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Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study

Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also... Background: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (U100; Humalog ; Ly-Lis). This study aimed to show similar efficacy, safety, and immunogenicity of SAR-Lis versus Ly-Lis in adult patients with type 2 diabetes mellitus (T2DM) treated with multiple daily injections, while using insulin glargine (GLA-100; Lantus ) as basal insulin. Methods: SORELLA 2 was a 6-month, randomized, open-label, Phase 3 study (NCT02294474). Insulin doses were adjusted to achieve fasting and 2-h postprandial glucose targets according to American Diabetes Asso- ciation guidelines. Primary endpoint was the HbA change from baseline to week 26 (tested for noninferiority 1c of SAR-Lis vs. Ly-Lis with a margin of 0.3%). Secondary endpoints included fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIA). Results: A total of 505 patients were randomized (1:1) to multiple daily injections of SAR-Lis (n = 253) or Ly- Lis (n = 252) plus once-daily GLA-100. Least square (LS) mean (standard error) change in HbA from baseline to 1c week 26 was similar in both treatment groups (SAR-Lis, -0.92% [0.051] and Ly-Lis, -0.85% [0.051]). Non- inferiority at prespecified 0.3% noninferiority margin was demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: -0.07% [95% CI: -0.215 to 0.067]) as was inverse noninferiority. Similar changes in FPG, seven-point SMPG profiles, including postprandial glucose excursions and mean glucose over 24 h, and insulin dosages were observed in the two groups. Hypoglycemia, TEAEs, and AIA (incidence and prevalence) did not differ between groups. Conclusions: Results from this controlled study in patients with T2DM also using GLA-100 support similar efficacy and safety (including immunogenicity) of SAR-Lis and Ly-Lis. Keywords: Biosimilar, Insulin antibodies, Immunogenicity, Insulin lispro, SORELLA 2. Introduction to achieve good glycemic control, most often start insulin therapy with a basal insulin, such as insulin glargine (GLA- atients with type 2 diabetes mellitus (T2DM) on 100; Lantus ), to control fasting blood glucose levels. If Poral antihyperglycemic treatment, who require insulin adequate glycemic control cannot be obtained by controlling Institut fu¨r Klinische Forschung und Entwicklung (IKFE) Berlin GmbH, Berlin, Germany. AMCR Institute, Escondido, California. Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. Sanofi, Bridgewater, New Jersey. Sanofi, Paris, France. Portions of this article have been presented at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, June 9–13, 2017. ª Karl-Michael Derwahl, et al., 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 49 50 DERWAHL ET AL. fasting blood glucose alone, it becomes necessary to also control insulin infusion, history of severe hypoglycemia requiring prandial glucose levels. Among the options is to add a short- or treatment by emergency room admission, or poor metabolic rapid-acting insulin. According to the American Diabetes As- control requiring hospitalization, all within the last 6 months sociation (ADA), recommended therapy for T2DM consists of before screening. Also excluded were women of childbearing matching the prandial insulin dose to premeal blood glucose, potential not protected by a highly effective contraceptive carbohydrate intake, and anticipated activity. For many method and patients with unstable proliferative diabetic ret- patients (especially if hypoglycemia is a problem), use of inopathy or any other rapidly progressive diabetic retinopa- insulin analogs is recommended. The use of rapid-acting thy, or macular edema likely to require treatment (e.g., laser, insulin analogs, such as insulin lispro, insulin aspart, or insulin surgical treatment, or injectable drugs) during the study. glulisine, also facilitates flexible dosing in these insulin treat- ment regimens. Study design Insulin lispro differs from human insulin in that the amino SORELLA 2 (NCT02294474) was a multicenter, 6-month, acid proline at position B28 is replaced by lysine and the lysine randomized, open-label, two-arm parallel-group, Phase 3 in position B29 is replaced by proline. This modification does study comparing SAR-Lis with Ly-Lis in adults with T2DM not alter insulin receptor binding, but blocks the formation of also using GLA-100 as basal insulin. The study consisted of a dimers and hexamers. As a consequence, higher amounts of screening period (up to 2 weeks), a 26-week treatment period, subcutaneous monomers are available for rapid absorption. and a 1-day safety follow-up (Supplementary Fig. S1; Sup- This enables a shorter waiting period after injection before plementary Data are available online at http://online.liebertpub starting the meal. Insulin lispro is the active ingredient of Hu- .com/doi/suppl/10.1089/dia.2017.0281). Clinical visits were malog (Ly-Lis; Lilly). Humalog was the first rapid-acting scheduled for screening, randomization (day 1), weeks 4, 8, insulin approved and marketed in the EU, the US, and many 12, 20, and 26 (endpoint). After the screening period, 480 other countries worldwide, and is used in the treatment of both patients were planned to be randomized 1:1 to receive either patients with type 1 diabetes mellitus (T1DM) and T2DM. SAR-Lis or Ly-Lis in addition to the once-daily Gla-100. SAR342434 (SAR-Lis; insulin lispro; Sanofi) has been The randomization was stratified by HbA obtained at the 1c developed as a biosimilar (follow-on) biological medicinal screening visit (<8.0%, ‡8.0%) and prior use of insulin lispro product to Humalog U100 in accordance with the relevant US (Yes, No). The randomization and the treatment kit allocation and EU guidelines, including the EU guidelines for similar were performed centrally by an interactive voice response medicinal products containing recombinant human insulin system/interactive web response system. The comparator 4–8 and insulin analogs, as well as product-specific guidelines. drug in the study was Ly-Lis. Patients randomized to Ly-Lis SAR-Lis was shown to be highly similar to Ly-Lis through received US- or EU-approved Ly-Lis, depending on the lo- physicochemical analyses and in vitro and in vivo nonclinical cation of their study site. Based on the similarity between Ly- studies. Similar pharmacokinetic (PK) exposure and phar- Lis US and Ly-Lis EU shown in physicochemical analyses, macodynamic (PD) activity were demonstrated for SAR-Lis nonclinical studies, and the PK/PD study, data from both to both Ly-Lis approved in the EU and Ly-Lis approved in the insulins were pooled in the comparator group of this study. US, as well as between Ly-Lis US and Ly-Lis EU in a PK/PD Study medications were dispensed on day 1, and weeks 4, 8, study in patients with T1DM using the euglycemic clamp 12, and 20. Self-monitored plasma glucose (SMPG) and insulin 9,10 technique. This report presents the results of a multina- dose data were obtained from the patient’s diary at each visit tional, open-label, randomized, controlled Phase 3 study when compliance was checked by reviewing the patient’s diary (SORELLA 2) comparing the efficacy and safety of SAR-Lis and counting/collecting used and unused pens. Starting dose of and the reference product Ly-Lis (100 U/mL) in patients with SAR-Lis or Ly-Lis was a unit-to-unit conversion from the T2DM, also using insulin glargine (GLA-100). Humalog/Liprolog or Novolog/NovoRapid dose used before the trial. SAR-Lis or Ly-Lis was administered subcutaneously Methods (SC), immediately before meal intake using insulin pens. Oc- The study was approved by relevant review boards/ethics casional postprandial injections soon after meal intake were committees, and was performed in accordance with the De- permitted if deemed necessary and if allowed by the national claration of Helsinki and the International Conference on product label for Ly-Lis. Mealtime insulin dose could be ad- Harmonisation guidelines. All participants provided written justed to achieve a target range for 2-h postprandial plasma informed consent before participation. glucose (PG) of 120–160 mg/dL (6.7–8.9 mmol/L). The start- ing dose of GLA-100 was the same as the prestudy dose. GLA- Study patients 100 was injected SC once daily at the same time throughout the study, and dose adjustments were made to achieve a fasting, Eligible patients were of the legal age of adulthood with prebreakfast PG of 80–130 mg/dL (4.4–7.2 mmol/L). No for- HbA ‡6.5% and £10%, T2DM diagnosed for at least 12 1c mal titration algorithm was recommended for basal insulin; months, and treated with Humalog/Liprolog (insulin lispro) patients were instructed to use dosage self-adjustment of rapid- or NovoLog /NovoRapid (rapid-acting insulin aspart) at acting insulin analogs according to local guidelines to achieve least thrice daily before each meal and GLA-100 as basal target glucose, while avoiding hypoglycemia. insulin in the 6 months before the screening visit. Noninsulin antihyperglycemic background therapy taken at a stable dose Efficacy, safety, and immunogenicity assessments for at least 3 months before the screening visit was permitted. Excluded were patients with body mass index (BMI) ‡40 kg/m , HbA and fasting plasma glucose (FPG) were determined 1c the use of noninsulin injectable peptides (e.g., GLP1-receptor in a central laboratory blinded for treatment (Covance, In- agonists or other peptides), use of continuous subcutaneous dianapolis, IN) at screening (HbA only), baseline, week 12, 1c BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 51 and week 26. Seven-point SMPG profiles (preprandial and gational medicinal product (IMP) intake up to 1 day after 2-h postprandial after breakfast, lunch, and dinner, and at last IMP intake. bedtime) were to be performed on at least 2 days in the week Hypoglycemia was categorized based on the ADA defi- before baseline, week 12, and week 26, measured in a sin- nitions. Documented symptomatic hypoglycemia was an gle, 24-h period using the Bluetooth-enabled glucometer event during which typical symptoms of hypoglycemia were ‘‘myGlucoHealth’’ (Entra Health Systems, San Diego, CA). accompanied by a measured PG concentration £3.9 mmol/L SMPG results, hypoglycemic events, and insulin doses were (£70 mg/dL); those with PG <3.0 mmol/L (<54 mg/dL) were recorded by the patients in a paper diary and manually en- also analyzed. Nocturnal hypoglycemia was defined as any tered in the e-CRF by the investigator. Adverse events (AEs), hypoglycemia that occurred between 00:00 and 05:59 a.m. including hypersensitivity events and injection site reac- hours. Severe hypoglycemia was an event that required tions, were documented at each visit. Further safety moni- assistance of another person to actively administer carbohy- toring included