Summary Basis of Decision for Nesina

Clinical Pharmacology

Alogliptin (the medicinal ingredient of Nesina) is a potent, reversible and selective inhibitor of dipeptidyl peptidase 4 (DPP-4) that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus (T2DM).

Alogliptin exposure increased two to four times in moderately renal impaired patients and severe renally impaired/End Stage Renal Disease (ESRD) or dialysis patients. Consequently, lower alogliptin starting dose of 12.5 mg once daily is recommended in patients with moderate renal impairment and 6.25 mg once daily is recommended in patients with severe renal impairment/ESRD or dialysis.

Pharmacodynamics

QT Prolongation

The QT prolongation potential of Nesina was assessed in a thorough QT-prolongation study. In this single-blind, randomized, placebo- and positive-controlled, parallel group electrocardiogram (ECG) study; healthy patients received Nesina 50 mg once daily for 7 days. In the Nesina 50 mg group, the maximum mean difference from placebo in the QTcF interval was 4.5 ms [90% Confidence Interval (CI) 0.4, 8.5] at 2 hours post-dosing on day 7 of treatment, and in the Nesina 400 mg group, the maximum mean difference was 5.8 ms (90% CI 1.8, 9.7) at 1 hour post-dosing on day 7. Although the therapeutic 25 mg dose of Nesina was not tested in this study, no clinically significant QTcF prolongation is predicted at the 25 mg dose, based on pharmacokinetic-pharmacodynamic modelling.

There is limited experience with Nesina therapy in patients with congestive heart failure of New York Heart Association (NYHA) functional classes III and IV. Nesina should, therefore, be used with caution in these patients.

Drug-Drug Interactions

Clinical data suggest that alogliptin pharmacokinetics was not significantly altered when co-administered with cytochrome P450 (CYP) 3A4, 2C8, 2C9, P glycoprotein (P-gp), organic cation transporter 2 (OCT-2), and alpha-glucosidase inhibitors. Alogliptin did not alter the pharmacokinetics of co-administered CYP3A4, 2C8, 2C9, 2D6, 1A2, P-gp, and OCT-2 substrates.

Overall, the data from clinical pharmacology studies are considered sufficient. No major concerns have been identified to prevent the market authorization of Nesina. The clinical pharmacological data support the use of Nesina for the specified indication.

For further details, please refer to the Nesina Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The Nesina clinical program included a total of fifty-five studies, Phase I through Phase III, conducted in both healthy volunteers and patients with T2DM. For this New Drug Submission (NDS), the sponsor submitted seven pivotal and eight non-pivotal clinical studies in support of the indications.

The market authorization for Nesina was based primarily on five Phase III studies, in addition to the evaluation of two long-term studies.

For the five Phase III studies, Nesina was evaluated either as a monotherapy (Study SYR-322-PLC-010), or as an add-on therapy to metformin (Study SYR-322-MET-008), or a sulfonylurea (Study SYR-322-SULF-007), or pioglitazone [with or without metformin or a sulfonylurea (Study SYR-322-TZD-009)], or insulin [with or without metformin (Study SYR-322-INS-011)].

The study design of all five Phase III studies were 26-week, multicenter, randomized, double-blinded, placebo-controlled, 3-treatment arm studies. The studies evaluated Nesina at doses of 12.5 mg and 25 mg once daily. All studies had a 2:2:1 randomization ratio of 12.5 mg: 25 mg: placebo, with the exception of the SYR-322-INS-011 study, which had a 1:1:1 randomization ratio. All five studies had a placebo-controlled stabilization period of four weeks prior to randomization, followed by a 26-week treatment period. Patients who entered the studies were required to have T2DM with inadequate glycemic control prior to randomization.

Demographic characteristics were generally representative of the target population and no meaningful differences across treatment groups were observed for any demographic or baseline characteristic with respect to sex, age, race, and body mass index (BMI). The average ages across all five studies ranged from 53 to 57 years (min-max, 21 to 80 years). Approximately 14% to 27% of all randomized patients were elderly (≥65 years). The majority of randomized patients were White, followed by Asian, and Black. The mean BMI for randomized patients ranged from 30 to 33.

Duration of T2DM ranged from a mean of 2.8 years in the monotherapy study (SYR-322-PLC-010) to 13.4 years in the insulin add-on study (SYR-322-INS-011). Mean baseline HbA1c was similar among most of the studies (mean 7.9 to 8.2) with the exception of the insulin add-on study (SYR-322-INS-011) which had a mean range of 9.3 years.

