Safety and tolerability of prescribed usage of Derise® (Darbepoetin Alfa, Hetero) in symptomatic anemia: A Post Marketing Surveillance Study

doi:10.21203/rs.3.rs-23193/v2

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Safety and tolerability of prescribed usage of Derise® (Darbepoetin Alfa, Hetero) in symptomatic anemia: A Post Marketing Surveillance Study

https://doi.org/10.21203/rs.3.rs-23193/v2

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Background This post marketing surveillance, observational, prospective, safety study evaluated the safety, tolerability and long term immunogenicity of prescribed usage of Darbepoetin alfa, (DA-α, manufactured by Hetero Biopharma) in Indian patients with chronic kidney disease with anemia.

Methods All patients with anemia of chronic kidney disease prescribed Hetero-Darbepoetin were the target patient population. The present study gathered the data from 503 Hetero-Darbepoetin alfa prescribed patients. This study collected information of patient demography, patient's medical history, concomitant medications, action taken with respect to Hetero-Darbepoetin-alfa, AE details (AE term, start date, stop date, severity, action taken, outcome and causality), periodic Hemoglobin (Hb) levels and abnormal laboratory tests results until treatment is discontinued or the patient is lost to follow-up. Immunogenicity data was collected in 121 patients at the end of treatment and after 1 year. Statistical analyses were performed to explore and analyze details of individual case safety reports of adverse events such as incidence, severity, seriousness, outcome, duration, action taken, and causality relationship of individual adverse event (AE) to the prescribed study drug.

Results 87 AEs were reported in this study and most of them were mild to moderate in intensity. No deaths or serious adverse events (SAEs) were reported in this study. Anti-drug antibodies were not detected in any subject at the end of treatment phase and after 12 months long term follow up period. Baseline mean Hemoglobin value was 8.34 (SD 1.24) g/dL and last visit mean Hemoglobin value was 10.42 (SD 1.28) g/dL. The mean difference between baseline and last visit was 2.10 [2.00, 2.20], statistically significant (p-value <.0001).

Conclusions The safety and tolerability of the usage of DA-α (manufactured by Hetero Biopharma)is similar to that reported in the published literature of the innovator. No patients showed anti-drug antibodies after treatment. Additionally, the patients also showed significant improvement in hemoglobin levels, compared to baseline.

Clinical Trial Registry Number: CTRI/2017/04/008338 [Registered on CTRI http://ctri.nic.in/Clinicaltrials/login.php : 12/04/2017]; Trial Registered Retrospectively

Urology & Nephrology

Anemia

Chronic kidney disease

Darbepoetin alfa

Post-marketing surveillance.

Biosimilars improve patient’s accessibility to Darbepoetin alfa with potentially low drug prices resulting in reduced treatment cost for patients and healthcare systems.
Hetero Biopharma Ltd. has developed Darbepoetin Alfa which in this post marketing surveillance study showed that it is safe for the treatment of symptomatic anemia in patients with chronic kidney disease.

The primary cause of renal anemia in chronic kidney disease (CKD) is the deficiency of endogenous erythropoietin mainly produced by kidneys.¹ Progression of renal anemia not only increases the risk of cardiovascular (CV) disease, but also is an independent risk factor for the deterioration of renal function, causing the vicious cycle known as cardio-renal anemia syndrome.² Erythropoietin alfa is the standard of care for treatment of anemia related to CKD undergoing dialysis and not on dialysis. Darbepoetin alfa has similar mechanism for erythropoiesis as native & recombinant human erythropoietin (rHuEPO). Darbepoetin alfa proven to achieve significant reductions in RBC transfusion requirements and clinically relevant improvements in fatigue and other patient-reported outcomes. Darbepoetin alfa has 3-fold longer elimination half-life and decreased clearance compared to erythropoietin alfa. This ensures a comparatively reduced number of (Darbepoetin alfa) injections in treatment of anemia in CKD patients.