hematology and clinical chemistry, as well as drate, glucagon, or other resuscitative actions. Severe hypo- body weight. glycemia associated with seizure, unconsciousness, or coma Blood samples for anti-insulin antibodies (AIA) deter- was also to be reported as a serious AE. mination were to be drawn at least 8 h after the last ad- Immunogenicity was assessed by incidence (patients with ministration of mealtime insulin on day 1, at weeks 4 and newly positive postbaseline [treatment induced] or with 12, and at the end of treatment at week 26. AIA were de- ‡4-fold increase in titer [treatment boosted], i.e., patients termined employing a validated radio immunoprecipitation with treatment-emergent AIA) and prevalence (patients with assay in a central laboratory blinded for treatment. The at least one positive sample at baseline or postbaseline) of assay was validated in agreement with recent literature. AIA, and using sample status, titer, and cross-reactivity to An Allergic Reaction Assessment Committee (ARAC) human insulin, insulin glargine, and insulin glargine M1 consisted of four experts, three of whom were board certi- metabolite. fied in allergy and clinical immunology and reviewed all hypersensitivity reactions reported on a specific allergic Statistical analysis reaction AE form or identified by Medical Dictionary for Regulatory Activities (MedDRA) search, and one of whom Efficacy analyses were performed in the intent-to-treat (ITT) was certified in diabetes mellitus and reviewed all cases of population, which included all randomized patients, irrespec- potential effects of AIA on efficacy (insulin dose, HbA ) tive of compliance with the study protocol and procedures. 1c and safety (hypoglycemia, injection site, and hypersensi- Noninferiority on the primary efficacy endpoint (change in tivity reaction). HbA from baseline to week 26) was tested at the prespecified 1c 0.3% margin, with a level of 0.025 (one sided). If noninferiority Study objectives of SAR-Lis over Ly-Lis was demonstrated, using a hierarchi- cal step-down testing procedure, the inverse noninferiority (of The primary objective of the study was to demonstrate Ly-Lis over SAR-Lis) was tested. Least square (LS) means noninferiority of SAR-Lis versus Ly-Lis in terms of changes were obtained from a mixed-effect model for repeated mea- in HbA from baseline to week 26 at a noninferiority mar- 1c sures using all available postbaseline HbA data, adjusted on 1c gin of 0.3% in patients with T2DM, also using GLA-100. treatment, randomization strata, visit, treatment-by-visit inter- Secondary objectives were to assess the immunogenicity of action, baseline, and baseline-by-visit interaction, and with an SAR-Lis and Ly-Lis in terms of positive/negative status and unstructured correlation matrix to model the within-patient antibody titers at baseline and during the course of the study; errors. Parameters were estimated using restricted maximum to assess the relationship of AIA with efficacy and safety; to likelihood method with the Newton-Raphson algorithm, assess the efficacy of SAR-Lis and Ly-Lis in terms of patients and denominator degrees of freedom were estimated using reaching target HbA <7.0% and £6.5%, FPG, SMPG pro- 1c Satterthwaite’s approximation. files, and insulin dose; and to assess the safety of SAR-Lis A sample size of 480 randomized patients (240 patients/ and Ly-Lis. arm) was considered sufficient to ensure that the upper bound of the two-sided 95% confidence interval (CI) for the adjusted Study endpoints mean difference between SAR-Lis and Ly-Lis on HbA 1c Efficacy endpoints included change from baseline to week change from baseline to week 26 would not exceed 0.3% 26 in HbA (primary endpoint), FPG, 24-h PG concentration HbA with at least 90% power. This calculation assumed 1c 1c from seven-point SMPG profiles and postprandial PG ex- a common standard deviation of 1.0% and a true differ- cursions (difference between 2-h postprandial and prepran- ence in HbA between the treatment groups of zero. All 1c dial PG values from seven-point SMPG profiles), as well as other efficacy, safety, and immunogenicity analyses were the proportion of patients reaching target HbA <7.0% and descriptive. 1c £6.5% at week 26. Safety endpoints included the percent- Safety analyses were based on the safety population, defined age of patients reporting at least one hypoglycemic event, as all patients randomized and exposed to at least one dose of hypoglycemic event rates, the occurrence of treatment- SAR-Lis or Ly-Lis, regardless of the amount of treatment emergent AEs (TEAEs), including hypersensitivity and in- administered. The AIA analyses were based on the AIA jection site reactions, and change in body weight and clinical population, defined as all patients from the safety population laboratory and hematology parameters. Hypersensitivity with at least one AIA sample available for analysis during events and injection site reactions were identified using the 6-month on-treatment period (from first IMP intake up to specific MedDRA codes. TEAEs were defined as events that 1 day after last IMP intake). All analyses were conducted occurred, worsened, or became serious from first investi- using SAS Enterprise Guide version 5.1. 52 DERWAHL ET AL. Results (0.294) U/kg/day for SAR-Lis and 0.433 (0.315) U/kg/day for Ly-Lis, and at 26 weeks was 0.524 (0.329) U/kg/day and Patient disposition and baseline characteristics 0.512 (0.420) U/kg/day, respectively (Table 2). The change A total of 707 patients were screened for the study; 202 from baseline to week 26 was 0.087 (0.209) U/kg/day for (28.6%) were screen failures (Fig. 1). The most common SAR-Lis and 0.080 (0.248) U/kg/day for Ly-Lis. Baseline reason for screen failure was HbA <6.5% or >10% (76 doses of GLA-100 were also similar in both groups. A modest 1c patients [10.7%]). Five hundred five patients were random- increase of the basal insulin daily doses was also observed in ized and treated (ITT and safety population): 253 patients in both treatment groups over the 26-week treatment period. the SAR-Lis group and 252 patients in the Ly-Lis group. Two Mean (SD) dose at baseline was 0.477 (0.265) U/kg/day for hundred twenty-eight patients (90.1%) in the SAR-Lis group the SAR-Lis group and 0.458 (0.239) U/kg/day for the Ly-Lis and 230 (91.3%) in the Ly-Lis group completed the treatment group, and change from baseline was 0.082 (0.133) U/kg/day period. A similar number of patients in each group discontinued for SAR-Lis and 0.071 (0.122) U/kg/day for Ly-Lis (Table 2). the study treatment prematurely (SAR-Lis, 25 [9.9%], and Ly- For the primary endpoint, the mean HbA decreased 1c Lis, 22 [8.7%]). The most common reasons for treatment similarly in both treatment groups from baseline to week 26, discontinuation were ‘‘Other reasons,’’ which included pa- with the mean decrease in HbA from baseline occurring 1c tient decision or consent withdrawal, and ‘‘Adverse events.’’ mostly during the first 12 weeks of treatment (Fig. 2B). The Demographic and baseline characteristics were well bal- LS mean (standard error [SE]) change in HbA from base- 1c anced between treatment groups (Table 1). The mean age of line to week 26 was similar in the SAR-Lis (-0.92 [0.051]%) the randomized population was 62.5 years, and more than and Ly-Lis (-0.85 [0.051]%) groups (Table 2). The LS mean 40% of the population was 65 years or older. Most patients difference (SE; 95% CI) between the SAR-Lis group and the (93%) were overweight or obese (BMI ‡25 to <30 kg/m or Ly-Lis group was -0.07% (0.072; -0.215 to 0.067). Non- 2 2 ‡30 kg/m ), and the mean BMI was 32.2 kg/m . The mean inferiority of SAR-Lis versus Ly-Lis was demonstrated, as duration of diabetes was 17.1 years, with 80.8% of patients the upper bound of the two-sided 95% CI of the difference with a duration ‡10 years. Overall, 19.8% of the population between SAR-Lis and Ly-Lis was below the prespecified had a moderate impairment (estimated glomerular filtration noninferiority margin of 0.3%. The inverse noninferiority of Ly- rate [eGFR] ‡30 and <60 mL/min/1.73 m ) and four patients Lis versus SAR-Lis was also demonstrated. At week 26, (0.8% of all patients) had a severe impairment of renal similar percentages of randomized patients reached HbA 1c function (eGFR <30 mL/min/1.73 m ). Previous mealtime target <7% (SAR-Lis: 42.3%; Ly-Lis: 40.5%) and HbA 1c insulin use was Humalog/Liprolog (51.4%), NovoLog/ target £6.5% (SAR-Lis: 27.3%; Ly-Lis: 24.2%). NovoRapid (48.2%), or both (0.4%). Mean HbA value Mean FPGalsodecreased similarlyinbothgroups 1c was 8.0% (64 mmol/mol). (Fig. 2C). The LS mean change (SE) from baseline in FPG to week 26 was similar in the SAR-Lis group (-0.62 [0.176] mmol/L) and the Ly-Lis group (-0.67 [0.176] mmol/L). The Efficacy LS mean (SE; 95% CI) difference between SAR-Lis and Ly- Changes in the daily mealtime insulin doses were small Lis was 0.06 (0.249; -0.430 to 0.547) mmol/L (Table 2). The and similar in both groups over the 26-week treatment pe- mean seven-point SMPG profiles in both treatment groups riod and occurred mainly within the first 4 to 8 weeks of improved at all time points at week 26 compared with treatment (Fig. 2A). Mean (SD) dose at baseline was 0.449 baseline (Fig. 2D). The LS mean difference (SE; 95% CI) for FIG. 1. Patient disposition. Table 1. Demographic and Baseline Characteristics—Randomized Population SAR-Lis (N = 253) Ly-Lis (N = 252) All (N = 505) Age (years), mean (SD) [n] 62.1 (9.4) [253] 62.8 (8.9) [252] 62.5 (9.1) [505] Age groups, n (%) <65 144 (56.9) 137 (54.4) 281 (55.6) ‡65 to <75 89 (35.2) 93 (36.9) 182 (36.0) ‡75 20 (7.9) 22 (8.7) 42 (8.3) Male gender, n (%) 136 (53.8) 132 (52.4) 268 (53.1) Race, n (%) Caucasian/White 228 (90.1) 218 (86.5) 446 (88.3) Black 14 (5.5) 17 (6.7) 31 (6.1) Asian/Oriental 11 (4.3) 16 (6.3) 27 (5.3) Other 0 1 (0.4) 1 (0.2) Ethnicity, n (%) Hispanic 43 (17.0) 47 (18.7) 90 (17.8) Not Hispanic 210 (83.0) 205 (81.3) 415 (82.2) Regions, n (%) United States 122 (48.2) 120 (47.6) 242 (47.9) Western Europe 32 (12.6) 37 (14.7) 69 (13.7) Eastern Europe 67 (26.5) 58 (23.0) 125 (24.8) Rest of the world 32 (12.6) 37 (14.7) 69 (13.7) Region-approved Humalog , n (%) US-approved Humalog 122 (48.2) 120 (47.6) 242 (47.9) EU-approved Humalog 131 (51.8) 132 (52.4) 263 (52.1) Baseline weight (kg), mean (SD) [n] 92.2 (17.5) [253] 91.2 (17.4) [252] 91.7 (17.4) [505] Baseline BMI (kg/m ), mean (SD) [n] 32.3 (4.8) [253] 32.1 (4.8) [252] 32.2 (4.8) [505] Baseline BMI categories, n (%) <25 17 (6.7) 18 (7.1) 35 (6.9) ‡25 to <30 62 (24.5) 72 (28.6) 134 (26.5) ‡30 174 (68.8) 162 (64.3) 336 (66.5) Baseline estimated GFR (mL/min/1.73 m ), 77.29 (22.89) [253] 78.48 (23.66) [252] 77.89 (23.26) [505] mean (SD) [n] Baseline estimated GFR categories (mL/min/1.73 m ), n (%) ‡90 69 (27.3) 67 (26.6) 136 (26.9) ‡60 to <90 130 (51.4) 135 (53.6) 265 (52.5) ‡30 to <60 51 (20.2) 