Diabetes and Hypertension

November 6, 2017

Kamada issued top-line results from a phase II of Alpha-1 Antitrypsin (AAT) in newly diagnosed type-1 diabetes (T1D) patients. The double-blind, placebo-controlled, multicenter trial enrolled 70 patients, ranging in age from 8 to 25 years old. They were randomized to three treatment groups in a 1:1:1 ratio; placebo and two doses of AAT, 60mg/kg or 120mg/kg. Study duration was 56 weeks and included three treatment periods. During the first 12 weeks, a once-weekly treatment was given, followed by eight weeks of treatment given every two weeks, then a follow-up period of 26 weeks, followed by a once-weekly treatment given for six weeks and a final four-week follow-up period. The key results for the 12 to 18-year-old patient subgroup treated included better preservation of beta-cell function, demonstrated as a smaller decline of the average (± SEM) Area Under the Curve (AUC) of stimulated (MMTT) C-peptide secretion over time (-0.18 ± 0.15nmol/L for AAT 120mg/kg, -0.47 ±0.13 nmol/L for 60mg/kg, and -0.34 ±0.10 nmol/L for the placebo group; p =0.543), suggesting a slower decline in pancreatic function for the 120mg/kg treatment arm. Similar differences were noted for Cmax (defined as maximum or peak serum concentration). There was also lower average HbA1c (AAT 120mg/kg: 6.66±0.32%, AAT 60mg/kg: 7.85±0.45%, placebo: 8.29±0.52%, p=0.052, in addition the p-value of the comparison between AAT 120mg/kg and placebo was p=0.048) and a higher percentage of patients who achieved the clinically meaningful target of HbA1c ≤7% (AAT 120mg/kg: 70%, AAT 60mg/kg: 29%, placebo: 25%, p=0.073).

October 10, 2016

Quantum Genomics issued results of a phase IIa study of QGC001 in patients with hypertension. In the double-blind crossover study, a total of 34 patients with moderate grade I to II hypertension were randomized, and received two 28-day sequences alternating the investigational product QGC001 versus placebo, separated by a 14-day washout (no treatment) period. The data show positive signals on several endpoints, in particular on the primary endpoint of the study, specifically a drop in daytime systolic blood pressure measured as ambulatory pressure in hypertensive patients treated with QGC001 as compared with placebo. The FDA has advised the company on the design of a phase II trial to be conducted in the U.S. to evaluate QGC001 in a targeted population of hypertensive patients. Quantum Genomics plans to submit an IND application for the trial in the first half of 2017. The company is also evaluating the possibility of further clinical trials in Europe and Asia.

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]). 

January 18, 2016

Mesoblast issued results of a phase II trial of mesenchymal precursor cells (MPCs) for the treatment of type 2 diabetes. The randomized, single-blind, placebo-controlled study was conducted across 18 sites in the U.S. and evaluated the effects of a single intravenous infusion of 0.3, 1 or 2 million MPCs/kilogram (kg) or placebo over 12 weeks in 61 patients with a mean diabetes duration of 10 years. A single MPC infusion ranging from 0.3 to 2 million MPCs/kg was safe and well-tolerated, with no treatment-related adverse events, and no serious adverse events over the 12-week study period. There were no anti-human leukocyte antigen antibody immune responses against MPC donor antigens identified in any subject. Following a single intravenous MPC infusion, there was an improvement in glycemic control as evidenced by a decrease at all timepoints after week one in HbA1c in MPC-treated patients compared with an increase in HbA1c in placebo-controlled patients. The highest dose (2 million MPCs/kg) showed the greatest overall reduction in HbA1c, with a peak decrease of 0.4% at eight weeks compared with placebo (p<0.05). In the less well-controlled subjects, as defined by a baseline HbA1c greater than 8%, a 0.6% decrease in HbA1c was seen at eight weeks in the high dose cohort compared with placebo. The clinical target of good glycemic control, HbA1c less than 7%, was achieved by 5/15 (33%) subjects in the MPC 2 million/ kg group v. 0/15 (0%) in the placebo group, (p<0.05).