Across the five studies, the primary efficacy variable was defined as change from baseline in HbA1c level at Week 26. Results from the five studies demonstrated that patients in the 12.5 mg and 25 mg groups did achieve statistically significant (p<0.001) mean reductions in HbA1c compared with the placebo group, regardless of add-on therapy. While patients in the 25 mg group achieved greater reductions in HbA1c than patients in the 12.5 mg group (in four of the five studies, with exception of Study SYR-322-MET-008), the mean difference between the two doses was not significant. A positive dose response was more apparent in patients with higher baseline HbA1c levels.

Nesina Monotherapy (SYR 322 PLC 010)

Monotherapy treatment with Nesina 25 mg resulted in statistically significant improvements from baseline in HbA1c as early as Week 4 and fasting plasma glucose (secondary endpoint) as early as Week 1 compared to placebo at Week 26. Fewer patients receiving Nesina 25 mg (8%) required hyperglycemic rescue compared with those receiving placebo (30%) during the study. Body weight did not differ significantly between the groups.

Nesina as Add on Therapy to Metformin (SYR 322 MET 008)

The addition of Nesina 25 mg once daily to metformin therapy (mean dose = 1,846.7 mg) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose (secondary endpoint) at Week 26 when compared to the addition of placebo. Significant improvements in HbA1c versus (vs.) the addition of placebo were noted as early as four weeks after the start of Nesina, and these remained significant at every time point until Week 26. Significant improvements in fasting plasma glucose compared to placebo were noted as early as one week after the start of Nesina, and these improvements in fasting plasma glucose remained significant at every time point until Week 26. Body weight did not differ significantly between the groups.

Fewer patients receiving 25 mg Nesina (8.2%) required hyperglycemic rescue compared to those receiving placebo (24.0%) during the study.

Nesina as Add on Therapy to a Sulfonylurea (SYR 322 SULF 007)

The addition of 25 mg Nesina once daily to glyburide therapy (mean dose = 12.2 mg) resulted in statistically significant improvements from baseline in HbA1c at Week 26 when compared to the addition of placebo. No significant differences from placebo were noted for mean change from baseline in fasting plasma glucose at Week 26 (25 mg Nesina showed a reduction of 0.47 mmol/L compared to an increase of 0.122 mmol/L with placebo). Also, fewer patients receiving 25 mg Nesina (15.7%) required hyperglycaemic rescue compared to those receiving placebo (28.3%) during the study. Body weight did not differ significantly between the groups.

Nesina as Add on Therapy to Pioglitazone (SYR 322 TZD 009)

The addition of 25 mg Nesina once daily to pioglitazone therapy (mean dose = 35.0 mg, with or without metformin or a sulfonylurea) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo. At baseline, approximately 56% and 21% of patients were receiving metformin or sulfonylurea, respectively. Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg Nesina regardless of whether patients were receiving concomitant metformin or sulfonylurea therapy. Also, fewer patients receiving 25 mg Nesina (9.0%) required hyperglycemic rescue compared to those receiving placebo (12.4%) during the study. Body weight did not differ significantly between the groups.

Nesina as Add on Therapy to Insulin - With or Without Metformin (SYR 322 INS-011)

Nesina was investigated in patients with a baseline HbA1c =8.0 and taking insulin at doses ranging from 15 to 100 IU/day either as monotherapy (42% of the total sample) or in combination with insulin (58% of the total sample). The majority of insulins used in this study were mixed and basal classes. The addition of 25 mg Nesina once daily to insulin therapy (mean dose = 56.5 IU, with or without metformin) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo. The completion rates in the study were low (42% completed in the placebo group and 60% completed in the Nesina 25 mg group). Fewer patients receiving 25 mg Nesina (19.4%) required hyperglycemic rescue compared to those receiving placebo (40%) during the study. Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg Nesina regardless of whether patients were receiving concomitant metformin therapy. Significant improvements in HbA1c compared to placebo were noted as early as four weeks after the start of Nesina, which remained significant at every time point until study end. Body weight did not differ significantly between the groups.

In regards to long-term use of Nesina, two studies (SYR 322 305 and 01 06 TL 322OPI 004) were also assessed during the NDS review. The primary endpoint in both these studies was the change from baseline in HbA1c level compared to Week 52 or Week 104 (results presented are based on an interim analysis at Week 52 for Study 305).