49 (19.4) 100 (19.8) <30 3 (1.2) 1 (0.4) 4 (0.8) Randomization strata of screening HbA categories, n (%) 1c <8% 105 (41.5) 104 (41.3) 209 (41.4) ‡8% 148 (58.5) 148 (58.7) 296 (58.6) Randomization strata of prior use of Humalog, n (%) Yes 155 (61.3) 155 (61.5) 310 (61.4) No 98 (38.7) 97 (38.5) 195 (38.6) Duration of T2DM (years), mean (SD) [n] 16.60 (7.93) [253] 17.52 (8.67) [252] 17.06 (8.31) [505] Duration of T2DM categories (years), n (%) <10 50 (19.8) 47 (18.7) 97 (19.2) ‡10 203 (80.2) 205 (81.3) 408 (80.8) Age at onset of T2DM (years), mean (SD) [n] 46.0 (10.1) [253] 45.8 (10.2) [252] 45.9 (10.1) [505] Duration of basal bolus insulin treatment (years), 7.10 (5.67) [247] 7.99 (6.76) [243] 7.54 (6.24) [490] mean (SD) [n] Duration of mealtime insulin treatment in patient life 6.43 (5.54) [250] 7.17 (6.33) [247] 6.80 (5.95) [497] (years), mean (SD) [n] Previous basal insulin type, n (%) Insulin glargine 253 (100) 251 (99.6) 504 (99.8) Duration of insulin glargine treatment (years), 5.75 (4.62) [253] 5.97 (4.69) [252] 5.86 (4.65) [505] mean (SD) [n] Previous mealtime insulin type, n (%) Humalog/Liprolog 133 (52.6) 126 (50.2) 259 (51.4) NovoLog /NovoRapid 119 (47.0) 124 (49.4) 243 (48.2) Both Humalog/Liprolog and NovoLog/NovoRapid 1 (0.4) 1 (0.4) 2 (0.4) Duration of previous treatment with Humalog/Liprolog 5.36 (5.29) [134] 4.64 (4.55) [127] 5.01 (4.95) [261] (years), mean (SD) [n] Duration of previous treatment with NovoLog/ 4.51 (4.41) [120] 5.72 (5.40) [125] 5.13 (4.97) [245] NovoRapid (years), mean (SD) [n] Baseline HbA ,%, mean (SD) [n] 7.99 (0.87) [253] 8.03 (0.91) [252] 8.01 (0.89) [505] 1c BMI, body mass index; GFR, glomerular filtration rate; Ly-Lis, Humalog insulin lispro; SAR-Lis, SAR342434 insulin lispro; SD, standard deviation; T2DM, type 2 diabetes mellitus. 53 54 DERWAHL ET AL. FIG. 2. Mean (SE) insulin dose (A), HbA (B), fasting plasma glucose (C), and seven-point SMPG time profiles (D). 1c Data for (A) is from the safety population, for (B–D), the ITT population. For (A), baseline is defined as the mean of daily doses available in the week before the first injection of SAR-Lis or Ly-Lis. ITT, intent-to-treat; Ly-Lis, Humalog insulin lispro; SAR-Lis, SAR342434 insulin lispro; SE, standard error; SMPG, self-monitored plasma glucose. SAR-Lis versus Ly-Lis for postprandial glucose excursions day was similar in the SAR-Lis (68.4%) and Ly-Lis (74.6%) at breakfast, lunch, and dinner were -0.48 (0.328; -1.127 to groups, and similar percentages of patients reported noctur- 0.164), -0.05 (0.357; -0.749 to 0.655), and 0.21 (0.374; nal hypoglycemia (00:00–05:59 h) in the SAR-Lis group and -0.525 to 0.945) mmol/L, respectively (Table 2). Mean 24-h the Ly-Lis group (regardless the category) (Table 3). The PG values at baseline and week 26 were also similar between occurrence of severe hypoglycemia, although imbalanced, the two groups, with an LS mean (SE; 95% CI) difference of was very low (<0.1 per patient-year) in both treatment -0.09 (0.191; -0.464 to 0.287) mmol/L (Table 2). groups. Severe hypoglycemia was reported in six patients In the SORELLA 2 study, the subgroup analyses based on (2.4%) in the SAR-Lis group and four patients (1.6%) in the baseline data in obese patients with BMI ‡30 versus <30 kg/ Ly-Lis group, and nocturnal severe hypoglycemia in two m , by diabetes duration (‡10 years vs. <10 years), in the patients (0.8%) and none, respectively. In all other predefined elderly (<65 years vs. ‡65 to <75 years), and by ethnicity categories of hypoglycemia, the percentages of patients were were consistent with the total patient population. similar with SAR-Lis and Ly-Lis. Most hypoglycemia was observed between 7 a.m. and midnight with small peaks around each meal (Supplementary Safety Fig. S2). There were no relevant differences in event rates The percentage of patients with at least one hypoglycemia between the two groups. The event rate of any hypoglycemia event (regardless of the category) reported at any time of the was similar in both treatment groups with 16.78 events per BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 55 Table 2. Summary of Insulin Doses and Glycemic Control SAR-Lis Ly-Lis Insulin dose—safety population Mealtime insulin, U/kg, mean (SD) Baseline [n] 0.449 (0.294) [231] 0.433 (0.315) [243] Week 26 [n] 0.524 (0.329) [214] 0.512 (0.420) [223] Change from baseline [n] 0.087 (0.209) [197] 0.080 (0.248) [218] Basal insulin, U/kg, mean (SD) Baseline [n] 0.477 (0.265) [232] 0.458 (0.239)[244] Week 26 [n] 0.555 (0.303) [214] 0.525 (0.262) [223] Change from baseline [n] 0.082 (0.133) [196] 0.071 (0.122) [218] Glycemic control—ITT population (patients included in the MMRM analysis) HbA , %-units; mean (SD) 1c Baseline [n] 8.00 (0.86) [239] 8.03 (0.91) [246] Week 26 [n] 7.06 (0.85) [231] 7.16 (0.88) [232] LS mean change (SE) from baseline [n] -0.92 (0.051) [239] -0.85 (0.051) [246] LS mean difference (SE) [95% CI] -0.07 (0.072) [-0.215 to 0.067] FPG, mmol/L; mean (SD) Baseline [n] 8.35 (2.67) [228] 8.18 (2.80) [235] Week 26 [n] 7.65 (2.71) [220] 7.53 (2.81) [220] LS mean change (SE) from baseline [n] –0.62 (0.176) [228] -0.67 (0.176) [228] LS mean difference (SE) [95% CI] vs. Ly-Lis 0.06 (0.249) [-0.430 to 0.547] Postprandial glucose excursion from SMPG, mmol/L; mean (SD) Breakfast Baseline [n] 1.96 (3.27) [194] 1.82 (3.46) [204] Week 26 [n] 1.30 (3.17) [171] 1.77 (3.14) [184] LS mean change (SE) from baseline [n] -0.72 (0.236) [194] -0.23 (0.228) [204] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.48 (0.328) [-1.127 to 0.164] Lunch Baseline [n] 1.71 (3.36) [195] 1.11 (3.68) [200] Week 26 [n] 1.42 (3.52) [170] 1.33 (3.26) [174] LS mean change (SE) from baseline [n] 0.06 (0.255) [195] 0.11 (0.250) [200] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.05 (0.357) [-0.749 to 0.655] Dinner Baseline [n] 1.00 (3.23) [190] 1.08 (3.40) [193] Week 26 [n] 1.11 (3.47) [167] 0.94 (3.36) [168] LS mean change (SE) from baseline [n] 0.11 (0.264) [190] -0.10 (0.264) [193] LS mean difference (SE) [95% CI] vs. Ly-Lis 0.21 (0.374) [-0.525 to 0.945] Mean 24-h plasma glucose from SMPG, mmol/L, mean (SD) Baseline [n] 10.07 (2.11) [201] 9.81 (2.05) [210] Week 26 [n] 9.01 (2.17) [180] 9.00 (1.75) [189] LS mean change (SE) from baseline [n] -1.00 (0.137) [201] 0.91 (0.133) [210] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.09 (0.191) [-0.464 to 0.287] LS means from MMRM with treatment group (SAR-Lis, Ly-Lis), randomization strata of screening HbA (<8.0, ‡8.0%) and prior use of 1c insulin lispro (Yes, No), visit (week 12, week 26), and treatment-by-visit interaction as fixed categorical effects, and baseline value and baseline value-by-visit interaction as continuous fixed covariates. FPG, fasting plasma glucose; ITT, intent-to-treat; LS, least square; MMRM, mixed-effect model for repeated measures; SE, standard error; SMPG, self-monitored plasma glucose. patient-year of exposure in the SAR-Lis group and 18.59 treatment. Serious TEAEs involving hypoglycemia were re- events per patient-year of exposure in the Ly-Lis group ported in two patients (0.8%) in each group. (Table 3). The nocturnal hypoglycemia event rate was low A similar percentage of patients in the SAR-Lis and Ly-Lis and also similar in the SAR-Lis and Ly-Lis groups, being group reported a TEAE (SAR-Lis, 46.6%; Ly-Lis, 42.9%; 2.22 and 2.51 events per patient-year of exposure, respec- Table 4), the most common of which was nasopharyngitis tively. The only category of hypoglycemia where a difference (SAR-Lis, 4.0%; Ly-Lis, 2.0%). Serious TEAEs were re- between the two groups was observed was severe hypogly- ported in a lower percentage of patients in the SAR-Lis group cemia where the annualized event rate was 0.08, with nine (5.5% [14 patients]) than in the Ly-Lis group (10.7% [27 events reported in six patients in the SAR-Lis group, and patients]). Events were distributed over a variety of system 0.03, with four events reported in four patients in the Ly-Lis organ classes (SOCs) with an incidence no higher than 1.6% group. The higher rate in the SAR-Lis group was due to one (four patients) in any SOC in any treatment group, except for patient who reported four events of severe hypoglycemia. No cardiac disorders, which was reported in 1.2% (three patients) factors were identified that may have contributed to this pa- in the SAR-Lis group and 4.4% (11 patients) in the Ly-Lis tient’s frequent low blood glucose. Most patients with severe group. Seven patients (2.8%) in the SAR-Lis group and six hypoglycemia had prompt recovery further to corrective patients (2.4%) in the Ly-Lis group reported TEAEs leading 56 DERWAHL ET AL. Table 3. Summary of Hypoglycemia Events—Safety Population All hypoglycemia Nocturnal hypoglycemia (00:00–05:59) Type of hypoglycemia SAR-Lis (N = 253) Ly-Lis (N = 252) SAR-Lis (N = 253) Ly-Lis (N = 252) Total patient years 118.69 121.23 118.69 121.23 Any hypoglycemia Patients, n (%) 173 (68.4) 188 (74.6) 74 (29.2) 85 (33.7) No. of events (rate/patient-year) 1992 (16.78) 2254 (18.59) 264 (2.22) 304 (2.51) Severe hypoglycemia Patients, n (%) 6 (2.4) 4 (1.6) 2 (0.8) 0 No. of events (rate/patient-year) 9 (0.08) 4 (0.03) 2 (0.02) 0 Documented symptomatic hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 152 (60.1) 167 (66.3) 64 (25.3) 69 (27.4) No. of events (rate/patient-year) 1345 (11.33) 1478 (12.19) 204 (1.72) 216 (1.78) Documented symptomatic hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 73 (28.9) 69 (27.4) 21 (8.3) 20 (7.9) No. of events (rate/patient-year) 193 (1.63) 196 (1.62) 33 (0.28) 33 (0.27) Asymptomatic hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 89 (35.2) 94 (37.3) 20 (7.9) 24 (9.5) No. of events (rate/patient-year) 409 (3.45) 598 (4.93) 26 (0.22) 49 (0.40) Asymptomatic hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 26 (10.3) 32 (12.7) 3 (1.2) 3 (1.2) No. of events (rate/patient-year) 47 (0.40) 66 (0.54) 4 (0.03) 3 (0.02) Severe and/or confirmed hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 169 (66.8) 183 (72.6) 73 (28.9) 79 (31.3) No. of events (rate/patient-year) 1907 (16.07) 2154 (17.77) 248 (2.09) 278 (2.29) Severe and/or confirmed hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 89 (35.2) 84 (33.3) 26 (10.3) 22 (8.7) No. of events (rate/patient-year) 271 (2.28) 277 (2.28) 40 (0.34) 39 (0.32) n (%), number and percentage of patients with at least one treatment-emergent hypoglycemia event. Severe and/or confirmed hypoglycemia= severe and/or confirmed by plasma glucose £3.9 mmol/L (70 mg/dL) or <3.0 mmol/L (54 mg/dL). to permanent discontinuation of the investigational drug. A additional patient in the Ly-Lis group died after the end of the total of three deaths occurred during the study period: one study of unknown causes. The deaths were considered not death (0.4%) in the SAR-Lis group due to a cardio-respiratory related to IMP. arrest and two deaths (0.8%) in the