Hetero conducted Phase-III interventional clinical studies with Darbepoetin alfa (DA-α, manufactured by Hetero Biopharma) for obtaining manufacturing authorization in India. This study showed efficacy and safety in improving anemia associated with CKD undergoing dialysis and those not on dialysis( CTRI/2012/07/002835) who were administered DA-α for a period of 12-24 weeks.^3,4The current study was subsequently conducted as an observational, prospective post-marketing surveillance study as per the local regulatory requirements to collect real world safety and long term immunogenicity data in prescriber setting.

Study Design

This was an observational, multicenter, prospective, non- interventional post-marketing surveillance study performed at nine centers across India between 21 Jun 2016 ( initiation) to 07 Sep 2018 ( termination) to evaluate the safety, tolerability and long term immunogenicity of DA- α (manufactured by Hetero Biopharma) in daily medical practice conditions. A total of 503 patients were included in this study to evaluate the safety, tolerability and long term immunogenicity of DA-α in prescribed settings. Data collection included patient demography, patient's medical history, concomitant medications, action taken with respect to DA-α, AE details, periodic Hb levels and abnormal laboratory tests results. DA- α was dosed either 0.45 mcg/kg once weekly (QW) or 0.75 mcg/kg once every 2 weeks (Q2W) or 1.5 mcg/kg once monthly, as per regulatory approval and as mentioned in the approved prescribing information. If the increase in Hb was less than 1 g/dL in four weeks, the dose was increased by 25%. If the rise in Hb is greater than 2 g/dL in four weeks, the dose was reduced by 25%. If the Hb exceeds 12 g/dL, a dose reduction was considered. If the Hb continued to increase, the dose was reduced by 25%. If after a dose reduction, Hb continued to increase, the dose was temporarily withheld until the Hb begins to decrease, with reinitiated at 25% lower than the previous dose. Safety, tolerability and immunogenicity data was recorded in the approved post-marketing surveillance (PMS) forms.

This study was conducted in accordance with the ethical guidelines outlined in the Declaration of Helsinki, 1964 as revised in 2013, Post Authorization Safety Studies (Post Marketing Surveillance study, (PMS)), as per the guidelines of Schedule Y (amended Drug &Cosmetic Act 2013), and Guidelines for Similar Biologics 2012, India along with subsequent amendments and Indian regulatory laws governing biomedical research in human patients. The study was approved by the Drugs Controller General, India (DCGI), CDSCO and subsequently registered with clinical trial registry (CTRI/2017/04/008338) retrospectively. Institutional ethics committee approvals were obtained from each participating study center before initiating the study.

Participants

In this study, patients of either gender with CKD suffering from renal anemia prescribed and administered DA-α (manufactured by Hetero Biopharma) as per the prescribing information were enrolled. Patients with clinical history/ evidence of allergy/ hypersensitivity to components of Hetero-Darbepoetin alfa, receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy were not included as per the prescribing information contraindications.

Study Assessments

Adverse events and immunogenicity were assessed during the study. Adverse events were evaluated based on their expectedness, seriousness, incidence, severity, outcome, duration, action taken and causality. Immunogenicity was evaluated by assessing serum for the presence of anti- darbepoetin alfa antibodies at baseline, end of treatment (up to 24 weeks) and long term follow up after 12 months. Immunogenicity samples were stored in the freezer at -65±10°C. Anti- darbepoetin alfa antibodies in human serum were detected by acid dissociation bridging ELISA. Samples with absorbance value (OD) less than the cut point was considered negative for anti-drug antibody. Sample with OD equal to or above the cut point was to be considered positive. As a routine, the Hb levels were monitored during the study.

Statistical analysis

This study was planned to include 500 patients prescribed DA-α for anemia associated with chronic kidney disease during the routine clinical practice in India. Baseline summary statistics, including mean, median and standard deviation for age, weight, and proportion of males/females to be provided by treatment group. The variables measured on continuous scale compared using t- test and the proportion of males/females compared using Fisher’s exact test. Adverse events (AEs) were summarized by system organ class (SOC) and by preferred terms using the Medical Dictionary for Regulatory Activities Terminology (MedDRA v21). The AE severities were graded by using Common Terminology Criteria for Adverse Events, CTCAE (v4). The causality was assessed by using WHO-UMC causality assessment system. All statistical analysis was performed using SAS® Version 9.4 (SAS Institute Inc., NC, USA).

