Efficacy and Safety of MYL-1501D vs Insulin Glargine in Patients with Type 1 Diabetes after 52 Weeks: Results of the INSTRIDE 1 Phase III Study

Design

Multicenter, open-label, randomized, parallel=group phase 3 study 

N= 558

Objective

To test the safety and efficacy of MYL-1501D [Semglee], a proposed insulin glargine biosimilar, in patients with type 1 diabetes mellitus (T1DM)

Study Groups

MYL-1501D [Semglee] (n= 280)

Reference Insulin glargine [Lantus] (n= 278)

Inclusion Criteria

Adults between the ages of 18 and 65 with an established diagnosis of T1DM, were treated with once-daily insulin glargine for ≥3 months, had an HbA1c ≤9.5% at screening, had a fasting plasma C-peptide <0.3 nmol/L at screening, and had a stable weight for 3 months and a body mass index between 18.5 and 35.0 kg/m2 at screening

Exclusion Criteria

None included

Methods

After a 4-week screening period, the 6-week run-in period began with titrations of insulin glargine and insulin lispro. An 8-point self-monitored blood glucose (SMBG) was performed 3 days a week for the first 8 weeks beginning at the run-in, and patients were encouraged to conduct the 4-point SMBG on the other days. Insulin glargine (Lantus) was titrated weekly using the dosing algorithm to attain fasting plasma glucose (FPG) 71-130 mg/dL. Once the glargine dose was optimized, three-times-daily insulin lispro was adjusted to attain a postprandial blood glucose of <180 mg/dL with considerations of planned physical activity and carbohydrate intake for the next meal.

After the run-in period, patients were randomized 1:1 to either continue their current treatment with Lantus or receive Semglee throughout the 52-week treatment period (1:1 unit for unit conversion). After randomization and the first 4 weeks of treatment, dose titrations were kept to a minimum unless required for safety, with the 8-point SMBG performed at 4-week intervals. Dosing of Semglee and lantus followed the glargine dosing algorithm. After 52 weeks, patients resumed standard of care and followed up at week 56.

Repeated-measures analysis employing a restricted maximum likelihood-based mixed-effects model (MMRM) approach was used for the difference in mean change in HbA1c. Non-inferiority was supported if the upper limit of the 2-sided 95% confidence interval for the difference in mean change was no greater than 0.4% at week 24. 

Duration

4 week screening; 6-week run-in; 52-week treatment with follow-up at week 56

Outcome Measures

Primary: Change in HbA1c from baseline to week 24 

Secondary: Compare MYL-1501D with reference insulin glargine at weeks 24 and 52; changes in FPG, insulin dose, SMBG, and immunogenicity from baseline, occurrence of hypoglycemic events (30-day rate), nocturnal hypoglycemic events, and adverse
events (AEs)

Baseline Characteristics

Semglee (n= 280)

Lantus (n= 278)

Age, years

Female

White

Geographic region

Europe

North America

South America

51.8%

45.0%

3.2%

52.2%

45.3%

2.5%

Weight, kg

BMI, kg/m²

HbA1c, %

FPG, mmol/L

78.9 ± 14.5

26.4 ± 3.7

7.37% ± 0.87%

9.3 ± 3.8

80.7 ± 16.0

26.6 ± 4.2

7.39% ± 0.84%

9.1 ± 3.4

Duration of diabetes, years

18.7 ± 11.8

19.7 ± 11.3

BMI: body mass index; FPG: fasting plasma glucose; HbA1c: glycosylated hemoglobin

Results

Endpoint

Semglee (n= 280)

Lantus (n= 278)

LS mean difference in change in HbA1c

Mean change in HbA1c from baseline to week 24 (SE)

95% CI

0.14% (0.054)

0.033 to 0.244

0.11% (0.054)

0.007 to 0.220

0.03% (0.046)

-0.066 to 0.117*

Mean change in HbA1c from baseline to week 52 (SE)

95% CI

0.21% (0.055)

CI 0.100 to 0.306

0.25% (0.056)

0.144 to 0.363

-0.05% (0.052)

-0.148 to 0.057

*Primary endpoint: within the inferiority margin of 0.4% at week 24

LS mean difference between treatments was similar at weeks 24 and 52; no significant difference in actual HbA1c profiles observed over time (p> 0.3)

Secondary endpoints:

No significant differences in change from baseline in FPG at weeks 12, 36, and 52 (transient significant difference at week 24)