April 27, 2015

Ultragenyx Pharmaceutical released results of an investigator-sponsored trial of triheptanoin (UX007) for the treatment of movement disorders associated with glucose transporter type-1 deficiency syndrome (Glut1 DS). The open-label, investigator-sponsored trial enrolled eight Glut1 DS patients between seven and 47 years old with non-epileptic paroxysmal manifestations, a neurological symptom characterized by sudden, transient, involuntary movements. Patients completed comprehensive diaries to record all motor and non-motor events as well as a clinical global impression scale during a baseline, treatment, and withdrawal phase, each lasting two months. Six patients completed the study. During the baseline phase without triheptanoin, patients experienced on average 31 paroxysmal manifestations, including 16 dystonic events. During the triheptanoin treatment phase, patients reported a statistically significant 90% reduction in these events to an average of three paroxysmal manifestations, including two dystonic events (p=0.028). In the withdrawal phase, when triheptanoin treatment was discontinued, the rate of paroxysmal manifestations increased substantially to an average of 24 events per patient, including 12 dystonic events (p=0.043). In addition, patients reported an improvement in the clinical global impression scale during the treatment phase with triheptanoin and a worsening after withdrawal. This improvement also was associated with a normalization of induction of brain energy metabolism during visual stimulation in patients receiving triheptanoin as measured by 31P-NMR spectroscopy (p=0.021). Triheptanoin was well-tolerated in all patients. Two patients were considered not compliant for reasons unrelated to safety or tolerability. Ultragenyx intends to initiate a confirmatory randomized double-blind placebo-controlled study of triheptanoin in the Glut1 DS movement disorder phenotype and anticipates discussions with the FDA on final study design details in the second half of 2015.

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.

October 8, 2012

Boehringer Ingelheim and Eli Lilly released pooled analysis of two phase IIb trials of empagliflozin in conjunction with metaformin for the treatment of type 2 diabetes (T2D). These randomized, double blind, placebo-controlled studies enrolled 903 patients. Subjects received 10mg or 25mg of empagliflozin plus metaformin, or placebo for 12 weeks. Results showed both dosages reduced the systolic blood pressure (SBP) and were statistically significant compared to placebo. SBP was reduced by 3.8mmHg and 4.5mmHg in the empagliflozin 10mg and 25mg arms, respectively, versus 1.2mmHg for placebo. Mean SBP at baseline of 131.3mmHg and 132.5mmHg were observed with empagliflozin 10mg and 25mg, respectively, versus 134.3mmHg with placebo. In patients with higher SBP at baseline (>140 mmHg), mean reductions of 17.0mmHg and 13.4mmHg were observed with empagliflozin 10mg and 25mg, respectively, and 10.4mmHg with placebo. The drug was well tolerated. The most frequent adverse events were urinary tract infection and genital infections. Empagliflozen is being investigated in 12 different ongoing multinational studies, with filing planned in the U.S. and Europe in 2013.

Merck issued results for a phase IIb trial of MK-3102 for the treatment of type 2 diabetes. This multi-center, randomized, double blind, placebo-controlled, dose-ranging study enrolled 685 patients with a mean baseline HbA1c of approximately 8%. Subjects received MK-3102 0.25mg, 1mg, 3mg, 10mg or 25mg once-weekly, or placebo, for 12 weeks. Results demonstrated MK-3102 significantly reduced HbA1c compared to placebo (p<0.001) from baseline across all doses. The placebo-adjusted reduction from baseline in HbA1c was 0.71% with MK-3102 25mg; 0.67% with 10mg; 0.49% with 3mg; 0.50% with 1mg; and 0.28% with 0.25mg. The drug was well tolerated. Based on these data, Merck is initiating a phase III study.

August 13, 2012

TWi Biotechnology reported results from a phase II trial of AC-201 for the treatment of type 2 diabetes (T2D). This multinational, dose-ranging study enrolled 259 patients whose T2D was uncontrollable on up to three oral medications. Subjects received AC-201 25mg, 50mg, 75mg or placebo twice daily for 24 weeks. In the intent-to-treat population, AC-201 showed placebo-corrected reductions in HbA1c of 0.20%, 0.29%, and 0.35% (p<0.05), respectively. In the perprotocol population, the placebo-corrected reduction in HbA1c was 0.37%, 0.42%, and 0.49%, respectively. AC-201 was well tolerated up to 75mg. The most frequent adverse event was diarrhea. TWi Biotechnology did not note its plans for AC-201.