Nesina Add on to Metformin versus Glipizide Add on to Metformin (SYR 322 305)

In this study, patients were randomized to the addition of either Nesina 25 mg daily or glipizide along with metformin. Patients receiving glipizide were given an initial dosage of 5 mg/day and then up-titrated by the investigator after at least two weeks only if demonstrating persistent hyperglycemia (fasting plasma glucose ≥13.9 mmol/L) over the next eighteen weeks. A maximum dosage of 20 mg/day was allowed. Thereafter, the glipizide dose had to be kept constant. The mean daily dose of glipizide after the titration period was 5.2 mg.

Based on an interim analysis at Week 52, results indicated that the addition of Nesina 25 mg once daily to metformin therapy (mean dose = 1,835.3 mg) demonstrated improvements from baseline in HbA1c (-0.61%) that were statistically non-inferior to those produced by glipizide and metformin therapy (mean dose = 1,823.5 mg, -0.52%). Mean change from baseline in fasting plasma glucose at Week 52 for 25 mg Nesina and metformin was significantly greater than that for glipizide and metformin (p<0.001). Significantly more patients receiving 25 mg Nesina and metformin (55.3%) achieved target HbA1c levels of ≤7.0% compared to those receiving glipizide and metformin (47.4%) at Week 52 (p<0.001). Also, fewer patients receiving Nesina 25 mg and metformin (8.9%) required hyperglycemic rescue compared to those receiving glipizide and metformin (11.8%) during the study. Body weight did not differ significantly between the groups.

Nesina Add on Therapy to Pioglitazone with Metformin (01-06 TL 322OPI 004)

The addition of 25 mg Nesina once daily to 30 mg pioglitazone and metformin therapy (mean dose = 1,867.9 mg) resulted in clinically meaningful improvements from baseline in HbA1c at Week 52 that were both non-inferior and statistically superior to those produced by 45 mg pioglitazone and metformin therapy (mean dose = 1,847.6 mg). The significant reductions in HbA1c observed with 25 mg Nesina plus 30 mg pioglitazone and metformin were consistent over the entire 52-week treatment period compared to 45 mg pioglitazone and metformin (p<0.001 at all-time points). Also, fewer patients receiving 25 mg Nesina plus 30 mg pioglitazone and metformin (10.9%) required hyperglycemic rescue compared to those receiving 45 mg pioglitazone and metformin (21.7%) during the study. Body weight did not differ significantly between the groups.

For more information, refer to the Nesina Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Nesina was based on one Phase II dose-ranging study and twelve controlled Phase III studies. The Phase III studies included seven pivotal studies previously described in the Clinical Efficacy section. Also reviewed was interim data from a long-term cardiovascular outcome study in high-risk patients, Study 402.

In the original New Drug Submission (NDS), the safety analysis conducted was based on the following pooled groups:

1. placebo, [Number of patients (N) = 793];
2. active comparator, N = 2,257 (patients received glipizide, metformin, or pioglitazone without Nesina);
3. Nesina 12.5 mg, N = 2,476 (including patients with background medication and combination treatment in addition to Nesina);
4. Nesina 25 mg (see comment for iii), N = 3,749; and
5. all Nesina, N = 6,354 (patients who received any Nesina dose).

During conduct of the interim analysis for Study 402, it was noted that a greater number of Nesina-treated patients showed elevated hepatic transaminases levels compared to that of the placebo group. As a result, the sponsor was asked to provide further safety data for this study. In response, the sponsor submitted updated data for the study, and also provided further updated safety data from the ongoing 104 week study SYR-322-305. In addition, to further augment the hepatic safety database, the sponsor also provided data from five Japanese Phase II/III studies (SYR-322-CCT-001, SYR-322-CCT-003-006) and a Chinese Phase III study (Study SYR-322-308). All of the supplementary data had been submitted previously to the United States Food and Drug Administration (FDA). Yet, unlike Studies SYR-322-402 and SYR-322-305, an integrated analysis of efficacy and safety results from the Japanese and Chinese studies was not submitted as part of the original NDS; therefore Health Canada considered these studies as supportive studies only.