Patient characteristics

A total of 503 patients post marketing data was included in this study ( Table 1). Of these, 121 patients were also evaluated for immunogenicity at the end of treatment and after one year for long term immunogenicity.

Table 1 Patient demographics

Variable	Gender	N	Mean	SD	Min/Max	P-value
Age	Male	310	50.85	11.51	23/76	0.4224
Age	Female	188	49.27	12.12	27/77	0.4224
Weight	Male	311	60.33	8.46	36/84.6	0.1413
Weight	Female	192	58.19	9.30	38/93.4	0.1413
HB	Male/Female	503	8.34	1.24	9.0/14.1	-

Safety evaluation

A total of 87 patients (17.3%) reported at least one adverse event during the treatment. Twenty seven (5.4%) AEs reported in nervous system disorders, 24 (4.8%) AEs reported in general disorders and administration site conditions, 19 (3.8%) AEs reported in gastrointestinal disorders, 9 (1.8%) AEs reported in respiratory, thoracic and mediastinal disorders, 3 (0.6%) AEs reported in skin and subcutaneous tissue disorders and 2 (0.4%) AEs reported in musculoskeletal and connective tissue disorders ( Table 2). Most frequently reported AEs were headache, reported in 25 (5.0%) patients, pyrexia 13 (2.6%) and pain 7 (1.4%). Three (0.59%) AEs were severe, 22 (4.37%) AEs were moderate and 62 (12.3%) AEs were mild in intensity. Two (0.4%) AEs were certainly related, 5 (1%) AEs were probably related, 40 (8.0%) AEs were possibly related, 39 (7.8%) AEs were unlikely related and 1 (0.2%) AE was unclassifiable as assessed by the treating doctor. There were no deaths, life threatening and serious adverse events reported in this study.

Table 2 List of Adverse events occurred in CKD Patients Treated with DA-α

Adverse Event	Patients Treated with DA-α N=503, n (%)
Any Treatment-Emergent Adverse Event	87 (17.3)
Gastrointestinal Disorders	19 (3.8)
Abdominal Distension	1 (0.2)
Abdominal Pain	1 (0.2)
Abdominal Pain Upper	1 (0.2)
Constipation	4 (0.8)
Diarrhoea	4 (0.8)
Nausea	5 (1.0)
Vomiting	3 (0.6)
General Disorders and Administration Site Conditions	24 (4.8)
Asthenia	1 (0.2)
Chills	1 (0.2)
Malaise	1 (0.2)
Oedema Peripheral	2 (0.4)
Pain	7 (1.4)
Pyrexia	13 (2.6)
Investigations	1 (0.2)
Blood Pressure Abnormal	1 (0.2)
Musculoskeletal and Connective Tissue Disorders	2 (0.4)
Back Pain	2 (0.4)
Nervous System Disorders	27 (5.4)
Dizziness	1 (0.2)
Headache	25 (5.0)
Pain	1 (0.2)
Psychiatric Disorders	3 (0.6)
Autism Spectrum Disorder	1 (0.2)
Somnolence	2 (0.4)
Respiratory, Thoracic and Mediastinal Disorders	9 (1.8)
Cough	2 (0.4)
Nasopharyngitis	2 (0.4)
Pain	1 (0.2)
Rhinorrhoea	1 (0.2)
Sneezing	3 (0.6)
Skin And Subcutaneous Tissue Disorders	3 (0.6)
Pruritus	1 (0.2)
Rash	2 (0.4)

Adverse events are classified by System Organ Class [a] Preferred Term as defined by the Med DRA v21, N = number of patients in specified treatment; n = number of patients at specified category

Immunogenicity Analysis

Out of 503 patients, 121 patients agreed for immunogenicity assessment during the treatment and after long term follow up of 12 months. Out of 121 patients, 111 patients had baseline and end of treatment immunogenicity data and 102 patients had baseline, end of treatment and long term immunogenicity data after 12 months. No anti – darbepoetin alfa antibodies were detected in this population of patients receiving DA-α at the end of treatment and after 12 months of follow up period.