Overall mean change in average glucose on SMBG from baseline at week 52: -0.082 for both groups; 1 occurrence of a statistically significnat blood glucose difference (p= 0.043) for the average noon excursion time period (considered not clinically relevant)

Slight increase in weight in both groups; no significant difference between groups (p= 0.633)

Mean change in daily basal insulin dose from baseline to week 52: increased in both groups; no difference between groups

CI: confidence interval; HbA1c: glycosylated hemoglobin; LS: least squares; SE: standard error

Adverse Events

Rates of treatment-emergent adverse event (TEAE): similar between groups at week 52

Semglee: 80.4% experienced ≥ 1 TEAE; hypoglycemia occurred in 55%

Lantus: 86% experienced ≥ TEAE; hypoglycemia occurred in 61.2%

1.1% discontinued treatment due to TEAE in both groups

Similar incidence of mild, moderate, and severe TEAE between groups

No significant difference between groups for anytime and nocturnal hypoglycemic rates (episodes/30 days) and incidence profiles 

Patients with ≥ 1 local and systemic reaction during treatment was similar between groups (1.8% vs 2.2%); systemic reactions were reported in 2 patients in each group

Immunogenicity profiles were comparable between groups; no significant differences for any type of insulin antibodies at any visit

Deaths: 2 patients in the Semglee (1 unlikely related to treatment and 1 due to hypoglycemia) and 1 patient in the Lantus group (unrelated to treatment)

Study Author Conclusions

The upper 95% CI limit for mean change in HbA1c at week 24 indicated that MYL-1501D [Semglee] was non-inferior to reference insulin glargine [Lantus]. There were no clinically meaningful differences between groups in incidence of overall and nocturnal hypoglycemia, local or systemic reactions, safety or immunogenicity

InpharmD Researcher Critique

The open-label design may present possible limitations, although patient blinding was not possible due to the prefilled disposable pens. Generalizability may also be limited, given the majority of patients were white and from Europe or North America. 

Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: Results ofthe phase III INSTRIDE 2 study

Design

Multicentre, open-label, randomized, parallel-group, phase III non-inferiority study

N= 560

Objective

To assess the non-inferiority in efficacy, safety, and immunogenicity of MYL-1501D [Semglee] to insulin glargine [Lantus] in based on change in glycated hemoglobin (HbA1c) in insulin-naive and insulin-non-naive patients with type 2 diabetes mellitus (T2DM) also receiving oral antidiabetic drugs (OADs)

Study Groups

Semglee (n= 277)

Lantus (n= 283)

Inclusion Criteria

Non-insulin naive patients: included if they had an established diagnosis of T2DM (American Diabetes Association 2014 criteria) for ≥1 year, on a stable dose of an OAD for ≥3 months, aged 18-65 years, were receiving once-daily insulin glargine at a stable dose for ≥3 months, and had a HbA1c concentration of <91 mmol/mol.

Insulin-naive patients: included if they had an established diagnosis of T2DM, aged 18-65 years and had an HbA1c concentration of >58 to ≤91 mmol/mol.

All patients had to have a stable weight for 3 months prior to screening and a BMI 18.5-40.0 kg/m².

Exclusion Criteria

Not disclosed

Methods

Patients were randomized 1:1 to receive either Semglee or Lantus and were stratified into 3 groups based on geographic region, prior insulin exposure, and preferred dosing time (morning or bedtime). Both treatments were administered as a subcutaneous injection via prefilled disposable pens. 

Recommended starting dose of Semglee or reference Lantus in insulin-naive patients was 10 U (or 0.2 U/kg) once daily and was adjusted weekly by investigators per protocol.

During weeks 0 to 12, insulin doses were titrated or adjusted to attain a fasting preprandial self-monitored blood glucose (SMBG) of 3.9 to 7.2 mmol/L (70 to 130 mg/dL).

During weeks 12 to 24, insulin doses were maintained with minimal titration. At week 12, if HbA1c had worsened by >1%, the test was repeated within 4 weeks to confirm that patients were eligible for rescue therapy, and/or treatment alterations.

A follow-up telephone call was made to all patients 4 weeks after the end of treatment to collect safety information.