Given the updated safety data submitted, total patient exposure for the Nesina 25 mg dose was increased roughly two-fold compared to the original NDS safety data. The increase in exposure was due chiefly to an extra year of safety data from Study 402 and, to a lesser extent, further data from Study SYR-322-305. Consequently, the updated pooled safety analysis groups comprised:

1. placebo, N = 3,647;
2. active comparator, N = 2,340;
3. all comparator, N = 5,987 [groups i) and ii) combined];
4. Nesina 12.5 mg, N = 2,944;
5. Nesina 25 mg, N = 6,626; and
6. all Nesina, N = 9,857.

In the updated safety data submitted, as in the original NDS, baseline characteristics across the safety analysis groups were generally similar, with mean age approximately 57 years and roughly 56% of patients male. Overall, 60% of patients were White and 28% Asian; mean BMI was roughly 30 kg/m², with approximately 44% of patients having a BMI ≥30 kg/m². Mean duration of T2DM was approximately seven years.

The proportion of patients with treatment-emergent adverse events (AEs) was comparable across treatment groups. In the original NDS data set, patients reporting any AE comprised 64.8% of placebo patients, 68.6% of active comparator patients, and 67.5% and 66.6% of Nesina 12.5 mg and 25 mg patients, respectively. Serious adverse events (SAEs) were reported by 3.2% of patients in the placebo group, 5.2% of those in the active comparator group, and 4.0% and 4.7% of patients in the Nesina 12.5 mg and 25 mg groups, respectively. Adverse events leading to discontinuation of study drug occurred in 2.3%, 5.8%, 3.6% and 4.1% of the placebo, active comparator, and Nesina 12.5 mg and 25 mg groups, respectively.

The most common (>3% of patients) treatment-emergent adverse events with Nesina use were headache (5.4%), upper respiratory tract infection (5.2%), nasopharyngitis (5.1%), urinary tract infection (4.2%), hypertension (3.9%), diarrhea (3.8%), and back pain (3.3%).

Events assessed by the sponsor as possibly related to Nesina, based on comparison to either active comparator or placebo, were nasopharyngitis, upper respiratory infection, influenza, headache, abdominal pain, nausea, dyspepsia, gastroesophageal reflux disease, diarrhea, pruritus, rash, hypersensitivity, musculoskeletal pain, back pain, myalgia, muscle spasms, and insomnia.

The most common serious adverse events (SAEs) observed with Nesina 25 mg in the Phase II/III clinical studies were non-cardiac chest pain [based on the original New Drug Submission (NDS) database, which did not include patients from Study 402] (0.3%), as well as angina (0.2%), unstable angina (0.1%), myocardial infarction (0.1%), coronary artery disease (0.1%), pulmonary embolism (0.1%), pneumonia (0.1%), osteoarthritis (0.1%) and cardiac failure, (based on both the original NDS database and updated safety databases) (0.1%). Similarly, the most common causes of death were cardiovascular events. Overall, these results are compatible with the relatively high cardiovascular risk patient populations participating in the studies, especially patients enrolled in Study 402.

Topics of Special Interest

Cardiovascular System

Cardiovascular safety of Nesina was assessed in a dedicated ongoing cardiovascular outcomes study, namely Study 402. Analysis of the study's primary composite Major Adverse Cardiac Events (MACE) endpoint (cardiovascular death, myocardial infarction, and stroke) indicated that Nesina is not associated with ≥51% increase in cardiovascular risk, when compared with placebo as add-on to standard-of-care therapies, with the upper bound of a one-sided 97.5% interim confidence interval (CI) equal to 1.51. The sponsor is however, committed to providing further data from the ongoing study to clearly establish that the upper bound of 95 percent confidence interval for the estimated risk ratio of less than 1.3.

Hepatic Impairment

Hepatic safety was a topic of particular interest during the evaluation of Nesina. Previously noted, based on interim results of Study 402, was an increased incidence of elevated hepatic transaminase levels in patients receiving Nesina compared to placebo-treated patients. This observation combined with several post-marketing reports of serious hepatotoxicity (some fatal), raised concern in regards to hepatic safety. However, with the availability of new data submitted in this NDS, as well as further data submitted at the request of Health Canada, this enabled a more complete assessment of hepatic safety to be conducted.

A pooled analysis of the updated safety data, combined with the safety data from Phase II/III studies, does not show evidence of more frequent marked elevations in hepatic transaminases between Nesina-treated patients and patients in the pooled all comparators group. The initial data from Study 402 indicated an increased incidence of elevated transaminase levels in the Nesina-treated patients compared to placebo-treated patients, specifically, patients with alanine aminotransferase (ALT) >3 times, >5 times and >10 times the upper limit of normal. With subsequent updates to, and increased events in, the Study 402 safety database, the imbalance in ALT elevations has become less apparent, with marked ALT abnormalities now showing only a trend to a slight increase in incidence, compared to placebo.