Ly-Lis group due to car- The mean increase in body weight from baseline to diopulmonary failure and bladder cancer with metastasis. One week 26 was similar in the SAR-Lis (+1.35 kg) and Ly-Lis Table 4. Summary of Injection Site and Hypersensitivity Reactions and Adverse Events (Safety Population), and Anti-Insulin Antibodies (AIA Population) Safety population SAR-Lis (N = 253) Ly-Lis (N = 252) Any injection site reaction 1 (0.4) 4 (1.6) Any hypersensitivity reactions 10 (4.0) 9 (3.6) Patients with any TEAE 118 (46.6) 108 (42.9) Patients with any treatment-emergent SAE 14 (5.5) 27 (10.7) Patients with any TEAE leading to death 1 (0.4) 2 (0.8) Patients with any TEAE leading to permanent IMP discontinuation 7 (2.8) 6 (2.4) AIA population SAR-Lis (N = 245) Ly-Lis (N = 248) Patients with AIA positive at baseline, n (%) 60/245 (24.5) 63/248 (25.4) Patients with ‡4-fold increase in titer (treatment boosted), n (%) 12/60 (20.0) 8/63 (12.7) Patients with AIA negative or missing at baseline, n (%) 185/245 (75.5) 185/248 (74.6) Patients newly positive postbaseline (treatment induced), n (%) 34/185 (18.4) 28/185 (15.1) Patients with at least one positive AIA sample (prevalence), n (%) 94/245 (38.4) 91/248 (36.7) Patients with treatment-emergent AIA (incidence), n (%) 46/245 (18.8) 36/248 (14.5) No. (%) of patients AIA positive at week 26 68/221 (30.8%) 66/226 (29.2%) Data are n (%) = number and percentage of patients with at least one TEAE. Prevalence: patients AIA positive at baseline plus those with treatment-induced AIAs. Incidence: patients with treatment-boosted or treatment-induced AIAs (i.e., patients with treatment-emergent AIAs). AIA, anti-insulin antibodies; IMP, investigational medicinal product; SAE, serious adverse event; TEAE, treatment-emergent adverse event. BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 57 (+1.32 kg) groups. No clinically meaningful changes from poglycemia with SAR-Lis than Ly-Lis due to one patient who baseline were observed in clinical laboratory and hematology reported four events. The general safety profile (percent- parameters, and no relevant differences between the two ages of patients with any TEAE, serious TEAEs, or TEAEs treatment groups occurred. leading to study medication discontinuation, as well as type of TEAEs) was also similar between treatment groups. Al- Immunogenicity though a slightly higher percentage of patients with treatment- emergent AIA was observed in the SAR-Lis group, no impact Similar percentages of patients in both treatment groups on efficacy and safety was observed in either group. were positive for AIA at baseline (SAR-Lis, 24.5%, and Ly- The original registration studies with Ly-Lis showed al- Lis, 25.4%) (Table 4). The percentage of patients with a tered efficacy of Ly-Lis in obese patients; thus the FDA treatment-emergent AIA response (i.e., treatment-boosted mandated postmarketing studies in obese patients after the or treatment-induced AIAs; incidence) was 18.8% (46/245) product was approved in 1996. In the SORELLA 2 study, in the SAR-Lis group and 14.5% (36/248) in the Ly-Lis the subgroup analyses based on baseline data in obese pa- group. Over the 6-month period, percentages of patients 2 2 tients with BMI ‡30 kg/m versus <30 kg/m , by diabetes positive for AIA slightly increased in both treatment groups: duration (‡10 years vs. <10 years), in the elderly (<65 years 30.8% of SAR-Lis patients and 29.2% of Ly-Lis patients at vs. ‡65 to <75 years), and by ethnicity were consistent with week 26. Similar percentages of patients in the SAR-Lis the total patient population. In particular, the incidence of group (38.4%) and Ly-Lis group (36.7%) were positive for hypoglycemia was comparable between treatments for the AIAs at least at one time point between baseline and month 6 subgroups, including incidence of severe hypoglycemia. (prevalence). Cross-reactivity with human insulin, insulin The study included a study population that is largely adult glargine, and insulin glargine M1 metabolite was high (80%– white Caucasian with small numbers of blacks and Asians. 90%) and consistent between treatment groups. No rela- Caution should be taken when extending the results to other tionship was observed between the individual maximal AIA ethnic populations or subgroups, as the study was not pow- titers and the change in total insulin dose, HbA , hypogly- 1c ered for them. The open-label study design was chosen as the cemia, injection site, and hypersensitivity reactions. prefilled, disposable pen injection devices for SAR-Lis and A low number of patients reported hypersensitivity reac- Ly-Lis could not be made indistinguishable. However, out- tions (SAR-Lis, 10 [4.0%] and Ly-Lis, 9 [3.6%]) and very come assessments were determined based on objectively few patients reported injection site reactions (SAR-Lis, 1 collected data determined by central laboratories blinded to [0.4%] and Ly-Lis, 4 [1.6%]) (Table 4). Most events were the study treatment. mild or moderate in intensity. All resolved while treatment We conclude that SAR-Lis and Ly-Lis when used for 6 was ongoing, with the exception of one event in the SAR-Lis months in combination with GLA-100 provided effective and group (dermatitis contact) and three events in the Ly-Lis similar glucose control in patients with T2DM. SAR-Lis and group (one event each of dermatitis, rash, and facial edema). Ly-Lis had similar safety and immunogenicity profiles and no Out of the 24 potential hypersensitivity reactions reported in specific safety concerns were observed. either treatment group, only four events (seasonal allergy, contact dermatitis, allergy to arthropod bite, and allergic Acknowledgments rhinitis) in the SAR-Lis group and three events (pruritus [two] and mouth swelling) in the Ly-Lis group were adju- The study was funded by Sanofi. Editorial support was dicated as allergic reaction by the ARAC; the two events of provided by Tom Claus, PhD, of PAREXEL, and was funded pruritus in the Ly-Lis group were considered related to IMP. by Sanofi. Discussion Author Disclosure Statement Insulins approved as biosimilars or follow-on biologics K.-M.D., Consultant to Astra Zeneca, Lilly, Novo Nordisk, expand the number of insulin brands available for those Sanofi; honorarium (lectures) from AstraZeneca, Sanofi, with diabetes and may have the potential to reduce diabetes Menarini, Novo Nordisk. T.S.B., Consultant to Astra Zeneca, treatment cost. Indeed, these products are usually marketed at Ascensia, BD, Calibra, Lilly, Medtronic, Novo Nordisk, a lower price than the originator product. This was first ob- Sanofi. Research support from Abbott, Ambra, Ascensia, BD, served after the market launch of erythropoietin biosimilars. Boehringer Ingelheim, Calibra, Companion Medical, Dex- In this study, we report on the pharmacological charac- com, Elcelyx, Glysens, Janssen, Lexicon, Lilly, Medtronic, teristics of SAR-Lis insulin, a biosimilar of Ly-Lis insulin Novo Nordisk, Sanofi, Senseonics, Versartis, and Xeris; with an identical amino acid sequence. Similar efficacy in Speaker’s Bureau for Abbott, Insulet, Medtronic, Lilly, terms of changes in HbA levels was noted between SAR- 1c Novo Nordisk, Sanofi. K.W.-P., Employee, Sanofi-Aventis Lis and Ly-Lis at the primary endpoint at week 26, and Deutschland GmbH; Stock/Shareholder, Sanofi. L.P., Em- noninferiority of SAR-Lis to Ly-Lis and of Ly-Lis to SAR- ployee, Sanofi, Bridgewater, NJ; Stock/Shareholder, Sanofi. Lis was demonstrated in accordance with the guidance from S.P., Employee, Sanofi, Paris, France; Stock/Shareholder, the US Food and Drug Administration (FDA) and European Sanofi. 4–8 Medicines Agency (EMA). The FPG and seven-point SMPG profiles were similar between treatment groups except References for some small differences at certain time points, which were not considered clinically relevant. All hypoglycemic events 1. American Diabetes Association: Intensive Diabetes Man- and event rates were similar in both treatment groups, across agement. Alexandria, VA: American Diabetes Association, all ADA categories, except for a higher rate of severe hy- 2009. 58 DERWAHL ET AL. 2. American Diabetes Association: Standards of Medical Care Humalog in subjects with type 1 diabetes. Diabetes Obes in Diabetes. Diabetes Care 2013;36(suppl 1): S11–S66. Metab 2017;19:622–627. 3. Humalog Prescribing Information. www.accessdata.fda 10. Shankar G, Devanarayan V, Amaravadi L, et al.: Rec- .gov/drugsatfda_docs/label/2013/020563s115lbl.pdf (accessed ommendations for the validation of immunoassays used for February 1, 2017). detection of host antibodies against biotechnology products. 4. EMA: Guideline on nonclinical and clinical development J Pharm Biomed Anal 2008;48:1267–1281. of similar biological medicinal products containing re- 11. Seaquist ER, Anderson J, Childs B, et al.: Hypoglycemia combinant human insulin and insulin analogues. 2015. and diabetes: a report of a Workgroup of the American EMA/CHMP/BMWP/32775/2005 Rev.1:1–12 Diabetes Association and the Endocrine Society. Diabetes 5. US Food and Drug Administration, Center for Drug Eval- Care 2013;36:1384–1395. uation and Research (CDER): Guidance for Industry. Ap- 12. Segal AR, Vootla T, Beaser RS: Insulin: making sense of plications covered by Section 505(b)(2). Draft Guidance current options. Endocrinol Metab Clin North Am 2016;45: 1999:1–15. 845–874. 6. EMA: Guideline on similar biological medicinal products. 13. Gagnon-Auger M, du Souich P, Baillargeon JP, et al.: Committee for Medicinal Products for Human Use (CHMP). Dose-dependent delay of the hypoglycemic effect of short- 2014. CHMP/437/04 Rev 1:1–7. acting insulin analogs in obese subjects with T2DM. Dia- 7. EMA: Guideline on clinical investigation of medicinal betes Care 2010;33:2502–2507. products in the treatment or prevention of diabetes mellitus. Address correspondence to: 2012.CPMP/EWP/1080/00 Rev 1:1–28. 8. US Food and Drug Administration, Center for Drug Eval- Karl-Michael Derwahl, MD, PhD uation and Research (CDER): Guidance for Industry. Institut fu¨r klinische Forschung und Diabetes Mellitus: Developing Drugs and Therapeutic Entwicklung (IKFE) Berlin GmbH Biologics for Treatment and Prevention. Draft Guidance Große Hamburger Straße 5-11 2008:1–34. 10115 Berlin 9. Kapitza C, Nowotny I, Lehmann A, et al.: Similar phar- Germany macokinetics and pharmacodynamics of rapid-acting insu- lin lispro products SAR342434 and US- and EU-approved E-mail: derwahl@ikfe-berlin.de http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Technology & Therapeutics Pubmed Central

Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study

Diabetes Technology & Therapeutics , Volume 20 (1) – Jan 1, 2018

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Pubmed Central
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© Karl-Michael Derwahl, et al., 2018; Published by Mary Ann Liebert, Inc.
