Summary Basis of Decision for Onglyza ™

3.3.1 Pharmacodynamics

In patients with type 2 diabetes, administration of saxagliptin led to a dose-dependent inhibition response of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1.

The pharmacodynamic data showed that 24 weeks of saxagliptin treatment increased postprandial insulin and C-peptide and decreased post-prandial glucagon concentrations in the treated patients. These changes in insulin and glucagon levels may lead to lower hemoglobin A1c and lower fasting and post-prandial glucose concentrations.

3.3.2 Pharmacokinetics

Absorption

Saxagliptin is absorbed after oral administration, with maximum plasma concentrations attained within 2 hours after dosing. Plasma exposure for saxagliptin and its active metabolite increased in proportion with the saxagliptin dose. No accumulation was observed upon repeated once-daily dosing at any dose up to 400 mg. No dose- and time-dependency was observed in saxagliptin clearance over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg. Food had modest effect on saxagliptin pharmacokinetics. Grapefruit juice however, being a weak inhibitor of CYP3A4 gut wall metabolism may increase plasma levels of saxagliptin.

Results of a bioavailability study conducted with the Onglyza 10 mg tablet indicated that the rate of absorption (C_max) of Onglyza is similar in the presence of food, but the extent of exposure (AUC) is increased approximately 26% following a high-fat meal. A bioequivalence waiver was granted for the 5 mg tablet formulation proposed for market given these tablets are considered to be proportionally formulated to the 10 mg clinical trial tablets.

Distribution

In vitro serum studies demonstrated saxagliptin and its major metabolite BMS-510849 do not bind to plasma proteins. This observation was further confirmed by a mass balance study. This suggests that saxagliptin and its related compounds are not retained in the body to a substantial extent.

Metabolism

Saxagliptin is metabolized primarily by the CYP3A4/5 enzyme to an active metabolite, 5-hydroxy saxagliptin. This active metabolite was also demonstrated to be a reversible, selective, competitive DPP-4 inhibitor. Systemic exposure values for the metabolite were between 2- and 7-times higher than those of saxagliptin. Saxagliptin is metabolized by the CYP3A4/5 enzyme and co-administered drugs that either inhibit or induce the CYP3A4/5 enzyme may increase or decrease the human exposure to saxagliptin.

Excretion

Mass balance and metabolic profiling data showed that saxagliptin is eliminated by both metabolic and renal pathways. Renal excretion is the primary elimination pathway for saxagliptin and its active metabolite. Based on the renal clearance values, saxagliptin renal elimination occurs by a combination of glomerular filtration and net tubular secretion, whereas the active metabolite appears to be only filtered.

Drug-Drug Interactions

Saxagliptin and its active metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4 in vitro. Therefore, saxagliptin and its major metabolite are unlikely to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes.

The pharmacokinetics of saxagliptin and its active metabolite were noted as not meaningfully altered by co-administration of the following drugs: metformin, glyburide, pioglitazone, digoxin, simvastatin, diltiazem, omeprazole, Malox max (aluminum hydroxide + magnesium hydroxide + simethicone) and famotidine. As well, the pharmacokinetics of the co-administered drugs (i.e. metformin, glyburide, pioglitazone, digoxin, simvastatin, diltiazem and ketoconazole) demonstrated to be not meaningfully altered by saxagliptin.

Special Populations

Age, Gender, Race and Obesity
Gender, race and obesity had no clinical relevance on Onglyza pharmacokinetics. Elderly subjects had 23% and 59% higher C_max and AUC values. Given geriatric patients are also more likely to have decreased renal function care should be taken when prescribing Onglyza within this population. The assessment of renal functions prior to administration of Onglyza and periodically thereafter is recommended.

Studies were not performed in the pediatric population. The use in this population is not recommended.

Renal Impairment
Given Onglyza is excreted through renal pathways, renal function plays an important role in the pharmacokinetics of Onglyza. Patients with moderate, severe, or with end-stage renal disease on dialysis had approximately a 2.1-fold higher plasma drug exposure compared to subjects with normal renal function following a single 10 mg dose of Onglyza. Clinical study experience with Onglyza in patients with moderate or severe renal insufficiency is limited; therefore, use of Onglyza in moderate or severe renal impaired patients is not recommended.

