A phase III double-blind, extension, placebo-controlled parallel group safety and efficacy trial of BI 10773 (10 and 25mg once daily) and sitagliptin (100mg once daily) given for minimum76 weeks (incl. 24 weeks of preceding trial) as monotherapy or with different back-ground therapies in patients with type 2 diabetes mellitus previously completing trial 1245.19, 1245.20 or 1245.23
BI 10773 is an orally available inhibitor of the sodium-glucose
co-transporter 2 (SGLT-2),
that promotes enhanced glucose excretion in the urine, thereby lowering blood glucose concentrations in patients with type 2 diabetes mellitus (T2DM).
1.1 MEDICAL BACKGROUND
T2DM accounts for 90 to 95% of all cases of diabetes and is an increasingly prevalent disease with an estimated 180 million affected people worldwide. Its incidence is expected to double during the next twenty years. Complications induced by hyperglycaemia are currently the most frequent cause of adult-onset loss of vision, renal failure, and amputation in the industrialized world. Diabetes is also associated with macrovascular complications with a 2- to 5-fold increase in cardiovascular disease risk. The high frequency of complications leads to a significant reduction of life expectancy. SGLT-2 is a member of a larger group of sodium substrate co-transporters, the sodiumglucose co-transport 5 (SLC5) gene family [R05-0939]. Under normoglycemia, glucose is almost completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the kidney is saturated at plasma glucose concentrations higher than approximately 10-11 mmol/L, resulting in increasing glucosuria typically seen in patients with diabetes mellitus. The capacity to reabsorb glucose can be decreased by inhibition of SGLT-2. In humans, BI 10773 very highly selectively blockades glucose transport via SGLT-2 (IC50 1.3 nmol/l), with a 5000-fold selectivity over SGLT-1 (IC50 6278 nM). The efficacy of BI 10773 is expected to be similar to the current oral antidiabetic drugs. Due to its insulin-independent mode of action, BI 10773 has the potential to be combined with other oral antidiabetic drugs and may show additional efficacy in terms of glucose control when used in combination with insulin.
1.2 DRUG PROFILE
Non-clinical assessment of safety. A comprehensive package of safety pharmacology, genetic toxicology, reproductive toxicology and general toxicology studies were conducted in mice, rats, rabbits and dogs to support the chronic administration of BI 10773 to humans. The compound is well tolerated in animals at clinically relevant plasma exposures, while adverse effects were observed at higher exposures. Noteworthy adverse findings at effect levels above the NOAEL (no observed adverse effect level) in general toxicology studies are body weight loss, lower weight gain, dehydratation, nephritis and nephropathy. Human clinical exposure at 25 mg/day is well below the exposure at the NOAEL of 100 mg/kg/day in male rats after 26 weeks of and the NOAEL of 10 mg/kg/day in the dog after 52 weeks of dosing and indicates a 9 to 10 fold therapeutic window to these NOAEL's. These toxicology data suggest BI 10773 can be safely administered to humans at 50 mg/day in long term studies.
BI 10773 predominantly showed linear pharmacokinetics following single oral doses and at steady-state after multiple oral doses. BI 10773 was rapidly absorbed reaching peak levels at approximately 1.5 h and showed a biphasic decline with the terminal elimination half-life ranging from 10 to 19 h.
BI 10773 exposure increases moderately with the extent of renal impairment without need for dose adjustment. The observations from the phase I study in patients with renal impairment indicate a rather low efficacy of BI 10773 in patients with severe renal impairment and end stage renal disease (ESRD).
Administration of BI 10773 tablets with high fat and high calorie meal had no clinically relevant effect on the overall absorption of BI 10773. Therefore, BI 10773 tablets can be administered with or without food.
No pharmacokinetic interactions were observed with metformin, glimepiride, sitagliptin and linagliptin. There was a moderate increase in pioglitazone exposure in one of 2 different pioglitazone interaction studies, so that monitoring of pioglitazone side effects in patients receiving BI 10773 on top of pioglitazone in clinical studies is recommended.
Clinical efficacy and safety
More than 190 healthy volunteers were exposed to BI 10773 (dose range: 0.5 mg to 800 mg per single dose and up to 50 mg in multiple dosing). Approximately 170 Caucasian and Japanese patients with type 2 diabetes were exposed to BI 10773 in phase I studies with a duration of 2-4 weeks and approximately 600 patients with T2DM completed up to 12 weeks of treatment with different doses of BI 10773 in two phase II studies. Increased urinary glucose excretion (UGE) compared with placebo was observed at all doses of BI 10773 in both healthy volunteers and T2DM patients. The twelve week phase II studies demonstrated an HbA1c reduction of up to 0.72 % (placebo subtracted), a fasting plasma glucose reduction of up to 32 mg/dL and a weight loss of approximately 1.5 kg, in both the monotherapy setting and as an add-on to metformin (≥ 1500 mg/day).
Treatment with BI 10773 resulted in a similar percentage of overall Adverse Events (AEs; approximately 44%) and serious AEs (approximately 2%) compared to placebo and/or active comparators. Treatment with BI 10773 showed a trend towards a higher frequency of genital tract infections and symptoms of pollakiuria/polyuria/nocturia, yet was not associated with a higher incidence of urinary tract infections or hypoglycaemia.
In summary, BI 10773 was well tolerated in Phase I and Phase II studies in healthy male volunteers and patients with T2DM. The safety profile of BI 10773 was comparable to placebo and there have been no deaths related to BI 10773. The vast majority of AEs considered related to BI 10773 have been of mild to moderate nature. Given the good safety profile in the preclinical studies of BI 10773 at all dose levels and the good tolerability seen in the clinical study program to date, the available clinical and non-clinical data support the further development of BI 10773 in larger studies with long term treatment durations of 24 weeks and above.
|type of project||clinical studies|
|start of project||2011|
|end of project||2013|
|responsible person||Prof. Bernd Schultes|