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1520-9156
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DOI
10.1089/dia.2017.0281
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Abstract

Background: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (U100; Humalog ; Ly-Lis). This study aimed to show similar efficacy, safety, and immunogenicity of SAR-Lis versus Ly-Lis in adult patients with type 2 diabetes mellitus (T2DM) treated with multiple daily injections, while using insulin glargine (GLA-100; Lantus ) as basal insulin. Methods: SORELLA 2 was a 6-month, randomized, open-label, Phase 3 study (NCT02294474). Insulin doses were adjusted to achieve fasting and 2-h postprandial glucose targets according to American Diabetes Asso- ciation guidelines. Primary endpoint was the HbA change from baseline to week 26 (tested for noninferiority 1c of SAR-Lis vs. Ly-Lis with a margin of 0.3%). Secondary endpoints included fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIA). Results: A total of 505 patients were randomized (1:1) to multiple daily injections of SAR-Lis (n = 253) or Ly- Lis (n = 252) plus once-daily GLA-100. Least square (LS) mean (standard error) change in HbA from baseline to 1c week 26 was similar in both treatment groups (SAR-Lis, -0.92% [0.051] and Ly-Lis, -0.85% [0.051]). Non- inferiority at prespecified 0.3% noninferiority margin was demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: -0.07% [95% CI: -0.215 to 0.067]) as was inverse noninferiority. Similar changes in FPG, seven-point SMPG profiles, including postprandial glucose excursions and mean glucose over 24 h, and insulin dosages were observed in the two groups. Hypoglycemia, TEAEs, and AIA (incidence and prevalence) did not differ between groups. Conclusions: Results from this controlled study in patients with T2DM also using GLA-100 support similar efficacy and safety (including immunogenicity) of SAR-Lis and Ly-Lis. Keywords: Biosimilar, Insulin antibodies, Immunogenicity, Insulin lispro, SORELLA 2. Introduction to achieve good glycemic control, most often start insulin therapy with a basal insulin, such as insulin glargine (GLA- atients with type 2 diabetes mellitus (T2DM) on 100; Lantus ), to control fasting blood glucose levels. If Poral antihyperglycemic treatment, who require insulin adequate glycemic control cannot be obtained by controlling Institut fu¨r Klinische Forschung und Entwicklung (IKFE) Berlin GmbH, Berlin, Germany. AMCR Institute, Escondido, California. Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. Sanofi, Bridgewater, New Jersey. Sanofi, Paris, France. Portions of this article have been presented at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, June 9–13, 2017. ª Karl-Michael Derwahl, et al., 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 49 50 DERWAHL ET AL. fasting blood glucose alone, it becomes necessary to also control insulin infusion, history of severe hypoglycemia requiring prandial glucose levels. Among the options is to add a short- or treatment by emergency room admission, or poor metabolic rapid-acting insulin. According to the American Diabetes As- control requiring hospitalization, all within the last 6 months sociation (ADA), recommended therapy for T2DM consists of before screening. Also excluded were women of childbearing matching the prandial insulin dose to premeal blood glucose, potential not protected by a highly effective contraceptive carbohydrate intake, and anticipated activity. For many method and patients with unstable proliferative diabetic ret- patients (especially if hypoglycemia is a problem), use of inopathy or any other rapidly progressive diabetic retinopa- insulin analogs is recommended. The use of rapid-acting thy, or macular edema likely to require treatment (e.g., laser, insulin analogs, such as insulin lispro, insulin aspart, or insulin surgical treatment, or injectable drugs) during the study. glulisine, also facilitates flexible dosing in these insulin treat- ment regimens. Study design Insulin lispro differs from human insulin in that the amino SORELLA 2 (NCT02294474) was a multicenter, 6-month, acid proline at position B28 is replaced by lysine and the lysine randomized, open-label, two-arm parallel-group, Phase 3 in position B29 is replaced by proline. This modification does study comparing SAR-Lis with Ly-Lis in adults with T2DM not alter insulin receptor binding, but blocks the formation of also using GLA-100 as basal insulin. The study consisted of a dimers and hexamers. As a consequence, higher amounts of screening period (up to 2 weeks), a 26-week treatment period, subcutaneous monomers are available for rapid absorption. and a 1-day safety follow-up (Supplementary Fig. S1; Sup- This enables a shorter waiting period after injection before plementary Data are available online at http://online.liebertpub starting the meal. Insulin lispro is the active ingredient of Hu- .com/doi/suppl/10.1089/dia.2017.0281). Clinical visits were malog (Ly-Lis; Lilly). Humalog was the first rapid-acting scheduled for screening, randomization (day 1), weeks 4, 8, insulin approved and marketed in the EU, the US, and many 12, 20, and 26 (endpoint). After the screening period, 480 other countries worldwide, and is used in the treatment of both patients were planned to be randomized 1:1 to receive either patients with type 1 diabetes mellitus (T1DM) and T2DM. SAR-Lis or Ly-Lis in addition to the once-daily Gla-100. SAR342434 (SAR-Lis; insulin lispro; Sanofi) has been The randomization was stratified by HbA obtained at the 1c developed as a biosimilar (follow-on) biological medicinal screening visit (<8.0%, ‡8.0%) and prior use of insulin lispro product to Humalog U100 in accordance with the relevant US (Yes, No). The randomization and the treatment kit allocation and EU guidelines, including the EU guidelines for similar were performed centrally by an interactive voice response medicinal products containing recombinant human insulin system/interactive web response system. The comparator 4–8 and insulin analogs, as well as product-specific guidelines. drug in the study was Ly-Lis. Patients randomized to Ly-Lis SAR-Lis was shown to be highly similar to Ly-Lis through received US- or EU-approved Ly-Lis, depending on the lo- physicochemical analyses and in vitro and in vivo nonclinical cation of their study site. Based on the similarity between Ly- studies. Similar pharmacokinetic (PK) exposure and phar- Lis US and Ly-Lis EU shown in physicochemical analyses, macodynamic (PD) activity were demonstrated for SAR-Lis nonclinical studies, and the PK/PD study, data from both to both Ly-Lis approved in the EU and Ly-Lis approved in the insulins were pooled in the comparator group of this study. US, as well as between Ly-Lis US and Ly-Lis EU in a PK/PD Study medications were dispensed on day 1, and weeks 4, 8, study in patients with T1DM using the euglycemic clamp 12, and 20. Self-monitored plasma glucose (SMPG) and insulin 9,10 technique. This report presents the results of a multina- dose data were obtained from the patient’s diary at each visit tional, open-label, randomized, controlled Phase 3 study when compliance was checked by reviewing the patient’s diary (SORELLA 2) comparing the efficacy and safety of SAR-Lis and counting/collecting used and unused pens. Starting dose of and the reference product Ly-Lis (100 U/mL) in patients with SAR-Lis or Ly-Lis was a unit-to-unit conversion from the T2DM, also using insulin glargine (GLA-100). Humalog/Liprolog or Novolog/NovoRapid dose used before the trial. SAR-Lis or Ly-Lis was administered subcutaneously Methods (SC), immediately before meal intake using insulin pens. Oc- The study was approved by relevant review boards/ethics casional postprandial injections soon after meal intake were committees, and was performed in accordance with the De- permitted if deemed necessary and if allowed by the national claration of Helsinki and the International Conference on product label for Ly-Lis. Mealtime insulin dose could be ad- Harmonisation guidelines. All participants provided written justed to achieve a target range for 2-h postprandial plasma informed consent before participation. glucose (PG) of 120–160 mg/dL (6.7–8.9 mmol/L). The start- ing dose of GLA-100 was the same as the prestudy dose. GLA- Study patients 100 was injected SC once daily at the same time throughout the study, and dose adjustments were made to achieve a fasting, Eligible patients were of the legal age of adulthood with prebreakfast PG of 80–130 mg/dL (4.4–7.2 mmol/L). No for- HbA ‡6.5% and £10%, T2DM diagnosed for at least 12 1c mal titration algorithm was recommended for basal insulin; months, and treated with Humalog/Liprolog (insulin lispro) patients were instructed to use dosage self-adjustment of rapid- or NovoLog /NovoRapid (rapid-acting insulin aspart) at acting insulin analogs according to local guidelines to achieve least thrice daily before each meal and GLA-100 as basal target glucose, while avoiding hypoglycemia. insulin in the 6 months before the screening visit. Noninsulin antihyperglycemic background therapy taken at a stable dose Efficacy, safety, and immunogenicity assessments for at least 3 months before the screening visit was permitted. Excluded were patients with body mass index (BMI) ‡40 kg/m , HbA and fasting plasma glucose (FPG) were determined 1c the use of noninsulin injectable peptides (e.g., GLP1-receptor in a central laboratory blinded for treatment (Covance, In- agonists or other peptides), use of continuous subcutaneous dianapolis, IN) at screening (HbA only), baseline, week 12, 1c BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 51 and week 26. Seven-point SMPG profiles (preprandial and gational medicinal product (IMP) intake up to 1 day after 2-h postprandial after breakfast, lunch, and dinner, and at last IMP intake. bedtime) were to be performed on at least 2 days in the week Hypoglycemia was categorized based on the ADA defi- before baseline, week 12, and week 26, measured in a sin- nitions. Documented symptomatic hypoglycemia was an gle, 24-h period using the Bluetooth-enabled glucometer event during which typical symptoms of hypoglycemia were ‘‘myGlucoHealth’’ (Entra Health Systems, San Diego, CA). accompanied by a measured PG concentration £3.9 mmol/L SMPG results, hypoglycemic