Hepatic Impairment
In patients with hepatic impairment (Child-Pugh classes A, B, and C) following administration of a single 10 mg dose of Onglyza, there were higher AUC values for Onglyza with increasing severity of hepatic impairment indicating a reduced capacity to metabolize Onglyza as hepatic function declines. There are limited clinical data in patients with hepatic impairment; therefore, use of Onglyza in moderate to severe hepatic impairment is not recommended. 

Congestive Heart Failure
Due to limited data in patients with congestive heart failure, Onglyza isnot recommended for use in this population.

3.3.3 Clinical Efficacy

Safety and efficacy were supported primarily from two 24-week Phase III, multicentre, randomized, double-blind, placebo-controlled studies, CV181014 and CV181040, and will hereafter be known by their abbrs, STUDY 1 and STUDY 2, respectively. STUDY 1 assessed the use of Onglyza in combination with metformin in type 2 diabetic patients with inadequate glycemic control on metformin alone. STUDY 2 assessed the use of Onglyza in combination with a sulfonylurea in type 2 diabetic patients who had inadequate glycemic control on a sulfonylurea alone. In both studies, treatment with Onglyza 5 mg produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose, and post-prandial glucose compared to the control group.

Add-On Combination Therapy with Metformin
STUDY 1 was a pivotal multicentre, randomized, double-blind, placebo-controlled, Phase III Study evaluating the efficacy and safety of Onglyza in combination with metformin in subjects with type 2 diabetes who had inadequate glycemic control on metformin alone. The clinical study enrolled 743 patients (191 received Onglyza 5 mg) with primary efficacy evaluated by the reduction in HbA1c at 24-weeks. Patients who met entrance criteria were enrolled in a single-blind, two-week, dietary and exercise placebo lead-in period during which patients received metformin at their pre-study dose, up to 2500 mg daily for the duration of the study. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of Onglyza or placebo in addition to their current dose of open-label metformin. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue therapy, added on to placebo or Onglyza plus metformin. Dose titrations of Onglyza and metformin were not allowed in this study. The results demonstrated that in patients already taking metformin, the addition of 5 mg Onglyza reduced the HbA1c baseline mean by -0.83% after 24-weeks of treatment as compared to metformin alone. A long-term extension period followed the 24-week study period for patients who met eligibility. Results from the long-term study showed that the reduction from baseline in HbA1c was upheld at every time-point measured thereafter up to 102-weeks of treatment at which point the placebo-adjusted reduction was -0.72%.

Support for the primary efficacy analysis was further demonstrated through review of the secondary efficacy endpoints which included the following:

• Change from baseline in fasting plasma glucose;
• Proportion of patients achieving a therapeutic glycemic response defined as HbA1c <7.0%;
• Change from baseline in the area under the curve (AUC) from 0 to 180 minutes for post-prandial glucose response to an oral glucose tolerance test.

Add-On Combination Therapy with a Sulfonylurea
STUDY 2 was a pivotal multicentre, randomized, double-blind, placebo-controlled, Phase III Study with 768 patients (253 received Onglyza 5 mg) evaluating the efficacy and safety of Onglyza in combination with a sulfonylurea (glyburide) in patients with type 2 diabetes who have inadequate glycemic control on glyburide alone (up-titrated to near maximal dose). The primary efficacy endpoint was the reduction in HbA1c at 24-weeks. Patients who met entrance criteria were enrolled in a single-blind, 4-week, dietary and exercise lead-in period and placed on glyburide 7.5 mg once daily. Following the lead-in period, eligible patients with HbA1c ≥ 7% to ≤ 10% were randomized to either 2.5 mg or 5 mg of Onglyza plus 7.5 mg glyburide, or placebo plus a 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated in blinded fashion to a total daily dose of 15 mg. Up titration of glyburide was not allowed in patients who received Onglyza 2.5 or 5 mg. Glyburide could be down-titrated in any treatment group once during the 24-week study period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to a final total daily dose of 15 mg during the study period. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to the Onglyza plus glyburide or the placebo plus up-titrated glyburide group. Dose titration of Onglyza was not permitted during the study. The results demonstrated that in patients already taking a sulfonlyurea, the addition of 5 mg Onglyza reduced the HbA1c baseline mean by -0.72% after 24-weeks on treatment, compared to up-titrated glyburide alone. Data for a long-term extension period of 50 weeks from baseline showed that the reduction from baseline in HbA1c was upheld with a placebo-adjusted HbA1c reduction of -0.63%.