The analysis of hepatic SAEs in patients receiving Nesina did not reveal any cases satisfying the criteria for Hy's law, that is suggestive of drug-induced severe hepatotoxicity, and other cases of marked elevations of transaminases generally had plausible alternative etiologies. Moreover, of the reported cases of markedly elevated transaminases with Nesina, no serious sequelae such as hepatic failure were seen, and observed abnormalities resolved with drug discontinuation.

Based on the above, it appears that if Nesina has a potential for hepatotoxicity it is of a very small magnitude. However, given the possibility that an increased risk for hepatotoxicity cannot be entirely ruled out, the Nesina Product Monograph does include a statement in the Warnings and Precautions section mentioning post market reports of severe hepatic dysfunction and thereby recommending close monitoring of patients for possible liver abnormalities. Also mentioned within the Nesina Product Monograph is a recommendation to conduct a pre treatment hepatic assessment, including liver function tests. Furthermore, initiating use of Nesina in patients with abnormal liver tests must be done with extreme caution and administration of Nesina should be discontinued if patients demonstrate clinically significant abnormal liver tests during treatment which cannot be otherwise explained. Nesina is not recommended for use in patients with severe hepatic impairment, due to lack of safety data in this population.

Pancreatitis and Pancreatic Cancer

In the Phase II/III clinical studies, acute pancreatitis was observed more frequently in Nesina-treated patients compared to the all comparators group. A fatal case of pancreatitis was reported in a patient with no apparent risk factors who was taking Nesina in an open-label, uncontrolled extension study. The overall incidence of pancreatitis was roughly 0.2% for patients receiving Nesina 25 mg, compared to 0.1% for patients in the all comparators group.

Use of other dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with pancreatitis, and as a result the Product Monographs for the other approved DPP-4 inhibitors bear class labelling warnings regarding this event. The Nesina Product Monograph also includes a statement in the Warnings and Precautions section describing the occurrence of acute pancreatitis, including fatal cases, in clinical studies and post-market reports, and recommends heightened vigilance for signs and symptoms of pancreatitis and prompt discontinuation of Nesina and institution of therapy if pancreatitis is suspected.

Recently, concern has been raised with regards to a possible increased risk of pancreatic cancer associated with use of the DPP-4 inhibitors and incretin analogues. No cases of pancreatic carcinoma were seen in the controlled Phase II/III clinical studies, which involved 9,857 patients, albeit for generally limited durations of exposure. However, two cases of pancreatic cancer, both in elderly (and therefore higher risk) patients, were reported in an uncontrolled, open label, Nesina extension study. In light of the lack of a comparator in that study, it was not possible to estimate the incidence of this event. This safety concern has been captured in the Nesina Risk Management Plan (RMP).

Hypersensitivity Reactions

In general, hypersensitivity reactions were reported with comparable frequencies in Nesina-treated patients and patients in the all comparators group, with the exception of events of pruritus and rash, which occurred more commonly in Nesina-treated patients. In light of post-market reports of serious hypersensitivity reactions in patients treated with Nesina, including severe cutaneous adverse reactions such as Stevens-Johnson syndrome, the Nesina Product Monograph contains a cautionary statement regarding hypersensitivity in Warning and Precautions section.

Renal Impairment

Nesina is eliminated through renal tubular secretion, therefore assessment of renal function is required prior to initiating therapy, and reduced doses are required for moderate renal impairment (12.5 mg) and severe impairment/end-stage renal disease (6.25 mg). Safety of Nesina was assessed in only a few patients with severe renal impairment; however no clear imbalance in AEs was evident compared to placebo.

Special Populations

Geriatrics

No clear increased risk of specific adverse events was evident with Nesina 25 mg in the pooled Phase II and III studies in elderly patients (≥65 years). The Nesina Product Monograph does advise conservative dosing in patients with advanced age.

Pediatrics

The safety and effectiveness of Nesina in pediatric patients under 18 years of age have not been established. Therefore, Nesina should not be used in this population.

A Risk Management Plan was reviewed by the Marketed Health Products Directorate and found to be acceptable subsequent to addressing a few minor deficiencies.

For more information, refer to the Nesina Product Monograph, approved by Health Canada and available through the Drug Product Database.