Duration

24 weeks

Outcome Measures

Primary: Change in HbA1c from baseline to week 24

Secondary: Changes from baeline in basal insulin dose; fasting plasma glucose (FPG); SMBG levels; safety; immunogenicity

Baseline Characteristics

Semglee (n= 277)

Lantus (n =283)

Age (mean), years

55.1 ± 7.5

Female

118 (41.7%)

White

Geographic region

  North America

  East Europe

  Middle East and Africa

  East Asia

225 (81.2%)

34 (12.3%)

14 (5.1%)

4 (1.4%)

228 (80.6%)

33 (11.7%)

18 (6.4%)

4 (1.4%)

Insulin naive

31.6 ± 4.8

12.0 ± 7.1

65.5 ± 12.5

FPG

  mmol/L

  mg/dL

8.6 ± 3.0

155 ± 54.1

8.6 ± 3.1

155 ± 55.9

Oral antidiabetic medications

  Metformin

  Glimepirides

  Glipizides

  Metformin hydrochloride

193 (69.7%)

61 (22.0%)

42 (15.2%)

28 (10.1%)

201 (71.0%)

62 (21.9%)

40 (14.1%)

34 (12.0%)

BMI: body mass index; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin

Results

Endpoint

Semglee (n= 277)

Lantus (n =283)

p-value

Change in HbA1c from baseline to week 24 (LS mean ± SE), % 

Change in FPG from baseline, mmol/L

Change in basal insulin from baseline, U/kg

Change in 7-point SMBG profile from baseline, mmol/L

The LS mean difference in change in HbA1c from baseline to week 24 between the two groups was 0.06% (95%CI −0.10, 0.22). The upper boundary of the 95% CI for mean change in HbA1c from baseline to week 24 was within the non-inferiority margin of 0.4%, indicating non-inferiority of Semglee to Lantus.

For patients who were insulin-naive, the LS mean (SE) change in HbA1c from baseline to week 24 was −1.01% (0.13) and −1.09% (0.13) for the Semglee (n = 96) and Lantus (n = 98) groups, respectively (p= 0.528). 

The majority of patients demonstrated negative responses for total ADAs (Semglee, 63.4%; Lantus, 61.3%; p= 0.693) and insulin cross-reactive antibodies (Semglee, 62.7%; Lantus, 62.8%; p= 0.921).

Adverse Events

Common Adverse Events (>3%): hypoglycemia (27.2% vs 23.4%); upper respiratory tract infection (6.2% vs 5.3%); urinary tract infection (4.3% vs 2.8%)

Serious Adverse Events: The number of patients with ≥1 local or systemic reaction during the treatment period was 4 (1.4%) in the Semglee group and 2 (0.7%) in the Lantus group (p= 0.446). No deaths were reported.

Discontinued due to Adverse Events: 3 patients in the Semglee group experienced a total of 6 treatment-emergent adverse events (asthma, pleuritic pain, hypoxia, depression, headache, dyspepsia) and discontinued treatment. No patients in the Lantus discontinued treatment due to treatment-emergent adverse events. 

Study Author Conclusions

Demonstration of non-inferiority between MYL-1501D [Semglee] and reference insulin glargine [Lantus] for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycemia and nocturnal hypoglycemia, local and systemic reactions, other safety variables, and immunogenicity.

InpharmD Researcher Critique

The open-label design may induce investigator bias, however, the length of the study was appropriate to detect a significant change in HbA1c. Rates of hypoglycemia were similar in both groups. Additional analysis, including OADs per insulin-naive and non-insulin-naive, may aid providers' treatment decisions for individual patients. 

Efficacy and Safety of MYL‐1501D Versus Insulin Glargine in People with Type 1 Diabetes Mellitus: Results of the INSTRIDE 3 Phase 3 Switch Study

Design

Randomized, multicenter, open-label, parallel-group, phase 3 study

N= 127

Objective

To assess the efficacy, insulin dose, safety, and immunogenicity when people with type 1 diabetes mellitus switched between MYL-1501D [Semglee] and reference insulin glargine [Lantus]

Study Groups

Semglee switching sequence (n= 64)

Reference Lantus (n= 63)

Inclusion Criteria

Patients who successfully completed the 52-week treatment in INSTRIDE 1 using the reference insulin glargine

Exclusion Criteria

History of clinically significant infections, moderate insulin resistance (requiring basal plus prandial insulin of ≥1.5 U/kg/d), or
planned to receive elective surgery requiring hospitalization or another investigational drug during the study period

Methods

Patients were randomized (1:1) to receive either continued Lantus for another 36 weeks or the treatment-switching group, which included Semglee weeks 0-12; Lantus weeks 12-24, and Semglee weeks 24-36. After week 36, all patients resumed their baseline treatment with a safety follow-up at week 40.