July 16, 2012

GlaxoSmithKline issued results from a phase III trial of albiglutide versus sitagliptin for the treatment of renal impairment. This double-blind, active-controlled, parallel-group, multicenter study, Harmony 8, enrolled patients with type 2 diabetes. Subjects received recommended doses of either albiglutide of sitagliptin for 52 weeks. At the 26-week primary endpoint, albiglutide showed clinically and statistically significant reductions in HbA1c from baseline (8.08% for albiglutide and 8.22% for sitagliptin) and superiority versus sitagliptin (reduction of 0.83% vs 0.52%; p<0.0001 for non-inferiority and p=0.0003 for superiority). At the primary endpoint, weight loss was significantly greater in the albiglutide group than the sitagliptin group (-0.79kg vs -0.19kg; p=0.0281). During the full 52-week treatment period, albiglutide was generally well tolerated. The most frequent adverse events were diarrhea (albiglutide 10%, sitagliptin 6.5%), nausea (4.8%, 3.3%) and vomiting (1.6%, 1.2%). With these data now available, GSK intends to commence global regulatory submissions for its investigational glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide for the treatment of type 2 diabetes in early 2013.

July 2, 2012

Lexicon Pharmaceuticals reported results from a phase IIb trial of LX4221 for the treatment of type 2 diabetes. The multi-center, randomized, dose-ranging study enrolled 299 patients who were concurrently being treated with metformin. Subjects received LX4221 75mg once daily (QD), 200mg QD, 200mg twice daily (BID) or 400mg QD, or placebo for 12 weeks. Top-line results showed that patients in the LX4211 treatment arms had mean HbA1C reductions from baseline of 0.43%, 0.52%, 0.79% and 0.95%, respectively (p<0.001 for all treatment arms). In patients randomized to placebo, HbA1C decreased by 0.09%. LX4211 treatment also produced significant reductions in body weight and blood pressure. The drug was well-tolerated and safe. Adverse events were similar to placebo. Based on these data, Lexicon plans to initiate a phase III trial of LX4221 in the first half of 2013.

June 18, 2012

Bristol-Myers Squibb and AstraZeneca reported results from a phase III trial of dapagliflozin for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled, parallel group study enrolled 447 adult patients with inadequate glycemic control who were on a stable dose of sitagliptin. Subjects in stratum one received dapagliflozin 10mg or placebo added to sitagliptin 100mg/d. Patients in stratum two received dapagliflozin 10mg or placebo added to sitagliptin 100mg/d plus metformin ≥1500mg/d. Both stratums were conducted for 24 weeks, plus a 24-week blinded extension. Subjects (n≡223) receiving dapagliflozin 10mg plus sitagliptin with or without metformin demonstrated significantly greater improvements in glycemic control at 24 weeks compared to subjects (n≡224) receiving placebo plus sitagliptin with or without metformin, with a change in baseline in HbA1c of -0.48% (p-value <0.0001, Last Observation Carried Forward [LOCF]). Significant reductions in body weight were observed with dapagliflozin compared to placebo in the entire treatment cohort (-1.89kg, LOCF), stratum one (-1.85kg, LOCF) and stratum two (-1.87kg, LOCF), and were sustained out to 48 weeks. The drug was well tolerated. The most common adverse events were nasopharyngitis, back pain, urinary tract infection, pharyngitis, arthralgia and headache. BMS and AstraZeneca are currently waiting for the European Commission to review dapagliflozin.

August 20, 2007

Oramed issued positive results from a phase Ia trial of their oral insulin gel capsule for the treatment of diabetes. This single blind, open-label trial enrolled a small group of healthy subjects in Israel. Subjects received several different dosing regimens and examined for changes in insulin, glucose and C-peptide plasma concentrations over time. With the exception of the anticipated insulin related hypoglycemic side effects, no significant adverse effects were noted after administration of the insulin gel capsule. Based on the good safety profile and positive pharmacokinetic and pharmacologic outcomes, Oramed plans to initiate additional phase I trials later in 2007.

August 22, 2005

Cardiome Pharma announced negative results of a phase II trial, dubbed "OPT-CHF," of oxypurinol for the treatment of congestive heart failure (CHF). Trial data failed to meet the primary composite endpoint relative to placebo (p= 0.357); this endpoint included improvement in NYHA functional class, rate of hospitalization or emergency intervention for worsening CHF, need for additional interventional treatment, withdrawal of drug treatment due to refractory disease and cardiovascular death. Trial data also failed to demonstrate drug efficacy in secondary endpoints, including Minnesota CHF Quality of Life assessment and time to acute clinical events. This randomized, double-blind, placebo-controlled study enrolled 405 CHF patients across 53 sites in the US and Canada, who received 600 mg oral oxypurinol or placebo daily for 24 weeks.