2-hour PPG increment ([95% CI] -0.36 [-0.81; 0.08] mmol/L). However, a statistically significant reduction in 1-hour PPG increment was shown with faster-acting insulin aspart ([95% CI] -0.59 [-1.09; -0.09] mmol/L)[2] which was a secondary supportive endpoint.

April 18, 2016

Novo Nordisk reported results of a phase IIIa trial of Saxenda for obesity and pre-diabetes. SCALE was a randomized, double-blind, placebo-controlled, multinational trial in adults without diabetes who have obesity, and adults without diabetes who are overweight with weight-related comorbidities. At week 160, individuals treated (n=2,254 adults) with Saxenda had lost more weight (6.1%) than those treated with placebo (1.9%) (estimated treatment difference [ETD] -4.3% [95% CI, -4.9; -3.7], P<0.0001). In addition, treatment with Saxenda achieved results beyond weight loss, including improvements in some cardiometabolic risk factors such as blood pressure and cholesterol. At week 160, participants randomized to treatment with Saxenda experienced a greater reduction in systolic blood pressure compared with placebo (ETD -2.8 mmHg [-3.8; -1.8], P<0.0001). Those treated with Saxenda also experienced greater improvements in triglycerides (ETD -6% [-9; -3], P=0.0003) and total cholesterol levels (ETD -2% [-3; 0], P=0.03) compared with placebo. Additionally, people treated with Saxenda showed a greater reduction in mean waist circumference (ETD -3.5 cm/-1.4 in [-4.2 cm/-1.7 in; -2.8 cm/-1.1 in]). 

September 15, 2014

Eli Lilly issued results of phase III trials of glargine (Lantus) for type 1 diabetes. IMAGINE-1 was a 78-week, open-label study designed to compare BIL (n=295) with insulin glargine (n=160) in combination with mealtime insulin in patients with type 1 diabetes. IMAGINE-3 was a 52-week, double-blind, randomized study designed to compare BIL (n=664) with insulin glargine (n=450) in combination with mealtime insulin in patients with type 1 diabetes. Significantly more patients taking BIL versus those taking insulin glargine achieved an HbA1c of less than 7%. Both trials also showed the rate of nocturnal hypoglycemia was significantly lower in patients taking BIL than in those taking insulin glargine. In both trials there was a statistically significant increase in the rate of total hypoglycemia for patients taking BIL compared with those taking insulin glargine due to a higher rate of daytime hypoglycemic events. In the open-label IMAGINE-1 trial, patients taking BIL reported a statistically significant higher rate of severe hypoglycemic events. However, in the larger, blinded IMAGINE-3 trial the rate of severe hypoglycemic events for treatment with BIL was numerically lower compared with insulin glargine, but was not statistically significant. Lilly is on track to file a submission with regulators by the end of the Q1 2015.

April 28, 2014

Lexicon Pharmaceuticals reported results of a phase II study of LX4211 in type 1 diabetes. In this multicenter study, 33 patients with poorly controlled type 1 diabetes on either an insulin pump or multiple insulin injection therapy were randomized 1:1 to receive either placebo or a 400mg dose of LX4211 orally once per day before breakfast for four weeks. The placebo-controlled, double-blind, 28-day study reduced the total daily mealtime bolus insulin dose by 32% compared to 6% for placebo (p=0.007), while significantly improving glycemic control with a mean HbA1c reduction of 0.55% in the LX4211-treated group compared to a reduction of only 0.06% with placebo (p=0.002). This improvement was accompanied by significant improvement in the time spent in a glucose range of 70mg/dl-180mg/dl, a significant reduction in time in hyperglycemic range, and no increase in hypoglycemia. Multiple measures indicated that LX4211 treatment resulted in reduced variability in blood glucose levels. Overall, LX4211 was well-tolerated with no discontinuations of study medication due to adverse events. These results demonstrate the effectiveness of LX4211 as an adjunct to insulin in type 1 diabetes in a longerterm phase III program.