The primary efficacy results were also supported by fasting plasma glucose at Weeks 24 and 50, responder analysis (subjects achieving <7% A1c) at Week 24 and 50, postprandial glucose AUC (Week 24), and 120 minute postprandial glucose (Week 24).

3.3.4 Clinical Safety

The clinical safety of Onglyza as an add-on combination therapy with either metformin or a sulfonylurea was primarily evaluated in the two studies (STUDY 1 and STUDY 2) described in the 3.3.4 Clinical Efficacy section. However, a non-pivotal study CV181039 (hereafter known as STUDY 3) was also reviewed for pertinent safety information regarding the combination of Onglyza and metformin, but it is considered non-pivotal given it was conducted in a healthier sample of diabetic patients (i.e. drug naïve). The non-pivotal study provided data on 320 patients taking Onglyza 5 mg plus metformin for up to 50 weeks. Additional safety information was obtained in 323 patients taking Onglyza 10 mg plus metformin.

The safety results from STUDY 1 and STUDY 3 did not reveal any serious concerns or trends inconsistent with the DPP-IV class. There were four deaths among subjects taking Onglyza when combining outcome results from both studies. These deaths were as follows: pulmonary embolism/pulmonary neoplasm (Onglyza 10 mg with metformin), tetanus (Onglyza 5 mg with metformin), sudden death- bundle branch block (Onglyza 10 mg with metformin), and coronary artery disease (Onglyza 10 mg monotherapy).

In both STUDY 1 and STUDY 3, there were slightly more Serious Adverse Events (SAEs) reported in the Onglyza/metformin group compared to the placebo/metformin group. Specifically in STUDY 1, over a two-year period, 9.9% of patients in the Onglyza 5 mg plus metformin group experienced SAEs in comparison to 5.6% of patients in the placebo/metformin group. In addition, STUDY 3 found that there were slightly more Onglyza 5 mg plus metformin patients with SAEs (3.8%) compared to the placebo/metformin patients (3%). However, neither trial showed any particular trends of specific SAEs for Onglyza/metformin subjects.

Although the overall incidence of adverse events (AEs) in the Onglyza/metformin group was quite similar to the placebo/metformin group, infections provided the highest number of AEs for both STUDY 1 (51.8% Onglyza 5 mg plus metformin versus 52.5% placebo/metformin) and STUDY 3 (25.3% Onglyza 5 mg plus metformin versus 27.1% placebo/metformin). The most common AE infections reported included: nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and gastroenteritis.

In STUDY 2, safety findings also showed slightly more adverse events among Onglyza/glyburide patients' compared to the placebo/glyburide patients notably with infections (urinary tract infection and pharyngitis), hypertension, hypoglycaemia, hypertriglyceridemia, and increased creatine kinase. Among patients taking Onglyza/glyburide, there was one death (myocardial infarct) in a patient taking Onglyza 5 mg plus glyburide. The death was attributed to atrioventricular block and cardiogenic shock and considered by the investigator to be unrelated to Onglyza.

There were no obvious trends observed among the SAEs. There were three SAEs considered by the investigator to be related to study treatment. These events, all in Onglyza subjects, were coronary artery disease, hypoglycemia, and thrombocytopenia consistent with a diagnosis of idiopathic thrombocytopenia purpura observed in the clinical program. The relationship of this event to Onglyza is not known.

There were also slightly more discontinuations due to AEs among the Onglyza/glyburide patients as compared to the placebo/glyburide patients, but there were no specific trends observed.