events, and insulin doses were (£70 mg/dL); those with PG <3.0 mmol/L (<54 mg/dL) were recorded by the patients in a paper diary and manually en- also analyzed. Nocturnal hypoglycemia was defined as any tered in the e-CRF by the investigator. Adverse events (AEs), hypoglycemia that occurred between 00:00 and 05:59 a.m. including hypersensitivity events and injection site reac- hours. Severe hypoglycemia was an event that required tions, were documented at each visit. Further safety moni- assistance of another person to actively administer carbohy- toring included hematology and clinical chemistry, as well as drate, glucagon, or other resuscitative actions. Severe hypo- body weight. glycemia associated with seizure, unconsciousness, or coma Blood samples for anti-insulin antibodies (AIA) deter- was also to be reported as a serious AE. mination were to be drawn at least 8 h after the last ad- Immunogenicity was assessed by incidence (patients with ministration of mealtime insulin on day 1, at weeks 4 and newly positive postbaseline [treatment induced] or with 12, and at the end of treatment at week 26. AIA were de- ‡4-fold increase in titer [treatment boosted], i.e., patients termined employing a validated radio immunoprecipitation with treatment-emergent AIA) and prevalence (patients with assay in a central laboratory blinded for treatment. The at least one positive sample at baseline or postbaseline) of assay was validated in agreement with recent literature. AIA, and using sample status, titer, and cross-reactivity to An Allergic Reaction Assessment Committee (ARAC) human insulin, insulin glargine, and insulin glargine M1 consisted of four experts, three of whom were board certi- metabolite. fied in allergy and clinical immunology and reviewed all hypersensitivity reactions reported on a specific allergic Statistical analysis reaction AE form or identified by Medical Dictionary for Regulatory Activities (MedDRA) search, and one of whom Efficacy analyses were performed in the intent-to-treat (ITT) was certified in diabetes mellitus and reviewed all cases of population, which included all randomized patients, irrespec- potential effects of AIA on efficacy (insulin dose, HbA ) tive of compliance with the study protocol and procedures. 1c and safety (hypoglycemia, injection site, and hypersensi- Noninferiority on the primary efficacy endpoint (change in tivity reaction). HbA from baseline to week 26) was tested at the prespecified 1c 0.3% margin, with a level of 0.025 (one sided). If noninferiority Study objectives of SAR-Lis over Ly-Lis was demonstrated, using a hierarchi- cal step-down testing procedure, the inverse noninferiority (of The primary objective of the study was to demonstrate Ly-Lis over SAR-Lis) was tested. Least square (LS) means noninferiority of SAR-Lis versus Ly-Lis in terms of changes were obtained from a mixed-effect model for repeated mea- in HbA from baseline to week 26 at a noninferiority mar- 1c sures using all available postbaseline HbA data, adjusted on 1c gin of 0.3% in patients with T2DM, also using GLA-100. treatment, randomization strata, visit, treatment-by-visit inter- Secondary objectives were to assess the immunogenicity of action, baseline, and baseline-by-visit interaction, and with an SAR-Lis and Ly-Lis in terms of positive/negative status and unstructured correlation matrix to model the within-patient antibody titers at baseline and during the course of the study; errors. Parameters were estimated using restricted maximum to assess the relationship of AIA with efficacy and safety; to likelihood method with the Newton-Raphson algorithm, assess the efficacy of SAR-Lis and Ly-Lis in terms of patients and denominator degrees of freedom were estimated using reaching target HbA <7.0% and £6.5%, FPG, SMPG pro- 1c Satterthwaite’s approximation. files, and insulin dose; and to assess the safety of SAR-Lis A sample size of 480 randomized patients (240 patients/ and Ly-Lis. arm) was considered sufficient to ensure that the upper bound of the two-sided 95% confidence interval (CI) for the adjusted Study endpoints mean difference between SAR-Lis and Ly-Lis on HbA 1c Efficacy endpoints included change from baseline to week change from baseline to week 26 would not exceed 0.3% 26 in HbA (primary endpoint), FPG, 24-h PG concentration HbA with at least 90% power. This calculation assumed 1c 1c from seven-point SMPG profiles and postprandial PG ex- a common standard deviation of 1.0% and a true differ- cursions (difference between 2-h postprandial and prepran- ence in HbA between the treatment groups of zero. All 1c dial PG values from seven-point SMPG profiles), as well as other efficacy, safety, and immunogenicity analyses were the proportion of patients reaching target HbA <7.0% and descriptive. 1c £6.5% at week 26. Safety endpoints included the percent- Safety analyses were based on the safety population, defined age of patients reporting at least one hypoglycemic event, as all patients randomized and exposed to at least one dose of hypoglycemic event rates, the occurrence of treatment- SAR-Lis or Ly-Lis, regardless of the amount of treatment emergent AEs (TEAEs), including hypersensitivity and in- administered. The AIA analyses were based on the AIA jection site reactions, and change in body weight and clinical population, defined as all patients from the safety population laboratory and hematology parameters. Hypersensitivity with at least one AIA sample available for analysis during events and injection site reactions were identified using the 6-month on-treatment period (from first IMP intake up to specific MedDRA codes. TEAEs were defined as events that 1 day after last IMP intake). All analyses were conducted occurred, worsened, or became serious from first investi- using SAS Enterprise Guide version 5.1. 52 DERWAHL ET AL. Results (0.294) U/kg/day for SAR-Lis and 0.433 (0.315) U/kg/day for Ly-Lis, and at 26 weeks was 0.524 (0.329) U/kg/day and Patient disposition and baseline characteristics 0.512 (0.420) U/kg/day, respectively (Table 2). The change A total of 707 patients were screened for the study; 202 from baseline to week 26 was 0.087 (0.209) U/kg/day for (28.6%) were screen failures (Fig. 1). The most common SAR-Lis and 0.080 (0.248) U/kg/day for Ly-Lis. Baseline reason for screen failure was HbA <6.5% or >10% (76 doses of GLA-100 were also similar in both groups. A modest 1c patients [10.7%]). Five hundred five patients were random- increase of the basal insulin daily doses was also observed in ized and treated (ITT and safety population): 253 patients in both treatment groups over the 26-week treatment period. the SAR-Lis group and 252 patients in the Ly-Lis group. Two Mean (SD) dose at baseline was 0.477 (0.265) U/kg/day for hundred twenty-eight patients (90.1%) in the SAR-Lis group the SAR-Lis group and 0.458 (0.239) U/kg/day for the Ly-Lis and 230 (91.3%) in the Ly-Lis group completed the treatment group, and change from baseline was 0.082 (0.133) U/kg/day period. A similar number of patients in each group discontinued for SAR-Lis and 0.071 (0.122) U/kg/day for Ly-Lis (Table 2). the study treatment prematurely (SAR-Lis, 25 [9.9%], and Ly- For the primary endpoint, the mean HbA decreased 1c Lis, 22 [8.7%]). The most common reasons for treatment similarly in both treatment groups from baseline to week 26, discontinuation were ‘‘Other reasons,’’ which included pa- with the mean decrease in HbA from baseline occurring 1c tient decision or consent withdrawal, and ‘‘Adverse events.’’ mostly during the first 12 weeks of treatment (Fig. 2B). The Demographic and baseline characteristics were well bal- LS mean (standard error [SE]) change in HbA from base- 1c anced between treatment groups (Table 1). The mean age of line to week 26 was similar in the SAR-Lis (-0.92 [0.051]%) the randomized population was 62.5 years, and more than and Ly-Lis (-0.85 [0.051]%) groups (Table 2). The LS mean 40% of the population was 65 years or older. Most patients difference (SE; 95% CI) between the SAR-Lis group and the (93%) were overweight or obese (BMI ‡25 to <30 kg/m or Ly-Lis group was -0.07% (0.072; -0.215 to 0.067). Non- 2 2 ‡30 kg/m ), and the mean BMI was 32.2 kg/m . The mean inferiority of SAR-Lis versus Ly-Lis was demonstrated, as duration of diabetes was 17.1 years, with 80.8% of patients the upper bound of the two-sided 95% CI of the difference with a duration ‡10 years. Overall, 19.8% of the population between SAR-Lis and Ly-Lis was below the prespecified had a moderate impairment (estimated glomerular filtration noninferiority margin of 0.3%. The inverse noninferiority of Ly- rate [eGFR] ‡30 and <60 mL/min/1.73 m ) and four patients Lis versus SAR-Lis was also demonstrated. At week 26, (0.8% of all patients) had a severe impairment of renal similar percentages of randomized patients reached HbA 1c function (eGFR <30 mL/min/1.73 m ). Previous mealtime target <7% (SAR-Lis: 42.3%; Ly-Lis: 40.5%) and HbA 1c insulin use was Humalog/Liprolog (51.4%), NovoLog/ target £6.5% (SAR-Lis: 27.3%; Ly-Lis: 24.2%). NovoRapid (48.2%), or both (0.4%). Mean HbA value Mean FPGalsodecreased similarlyinbothgroups 1c was 8.0% (64 mmol/mol). (Fig. 2C). The LS mean change (SE) from baseline in FPG to week 26 was similar in the SAR-Lis group (-0.62 [0.176] mmol/L) and the Ly-Lis group (-0.67 [0.176] mmol/L). The Efficacy LS mean (SE; 95% CI) difference between SAR-Lis and Ly- Changes in the daily mealtime insulin doses were small Lis was 0.06 (0.249; -0.430 to 0.547) mmol/L (Table 2). The and similar in both groups over the 26-week treatment pe- mean seven-point SMPG profiles in both treatment groups riod and occurred mainly within the first 4 to 8 weeks of improved at all time points at week 26 compared with treatment (Fig. 2A). Mean (SD) dose at baseline was 0.449 baseline (Fig. 2D). The LS mean difference (SE; 95% CI) for FIG. 1. Patient disposition. Table 1. Demographic and Baseline Characteristics—Randomized Population SAR-Lis (N = 253) Ly-Lis (N = 252) All (N = 505) Age (years), mean (SD) [n] 62.1 (9.4) [253] 62.8 (8.9) [252] 62.5 (9.1) [505] Age groups, n (%) <65 144 (56.9) 137 (54.4) 281 (55.6) ‡65 to <75 89 (35.2) 93 (36.9) 182 (36.0) ‡75 20 (7.9) 22 (8.7) 42 (8.3) Male gender, n (%) 136 (53.8) 132 (52.4) 268 (53.1) Race, n (%) Caucasian/White 228 (90.1) 218 (86.5) 446 (88.3) Black 14 (5.5) 17 (6.7) 31 (6.1) Asian/Oriental 11 (4.3) 16 (6.3) 27 (5.3) Other 0 1 (0.4) 1 (0.2) Ethnicity, n (%) Hispanic 43 (17.0) 47 (18.7) 90 (17.8) Not Hispanic 210 (83.0) 205 (81.3) 415 (82.2) Regions, n (%) United States 122 (48.2) 120 (47.6) 242 (47.9) Western Europe 32 (12.6) 37 (14.7) 69 (13.7) Eastern Europe 67 (26.5) 58 (23.0) 125 (24.8) Rest of the world 32 (12.6) 37 (14.7) 69 (13.7) Region-approved Humalog , n (%) US-approved Humalog 122 (48.2) 120 (47.6) 242 (47.9) EU-approved Humalog 131 (51.8) 132 (52.4) 263 (52.1) Baseline weight (kg), mean (SD) [n] 92.2 (17.5) [253] 91.2 (17.4) [252] 91.7 (17.4) [505] Baseline BMI (kg/m ), mean (SD) [n] 32.3 (4.8) [253] 32.1 (4.8) [252] 32.2 (4.8) [505] Baseline BMI categories, n (%) <25 17 (6.7) 18 (7.1) 35 (6.9) ‡25 to <30 62 (24.5) 72 (28.6) 134 (26.5) ‡30 174 (68.8) 162 (64.3) 336 (66.5) Baseline estimated GFR (mL/min/1.73 m ), 77.29 (22.89) [253] 78.48 (23.66) [252] 77.89 (23.26) [505] mean (SD) [n] Baseline estimated GFR categories (mL/min/1.73 m ), n (%) ‡90 69 (27.3) 67 (26.6) 136 (26.9) ‡60 to <90 130 (51.4) 135 (53.6) 265 (52.5) ‡30 to <60 51 (20.2) 49 (19.4) 100 (19.8) <30 3 (1.2) 1 (0.4) 4 (0.8) Randomization strata of screening HbA categories, n (%) 1c <8% 105 (41.5) 104 (41.3) 209 (41.4) ‡8% 148 (58.5) 148 (58.7) 296 (58.6) Randomization strata of prior use of Humalog, n (%) Yes 155 (61.3) 155 (61.5) 310 (61.4) No 98 (38.7) 97 (38.5) 195 (38.6) Duration of T2DM (years), mean (SD) [n] 16.60 (7.93) [253] 17.52 (8.67) [252] 17.06 (8.31) [505] Duration of T2DM categories (years), n (%) <10 50 (19.8) 47 (18.7) 97 (19.2) ‡10 203 (80.2) 205 (81.3) 408 (80.8) Age at onset of T2DM (years), mean (SD) [n] 46.0 (10.1) [253] 45.8 (10.2) [252] 45.9 (10.1) [505] Duration of basal bolus insulin treatment (years), 7.10 (5.67) [247] 7.99 (6.76) [243] 7.54 (6.24) [490] mean (SD) [n] Duration of mealtime insulin treatment in patient life 6.43 (5.54) [250] 7.17 (6.33) [247] 6.80 (5.95) [497] (years), mean (SD) [n] Previous basal insulin type, n (%) Insulin glargine 253 (100) 251 (99.6) 504 (99.8) Duration of insulin glargine treatment (years), 5.75 (4.62) [253] 5.97 (4.69) [252] 5.86 (4.65) [505] mean (SD) [n] Previous mealtime insulin type, n (%) Humalog/Liprolog 133 (52.6) 126 (50.2) 259 (51.4) NovoLog /NovoRapid 119 (47.0) 124 (49.4) 243 (48.2) Both Humalog/Liprolog and NovoLog/NovoRapid 1 (0.4) 1 (0.4) 2 (0.4) Duration of previous treatment with Humalog/Liprolog 5.36 (5.29) [134] 4.64 (4.55) [127] 5.01 (4.95) [261] (years), mean (SD) [n] Duration of previous treatment with NovoLog/ 4.51 (4.41) [120] 5.72 (5.40) [125] 5.13 (4.97) [245] NovoRapid (years), mean (SD) [n] Baseline HbA ,%, mean (SD) [n] 7.99 (0.87) [253] 8.03 (0.91) [252] 8.01 (0.89) [505] 1c BMI, body mass index; GFR, glomerular filtration rate; Ly-Lis, Humalog insulin lispro; SAR-Lis, SAR342434 insulin lispro; SD, standard deviation; T2DM, type 2 diabetes mellitus. 53 54 DERWAHL ET AL. FIG. 2. Mean (SE) insulin dose (A), HbA (B), fasting plasma glucose (C), and seven-point SMPG time profiles (D). 1c Data for (A) is from the safety population, for (B–D), the ITT population. For (A), baseline is defined as the mean of daily doses available in the week before the first injection of SAR-Lis or Ly-Lis. ITT, intent-to-treat; Ly-Lis, Humalog insulin lispro; SAR-Lis, SAR342434 insulin lispro; SE, standard error; SMPG, self-monitored plasma glucose. SAR-Lis versus Ly-Lis for postprandial glucose excursions day was similar in the SAR-Lis (68.4%) and Ly-Lis (74.6%) at breakfast, lunch, and dinner were -0.48 (0.328; -1.127 to groups, and similar percentages of patients reported noctur- 0.164), -0.05 (0.357; -0.749 to 0.655), and 0.21 (0.374; nal hypoglycemia (00:00–05:59 h) in the SAR-Lis group and -0.525 to 0.945) mmol/L, respectively (Table 2). Mean 24-h the Ly-Lis group (regardless the category) (Table 3). The PG values at baseline and week 26 were also similar between occurrence of severe hypoglycemia, although imbalanced, the two groups, with an LS mean (SE; 95% CI) difference of was very low (<0.1 per patient-year) in both treatment -0.09 (0.191; -0.464 to 0.287) mmol/L (Table 2). groups. Severe hypoglycemia was reported in six patients In the SORELLA 2 study, the subgroup analyses based on (2.4%) in the SAR-Lis group and four patients (1.6%) in the baseline data in obese patients with BMI ‡30 versus <30 kg/ Ly-Lis group, and nocturnal severe hypoglycemia in two m , by diabetes duration (‡10 years vs. <10 years), in the patients (0.8%) and none, respectively. In all other predefined elderly (<65 years vs. ‡65 to <75 years), and by ethnicity categories of hypoglycemia, the percentages of patients were were consistent with the total patient population. similar with SAR-Lis and Ly-Lis. Most hypoglycemia was observed between 7 a.m. and midnight with small peaks around each meal (Supplementary Safety Fig. S2). There were no relevant differences in event rates The percentage of patients with at least one hypoglycemia between the two groups. The event rate of any hypoglycemia event (regardless of the category) reported at any time of the was similar in both treatment groups with 16.78 events per BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 55 Table 2. Summary of Insulin Doses and Glycemic Control SAR-Lis Ly-Lis Insulin dose—safety population Mealtime insulin, U/kg, mean (SD) Baseline [n] 0.449 (0.294) [231] 0.433 (0.315) [243] Week 26 [n] 0.524 (0.329) [214] 0.512 (0.420) [223] Change from baseline [n] 0.087 (0.209) [197] 0.080 (0.248) [218] Basal insulin, U/kg, mean (SD) Baseline [n] 0.477 (0.265) [232] 0.458 (0.239)[244] Week 26 [n] 0.555 (0.303) [214] 0.525 (0.262) [223] Change from baseline [n] 0.082 (0.133) [196] 0.071 (0.122) [218] Glycemic control—ITT population (patients included in the MMRM analysis) HbA , %-units; mean (SD) 1c Baseline [n] 8.00 (0.86) [239] 8.03 (0.91) [246] Week 26 [n] 7.06 (0.85) [231] 7.16 (0.88) [232] LS mean change (SE) from baseline [n] -0.92 (0.051) [239] -0.85 (0.051) [246] LS mean difference (SE) [95% CI] -0.07 (0.072) [-0.215 to 0.067] FPG, mmol/L; mean (SD) Baseline [n] 8.35 (2.67) [228] 8.18 (2.80) [235] Week 26 [n] 7.65 (2.71) [220] 7.53 (2.81) [220] LS mean change (SE) from baseline [n] –0.62 (0.176) [228] -0.67 (0.176) [228] LS mean difference (SE) [95% CI] vs. Ly-Lis 0.06 (0.249) [-0.430 to 0.547] Postprandial glucose excursion from SMPG, mmol/L; mean (SD) Breakfast Baseline [n] 1.96 (3.27) [194] 1.82 (3.46) [204] Week 26 [n] 1.30 (3.17) [171] 1.77 (3.14) [184] LS mean change (SE) from baseline [n] -0.72 (0.236) [194] -0.23 (0.228) [204] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.48 (0.328) [-1.127 to 0.164] Lunch Baseline [n] 1.71 (3.36) [195] 1.11 (3.68) [200] Week 26 [n] 1.42 (3.52) [170] 1.33 (3.26) [174] LS mean change (SE) from baseline [n] 0.06 (0.255) [195] 0.11 (0.250) [200] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.05 (0.357) [-0.749 to 0.655] Dinner Baseline [n] 1.00 (3.23) [190] 1.08 (3.40) [193] Week 26 [n] 1.11 (3.47) [167] 0.94 (3.36) [168] LS mean change (SE) from baseline [n] 0.11 (0.264) [190] -0.10 (0.264) [193] LS mean difference (SE) [95% CI] vs. Ly-Lis 0.21 (0.374) [-0.525 to 0.945] Mean 24-h plasma glucose from SMPG, mmol/L, mean (SD) Baseline [n] 10.07 (2.11) [201] 9.81 (2.05) [210] Week 26 [n] 9.01 (2.17) [180] 9.00 (1.75) [189] LS mean change (SE) from baseline [n] -1.00 (0.137) [201] 0.91 (0.133) [210] LS mean difference (SE) [95% CI] vs. Ly-Lis -0.09 (0.191) [-0.464 to 0.287] LS means from MMRM with treatment group (SAR-Lis, Ly-Lis), randomization strata of screening HbA (<8.0, ‡8.0%) and prior use of 1c insulin lispro (Yes, No), visit (week 12, week 26), and treatment-by-visit interaction as fixed categorical effects, and baseline value and baseline value-by-visit interaction as continuous fixed covariates. FPG, fasting plasma glucose; ITT, intent-to-treat; LS, least square; MMRM, mixed-effect model for repeated measures; SE, standard error; SMPG, self-monitored plasma glucose. patient-year of exposure in the SAR-Lis group and 18.59 treatment. Serious TEAEs involving hypoglycemia were re- events per patient-year of exposure in the Ly-Lis group ported in two patients (0.8%) in each group. (Table 3). The nocturnal hypoglycemia event rate was low A similar percentage of patients in the SAR-Lis and Ly-Lis and also similar in the SAR-Lis and Ly-Lis groups, being group reported a TEAE (SAR-Lis, 46.6%; Ly-Lis, 42.9%; 2.22 and 2.51 events per patient-year of exposure, respec- Table 4), the most common of which was nasopharyngitis tively. The only category of hypoglycemia where a difference (SAR-Lis, 4.0%; Ly-Lis, 2.0%). Serious TEAEs were re- between the two groups was observed was severe hypogly- ported in a lower percentage of patients in the SAR-Lis group cemia where the annualized event rate was 0.08, with nine (5.5% [14 patients]) than in the Ly-Lis group (10.7% [27 events reported in six patients in the SAR-Lis group, and patients]). Events were distributed over a variety of system 0.03, with four events reported in four patients in the Ly-Lis organ classes (SOCs) with an incidence no higher than 1.6% group. The higher rate in the SAR-Lis group was due to one (four patients) in any SOC in any treatment group, except for patient who reported four events of severe hypoglycemia. No cardiac disorders, which was reported in 1.2% (three patients) factors were identified that may have contributed to this pa- in the SAR-Lis group and 4.4% (11 patients) in the Ly-Lis tient’s frequent low blood glucose. Most patients with severe group. Seven patients (2.8%) in the SAR-Lis group and six hypoglycemia had prompt recovery further to corrective patients (2.4%) in the Ly-Lis group reported TEAEs leading 56 DERWAHL ET AL. Table 3. Summary of Hypoglycemia Events—Safety Population All hypoglycemia Nocturnal hypoglycemia (00:00–05:59) Type of hypoglycemia SAR-Lis (N = 253) Ly-Lis (N = 252) SAR-Lis (N = 253) Ly-Lis (N = 252) Total patient years 118.69 121.23 118.69 121.23 Any hypoglycemia Patients, n (%) 173 (68.4) 188 (74.6) 74 (29.2) 85 (33.7) No. of events (rate/patient-year) 1992 (16.78) 2254 (18.59) 264 (2.22) 304 (2.51) Severe hypoglycemia Patients, n (%) 6 (2.4) 4 (1.6) 2 (0.8) 0 No. of events (rate/patient-year) 9 (0.08) 4 (0.03) 2 (0.02) 0 Documented symptomatic hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 