Treatments were administered via prefilled disposable pens with dosages adapted to blood glucose levels. Titration of Semglee and Lantus was minimized but allowed for safety concerns. Insulin lispro pens were used at mealtimes; all other antidiabetic medications were prohibited.

Duration

36-week treatment with follow-up at week 40

Outcome Measures

Primary (equivalence between groups): change in HbA1c from baseline to week 36 

Secondary: change from baseline in fasting plasma glucose (FPG), eight-point self-monitored blood glucose (SMBG) profile and insulin dose per unit body weight, and immunogenicity at week 36, occurrence of hypoglycemic events (30-day rate), nocturnal hypoglycaemic events, and adverse events (AEs)

Baseline Characteristics

Semglee (switch sequence)

(n= 64)

Lantus 

(n= 63)

Age, years

Male

White

Geographic region

Europe

North America

46.9%

53.1%

42.9%

57.1%

Weight, kg

BMI, kg/m²

Duration of diabetes, years

80.7 ± 16.5

26.7 ± 4.2

21.4 ± 12.9

82.4 ± 15.3

27.1 ± 4.4

20.2 ± 9.0

FPG

mmol/L

mg/dL

9.8 ± 3.5

176.6 ± 63.1

9.5 ± 4.1

171.2 ± 73.9

HbA1c

mmol/mol 

% 

60.0 ± 10.9

7.6 ± 1.0

62.5 ± 10.0

7.9 ± 0.9

Baseline insulin dose, U/kg

Basal 

Mealtime  

Total daily 

0.31 ± 0.12

0.37 ± 0.16

0.68 ± 0.24

0.36 ± 0.18

0.36 ± 0.15

0.72 ± 0.25

BMI: body mass index; FPG: fasting plasma glucose; HbA1c: glycated haemoglobin

Results

Endpoint

Semglee switch sequence

Lantus

LS mean difference in change in HbA1c

LS mean change in HbA1c% from baseline to week 36 (SE) 

Mean daily basal insulin dose at week 36, U/kg

CI: confidence interval; LS: least square; N/A: not applicable; SE: standard error

*Primary endpoint: within the equivalence margin of 0.4% at week 36

HbA1c remained relatively stable for both treatment sequences, with no statistically significant changes from baseline (p >0.05) or between treatment sequences at any time point throughout the three treatment periods (weeks 0-12; 12-24; 24-36)

Secondary endpoints: 

• FPG and SMBG remained relatively stable with no significant changes from baseline or between groups 
• Mean [SD] daily basal insulin dose was slightly higher in the insulin glargine group at week 36; however also slightly higher at baseline (0.36 vs 0.31 U/kg)
• †Semglee had a significant increase from baseline mean daily basal insulin dose, primarily in the first 4 weeks but then remained relatively stable; significant difference in change in daily basal insulin dose at week 36 between groups (0.019 U/kg; 95% CI 0.007 to 0.031; p = 0.002). The finding was considered not clinically meaningful given the magnitude of change and slightly lower baseline for Semglee
• Total daily insulin dose remained relatively stable; no statistically significant differences in total daily insulin dose change from baseline at any time point 

Adverse Events

Rates of treatment-emergent adverse events (TEAEs) were similar between groups during the 36 weeks

• Semglee sequence: 64.1% experienced ≥ 1 TEAE; 3.1% with ≥ 1 TEAE grade 3-5
• Glargine: 66.7 % experienced ≥ 1 TEAE; 4.8% with ≥ 1 TEAE grade 3-5
• Most common TEAE was infection (upper respiratory tract infection and influenza)
• No patients discontinued treatment due to TEAE
• Overall incidences of any hypoglycemic event or nocturnal hypoglycaemic events: no significant difference between groups observed at any visit
• The 30-day adjusted event rates for anytime and nocturnal hypoglycaemic events were similar for both groups
• No severe hypoglycemic events occurred at any time point in the study

3 reported local and/or systemic allergic reactions: (2 in the Semglee sequence and 1 in the Lantus sequence); none of the events were considered related to study treatment

Immunogenicity profiles were comparable between groups

Study Author Conclusions

Switching participants between MYL-1501D [Semglee] and reference insulin glargine [Lantus] demonstrated equivalent efficacy and similar safety and immunogenicity, showing that people taking reference insulin glargine can safely switch to MYL-1501D.

InpharmD Researcher Critique

Limitations to this study are extended from the initial INSTRIDE 1 study, which include open-label design and potential limitations of generalizability due to study participants being mostly male, white, and from Europe and North America. Additionally this study was smaller with a shorter duration of 36 weeks.