April 21, 2014

Adocia released results of a phase IIa trial of BioChaperone Lispro in comparison to Eli Lilly’s Humalog commercial insulin for type 1 diabetes. In this double-blind, crossover study, the pharmacokinetic and pharmacodynamic characteristics of BioChaperone Lispro were compared to those of Humalog in 36 patients who received single 0.2U/kg doses of BioChaperone Lispro and Humalog under automated euglycemic clamp conditions (ClampArt, target blood glucose 100mg/dL, clamp duration six hours post-dosing). BioChaperone Lispro had a significantly faster rate of absorption than Humalog with an increase in the early insulin exposure of 170% (primary endpoint, AUCLispro_0-30min 23.7 ± 11.4 v. 9.5 ± 6.2 hmU/L; p<0.0001). The time to peak insulin concentration was reduced by more than 35% (Tmax 42 ± 11 v. 69 ± 22 min; p<0.0001). BioChaperone Lispro was cleared from the blood significantly earlier than Humalog, reflected in the time to half-maximum insulin levels after Tmax (late T 50% max = 141 ± 43 v. 173 ± 41 min, p<0.0001). The acceleration of insulin Lispro absorption translated into a significant acceleration of insulin action. The metabolic effect is triggered significantly earlier for BioChaperone Lispro than for Humalog with 30% faster onset of action (T onset = 23.1 ± 7.0 v. 34.4 ± 15.3 min; p<0.0001). The early metabolic effect is increased by 69% relative to Humalog during the first hour after administration (AUCGIR_0-1h = 218 ± 88 v. 129 ± 63mg/kg; p<0.0001). The time to reach the maximal observed hypoglycemic effect is significantly shorter relative to Humalog (TGIR_max = 99 ± 42 v. 133 ± 45 min; p=0.0002). Another clinical trial is planned to start in Germany.

March 10, 2014

Adocia released results of a formulation combining insulin analog Glargine (Lantus, Sanofi) and insulin analog Lispro (Humalog, Eli Lilly), using Adocia’s BioChaperone technology. The trial was a double-blind, two-way crossover study that enrolled 20 patients with type 1 diabetes under euglycemic clamp conditions. All patients were treated with BioChaperone Combo and Humalog Mix 25 at the same dose of 0.8IU/kg. The composition of BioChaperone Combo is based on 75/25 basal prandial ratio as in Humalog Mix 25. Pharmacokinetic (PK) and pharmacodynamic (PD) measurements were taken as patients were monitored for 30 hours after administration. BioChaperone Combo had a faster than 30% onset of action as compared to Humalog Mix. Almost all patients treated with BioChaperone Combo experienced a minimal duration of action in excess of 30 hours (end of monitoring). Both formulations of insulins (BioChaperone Combo and Humalog Mix) were well-tolerated.

September 2, 2013

MannKind issued results of a phase III clinical trial of AFREZZA (insulin human [rDNA origin]) Inhalation Powder in patients with type 1 diabetes, administered using MannKind’s (Gen2) inhaler. The randomized, open-label study involved 518 patients with type 1 diabetes on basal/bolus insulin therapy studied at sites in the U.S., Russia, Ukraine and Brazil. After a four-week run-in period to optimize their basal insulin, patients entered a 24-week treatment period. The treatment period consisted of 12 weeks of prandial insulin optimization with continued basal titration followed by a 12-week period during which subjects maintained stable doses of insulin (prandial and basal). A1c levels decreased comparably in the AFREZZA-Gen2 group (-0.21%) and the insulin aspart group (-0.40%). The 95% confidence interval (0.02% to 0.36%) of the between-group difference did not exceed the predetermined threshold of 0.40%, thereby establishing non-inferiority between AFREZZA-Gen2 and insulin aspart, which was the primary endpoint of the study.

May 27, 2013

Rhythm released results from a phase Ib trial of RM-131 for diabetic gastroparesis in type 1 diabetes. This randomized, double-blind, placebo-controlled, single-dose, two-period crossover study enrolled 10 patients with type 1 diabetes, a history and symptoms of diabetic gastroparesis and documentation of delayed gastric emptying. Subjects received a single dose of RM-131 100mcg. Results showed RM-131 significantly accelerates early gastric emptying and reduces upper gastrointestinal (GI) symptoms in type 1 diabetic patients. The median gastric emptying half-time was reduced by ~55%. RM-131 was generally well tolerated, with no serious adverse events. The FDA has granted Fast Track review status to RM-131 for the treatment of diabetic gastroparesis.

January 9, 2012

Osiris released interim results from a phase II trial of Prochymal, a formulation of adult mesenchymal stem cells, for the treatment of type I diabetes. This double-blind, placebo-controlled trial enrolled 63 subjects who received Prochymal (from unrelated adult donors) or placebo, both with standard of care. The primary endpoint was measurement of C-peptide produced during a Mixed Meal Tolerance Test. The interim assessment at one year showed no significant differences in the rates of disease progression, as measured by stimulated C-peptide levels. There was a trend towards fewer hypoglycemic events for subjects treated with Prochymal as compared to controls. Systemic infusions of Prochymal were well-tolerated and there were no differences in adverse events between the Prochymal and placebo groups and no reactions to the infusions.

April 5, 2010

Living Cell Technologies issued positive interim results from a phase II trial of DiabeCell for the treatment of type I diabetes. This open label trial planned to enroll 8 subjects with difficult to control or unstable type I diabetes. Data are from the first four subjects who received 10,000 islet equivalents/kg body weight (IEQ/kg) DiabeCell encapsulated porcine islets implanted into the abdomen via a laparoscopic procedure. Data showed significantly improved control of blood glucose and two subjects eliminated or reduced life-threatening episodes of hypoglycaemic unawareness. In the first subject who was treated and followed for 24 weeks after implant, daily insulin dose was reduced by 25% and hypoglycaemic unawareness was completely eliminated. The next phase of this trial is currently underway in New Zealand.