152 (60.1) 167 (66.3) 64 (25.3) 69 (27.4) No. of events (rate/patient-year) 1345 (11.33) 1478 (12.19) 204 (1.72) 216 (1.78) Documented symptomatic hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 73 (28.9) 69 (27.4) 21 (8.3) 20 (7.9) No. of events (rate/patient-year) 193 (1.63) 196 (1.62) 33 (0.28) 33 (0.27) Asymptomatic hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 89 (35.2) 94 (37.3) 20 (7.9) 24 (9.5) No. of events (rate/patient-year) 409 (3.45) 598 (4.93) 26 (0.22) 49 (0.40) Asymptomatic hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 26 (10.3) 32 (12.7) 3 (1.2) 3 (1.2) No. of events (rate/patient-year) 47 (0.40) 66 (0.54) 4 (0.03) 3 (0.02) Severe and/or confirmed hypoglycemia £3.9 mmol/L (70 mg/dL) Patients, n (%) 169 (66.8) 183 (72.6) 73 (28.9) 79 (31.3) No. of events (rate/patient-year) 1907 (16.07) 2154 (17.77) 248 (2.09) 278 (2.29) Severe and/or confirmed hypoglycemia <3.0 mmol/L (54 mg/dL) Patients, n (%) 89 (35.2) 84 (33.3) 26 (10.3) 22 (8.7) No. of events (rate/patient-year) 271 (2.28) 277 (2.28) 40 (0.34) 39 (0.32) n (%), number and percentage of patients with at least one treatment-emergent hypoglycemia event. Severe and/or confirmed hypoglycemia= severe and/or confirmed by plasma glucose £3.9 mmol/L (70 mg/dL) or <3.0 mmol/L (54 mg/dL). to permanent discontinuation of the investigational drug. A additional patient in the Ly-Lis group died after the end of the total of three deaths occurred during the study period: one study of unknown causes. The deaths were considered not death (0.4%) in the SAR-Lis group due to a cardio-respiratory related to IMP. arrest and two deaths (0.8%) in the Ly-Lis group due to car- The mean increase in body weight from baseline to diopulmonary failure and bladder cancer with metastasis. One week 26 was similar in the SAR-Lis (+1.35 kg) and Ly-Lis Table 4. Summary of Injection Site and Hypersensitivity Reactions and Adverse Events (Safety Population), and Anti-Insulin Antibodies (AIA Population) Safety population SAR-Lis (N = 253) Ly-Lis (N = 252) Any injection site reaction 1 (0.4) 4 (1.6) Any hypersensitivity reactions 10 (4.0) 9 (3.6) Patients with any TEAE 118 (46.6) 108 (42.9) Patients with any treatment-emergent SAE 14 (5.5) 27 (10.7) Patients with any TEAE leading to death 1 (0.4) 2 (0.8) Patients with any TEAE leading to permanent IMP discontinuation 7 (2.8) 6 (2.4) AIA population SAR-Lis (N = 245) Ly-Lis (N = 248) Patients with AIA positive at baseline, n (%) 60/245 (24.5) 63/248 (25.4) Patients with ‡4-fold increase in titer (treatment boosted), n (%) 12/60 (20.0) 8/63 (12.7) Patients with AIA negative or missing at baseline, n (%) 185/245 (75.5) 185/248 (74.6) Patients newly positive postbaseline (treatment induced), n (%) 34/185 (18.4) 28/185 (15.1) Patients with at least one positive AIA sample (prevalence), n (%) 94/245 (38.4) 91/248 (36.7) Patients with treatment-emergent AIA (incidence), n (%) 46/245 (18.8) 36/248 (14.5) No. (%) of patients AIA positive at week 26 68/221 (30.8%) 66/226 (29.2%) Data are n (%) = number and percentage of patients with at least one TEAE. Prevalence: patients AIA positive at baseline plus those with treatment-induced AIAs. Incidence: patients with treatment-boosted or treatment-induced AIAs (i.e., patients with treatment-emergent AIAs). AIA, anti-insulin antibodies; IMP, investigational medicinal product; SAE, serious adverse event; TEAE, treatment-emergent adverse event. BIOSIMILAR INSULIN LISPRO IN TYPE 2 DIABETES 57 (+1.32 kg) groups. No clinically meaningful changes from poglycemia with SAR-Lis than Ly-Lis due to one patient who baseline were observed in clinical laboratory and hematology reported four events. The general safety profile (percent- parameters, and no relevant differences between the two ages of patients with any TEAE, serious TEAEs, or TEAEs treatment groups occurred. leading to study medication discontinuation, as well as type of TEAEs) was also similar between treatment groups. Al- Immunogenicity though a slightly higher percentage of patients with treatment- emergent AIA was observed in the SAR-Lis group, no impact Similar percentages of patients in both treatment groups on efficacy and safety was observed in either group. were positive for AIA at baseline (SAR-Lis, 24.5%, and Ly- The original registration studies with Ly-Lis showed al- Lis, 25.4%) (Table 4). The percentage of patients with a tered efficacy of Ly-Lis in obese patients; thus the FDA treatment-emergent AIA response (i.e., treatment-boosted mandated postmarketing studies in obese patients after the or treatment-induced AIAs; incidence) was 18.8% (46/245) product was approved in 1996. In the SORELLA 2 study, in the SAR-Lis group and 14.5% (36/248) in the Ly-Lis the subgroup analyses based on baseline data in obese pa- group. Over the 6-month period, percentages of patients 2 2 tients with BMI ‡30 kg/m versus <30 kg/m , by diabetes positive for AIA slightly increased in both treatment groups: duration (‡10 years vs. <10 years), in the elderly (<65 years 30.8% of SAR-Lis patients and 29.2% of Ly-Lis patients at vs. ‡65 to <75 years), and by ethnicity were consistent with week 26. Similar percentages of patients in the SAR-Lis the total patient population. In particular, the incidence of group (38.4%) and Ly-Lis group (36.7%) were positive for hypoglycemia was comparable between treatments for the AIAs at least at one time point between baseline and month 6 subgroups, including incidence of severe hypoglycemia. (prevalence). Cross-reactivity with human insulin, insulin The study included a study population that is largely adult glargine, and insulin glargine M1 metabolite was high (80%– white Caucasian with small numbers of blacks and Asians. 90%) and consistent between treatment groups. No rela- Caution should be taken when extending the results to other tionship was observed between the individual maximal AIA ethnic populations or subgroups, as the study was not pow- titers and the change in total insulin dose, HbA , hypogly- 1c ered for them. The open-label study design was chosen as the cemia, injection site, and hypersensitivity reactions. prefilled, disposable pen injection devices for SAR-Lis and A low number of patients reported hypersensitivity reac- Ly-Lis could not be made indistinguishable. However, out- tions (SAR-Lis, 10 [4.0%] and Ly-Lis, 9 [3.6%]) and very come assessments were determined based on objectively few patients reported injection site reactions (SAR-Lis, 1 collected data determined by central laboratories blinded to [0.4%] and Ly-Lis, 4 [1.6%]) (Table 4). Most events were the study treatment. mild or moderate in intensity. All resolved while treatment We conclude that SAR-Lis and Ly-Lis when used for 6 was ongoing, with the exception of one event in the SAR-Lis months in combination with GLA-100 provided effective and group (dermatitis contact) and three events in the Ly-Lis similar glucose control in patients with T2DM. SAR-Lis and group (one event each of dermatitis, rash, and facial edema). Ly-Lis had similar safety and immunogenicity profiles and no Out of the 24 potential hypersensitivity reactions reported in specific safety concerns were observed. either treatment group, only four events (seasonal allergy, contact dermatitis, allergy to arthropod bite, and allergic Acknowledgments rhinitis) in the SAR-Lis group and three events (pruritus [two] and mouth swelling) in the Ly-Lis group were adju- The study was funded by Sanofi. Editorial support was dicated as allergic reaction by the ARAC; the two events of provided by Tom Claus, PhD, of PAREXEL, and was funded pruritus in the Ly-Lis group were considered related to IMP. by Sanofi. Discussion Author Disclosure Statement Insulins approved as biosimilars or follow-on biologics K.-M.D., Consultant to Astra Zeneca, Lilly, Novo Nordisk, expand the number of insulin brands available for those Sanofi; honorarium (lectures) from AstraZeneca, Sanofi, with diabetes and may have the potential to reduce diabetes Menarini, Novo Nordisk. T.S.B., Consultant to Astra Zeneca, treatment cost. Indeed, these products are usually marketed at Ascensia, BD, Calibra, Lilly, Medtronic, Novo Nordisk, a lower price than the originator product. This was first ob- Sanofi. Research support from Abbott, Ambra, Ascensia, BD, served after the market launch of erythropoietin biosimilars. Boehringer Ingelheim, Calibra, Companion Medical, Dex- In this study, we report on the pharmacological charac- com, Elcelyx, Glysens, Janssen, Lexicon, Lilly, Medtronic, teristics of SAR-Lis insulin, a biosimilar of Ly-Lis insulin Novo Nordisk, Sanofi, Senseonics, Versartis, and Xeris; with an identical amino acid sequence. Similar efficacy in Speaker’s Bureau for Abbott, Insulet, Medtronic, Lilly, terms of changes in HbA levels was noted between SAR- 1c Novo Nordisk, Sanofi. K.W.-P., Employee, Sanofi-Aventis Lis and Ly-Lis at the primary endpoint at week 26, and Deutschland GmbH; Stock/Shareholder, Sanofi. L.P., Em- noninferiority of SAR-Lis to Ly-Lis and of Ly-Lis to SAR- ployee, Sanofi, Bridgewater, NJ; Stock/Shareholder, Sanofi. Lis was demonstrated in accordance with the guidance from S.P., Employee, Sanofi, Paris, France; Stock/Shareholder, the US Food and Drug Administration (FDA) and European Sanofi. 4–8 Medicines Agency (EMA). 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CHMP/437/04 Rev 1:1–7. acting insulin analogs in obese subjects with T2DM. Dia- 7. EMA: Guideline on clinical investigation of medicinal betes Care 2010;33:2502–2507. products in the treatment or prevention of diabetes mellitus. Address correspondence to: 2012.CPMP/EWP/1080/00 Rev 1:1–28. 8. US Food and Drug Administration, Center for Drug Eval- Karl-Michael Derwahl, MD, PhD uation and Research (CDER): Guidance for Industry. Institut fu¨r klinische Forschung und Diabetes Mellitus: Developing Drugs and Therapeutic Entwicklung (IKFE) Berlin GmbH Biologics for Treatment and Prevention. Draft Guidance Große Hamburger Straße 5-11 2008:1–34. 10115 Berlin 9. Kapitza C, Nowotny I, Lehmann A, et al.: Similar phar- Germany macokinetics and pharmacodynamics of rapid-acting insu- lin lispro products SAR342434 and US- and EU-approved E-mail: derwahl@ikfe-berlin.de

Journal

Diabetes Technology & TherapeuticsPubmed Central

Published: Jan 1, 2018

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