September 22, 2008

MannKind issued positive results from a phase III trial of their Technosphere Insulin System for the treatment of type I diabetes. This study (009) enrolled 565 subjects with type I diabetes in the United States, Europe and Latin America. The subjects received prandial inhalations of Technosphere Insulin (the TI group) or prandial subcutaneous injections of insulin aspart. Both groups also received daily subcutaneous injections of basal insulin (insulin glargine). The primary objective was to compare the efficacy, as expressed by the change in A1C levels, between the two treatment arms. Over the 52-week study duration, A1C levels decreased comparably in the two treatment groups, with a between-group difference of -0.24%, thus establishing non-inferiority. Comparable A1C target levels were also reached between the two treatment groups. Secondary endpoints were also reached. Fasting blood glucose (FBG) levels decreased significantly in the TI group compared to the FBG levels observed in the insulin aspart group (p<0.01). In the TI arm, mean FBG had decreased by 48.8 mg/dL at the 52-week time period compared to a decrease of 20.2 mg/dL in the comparator group. There was also a significant difference in weight loss versus weight gain. Subjects receiving TI lost an average of 4.3 pounds over the 52-week treatment period compared to the average gain of 3.0 pounds in the insulin aspart group (p=0.02). The TI group also exhibited significantly lower mean postprandial blood glucose levels (p<0.01) and significantly fewer hypoglycemic events (p<0.02). Based on positive phase III results, MannKind plans to submit an NDA by late 2008 or early 2009.

January 28, 2008

Diamyd Medical issued positive long-term results from a phase IIb trial of Diamyd for the treatment of type I diabetes. This randomized study enrolled seventy pediatric and adolescent subjects in Sweden. The subjects received two single injections of Diamyd or placebo. The primary endpoint was preservation of beta cell function as measured by C-peptide. Thirty months after the first injection, preservation of insulin was significantly higher in subjects receiving Diamyd, both in the fasting state and after meal stimulation, compared with placebo-treated subjects. Diamyd also increased GAD antibody levels at fifteen and twenty one months post-injection. Based on the data, phase III trials are planned.

Indevus reported results from a phase III trial of Nebido for the treatment of hypogonadism. This open label trial enrolled one hundred and thirty male subjects with hypogonadism. The subjects received an initial injection of 750 mg of Nebido, followed four weeks later by an additional 750 mg loading injection and then 750 mg injections every ten weeks thereafter. The primary endpoint was responder analysis, defined as a one who, during steady state, had an average concentration of serum total testosterone (Cavg) within the normal range (300 to 1000 ng/dL). The primary response endpoint was met if at least 75% of patients achieved a Cavg within this normal range. In addition, maximum testosterone (Cmax) levels were evaluated. This endpoint was reached if no subjects exceeded a testosterone concentration of 2500 ng/dL, no more than 5% exceeded a concentration of 1800 ng/dL, and no more than 15% of exceeded a concentration of 1500 ng/dL. Of the one hundred and seventeen subjects who completed the study, 94% had Cavg levels within the normal range. None of these subjects exceeded a testosterone level of either 2500 ng/dL or 1800 ng/dL, and nine (7.7%) had a peak level exceeding 1500 ng/dL. Steady state testosterone pharmacokinetics were achieved within weeks under the new regimen, whereas the 1000 mg regimen reached steady state pharmacokinetics after several months. An NDA is currently under review by the FDA for a 1,000 mg dose of Nebido. Based on the results, Indevus intends to ask for approval of this 750 mg regimen rather than the higher treatment schedule.

April 24, 2006

MannKind announced results of a phase II trial of Technosphere insulin for the treatment of Type 1 diabetes. Results from the study indicated that the drug was non-inferior to an approved regimen of insulin injection, with both treatments significantly improving HbA1c scores from baseline (0.83% vs. 0.99%, respectively). The mean increase in post-prandial glucose was also non-inferior for Technosphere insulin, and trended towards superiority (18.7 mg/dl vs. 46.8 mg/dl; p=0.09); total post-prandial glucose fluctuation was considerably lower for the inhaled drug (+96.7 mg/dl to -136.2 mg/dl from baseline, total 232.9 mg/dl; vs. +400.6 mg/dl to -182.2 mg/dl, total 582.8 mg/dl). At 12 weeks, there was a significant 1.3 kg difference in mean body weight from baseline (-0.41 kg vs. +0.89 kg; p=0.0018). This controlled study enrolled 110 patients, who received either inhaled Technosphere insulin or an approved regimen of NovoLog (insulin aspart) plus Lantus (insulin glargine) via injection for 12 weeks.

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