Beneficial Effects

The mean Hb levels improved from 8.34 (SD 1.24) g/dL at baseline to 10.42 (SD 1.28) g/dL at the end of the treatment (Fig:1). The change in mean Hb levels from baseline to end of treatment was statistically significant [ 2.10 g/dL (95% CI 2.00, 2.20); p= <.0001].

Darbepoetin alfa (DA-α manufactured by Hetero Biopharma) is the long-acting ESA with less frequent dosing intervals compared to epoetins alfa and beta. This study was conducted to evaluate the safety, tolerability and long term immunogenicity of DA-α (manufactured by Hetero Biopharma) in treatment of anemia associated with chronic kidney disease in real world prescriber setting. Overall, 17.3% patients reported AEs in this study which is lesser than the phase III study reported AEs (39.7% in dialysis and 25.8% in pre-dialysis) conducted in CKD patients.⁴ ^,4 The AEs reported in various SOCs are lesser than the pre-approval studies by DA-α in CKD patients. Respiratory, thoracic and mediastinal disorders (1.8% vs 14.3%) and General disorders and administration site conditions (3.8% vs 12.7%) SOCs reported lesser AEs than the pre-approval studies.¹⁶ Similarly the most commonly reported AEs like headache (5% vs 9.5%) and pyrexia (2.6% vs 4.8%) reported less frequently in this study compared to previous studies. The concernregarding development of antibodies against darbepoetin leading to loss of its effectiveness ruled out by negative antibodies at the end of treatment and after 1 year.⁵ Patients who were treated with DA-α (manufactured by Hetero Biopharma) could effectively maintain their Hb levels in the target therapeutic ranges during the treatment period and one year follow up. The AEs reported in this study were lesser than the popular DREAM-J surveillance study of long-term use of darbepoetin alfa in nondialysis patients with chronic kidney disease. DREAM-J study reported 44.4% AEs.⁶ This post marketing surveillance study results suggests that there is no apparent risk for life threatening or serious adverse events under clinical conditions where DA-α (manufactured by Hetero Biopharma) is prescribed for the management of anemia associated with chronic kidney disease.

Our study results demonstrate that DA-α (manufactured by Hetero Biopharma) is safe and tolerable in treating patients with anemia associated with chronic kidney disease with significant improvement in hemoglobin levels. This data provides a trend of its safety profile and efficacy in real world scenario of prescribed settings and is consistent with the phase-III study and published literature.^7,8

ADAs: antidrug antibodies; ADRs: Adverse drug reactions; AE: adverse event; CDSCO: Central Drugs Standard Control Organization; CKD: chronic kidney disease; CTCAE : Common Terminology Criteria for Adverse Events ; DA-α: Darbepoetin alfa; DCGI: Drugs Controller General India; ELISA: Enzyme linked immunosorbent assay; Hb: Hemoglobin; ICH: International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; MedDRA: Medical Dictionary for Regulatory Activities Terminology; OD: absorbance value ; PMS: post-marketing surveillance; QW: once weekly; Q2W: once every 2 weeks; rHuEPO: recombinant human erythropoietin; SOC: system organ class; SAEs: serious adverse events; TEAEs: Treatment emergent adverse events; WHO: World Health Organization; UMC: Uppsala Monitoring Centre.

Ethics approval and consent to participate

The study was conducted in accordance with the ethical guidelines outlined in the Declaration of Helsinki, 1964 as revised in 2013, Schedule Y along with subsequent amendments and Indian regulatory laws governing biomedical research in human patients. Institutional ethics committee approval was obtained from each participating study center before initiating the study. The study was an observational, non- interventional post marketing surveillance (PMS) study based on prescribed usage of the darbepoetin alpha in patients having diseases as per approved indications. As per the applicable regulatory guidelines, written informed consent is not mandatory to be obtained from the subjects in who are being prescribed the marketed study drug in these studies. However, for the purpose of good documentation practices & upholding the ethics considerations, written informed consent was obtained from each subject before enrolling them into the study. The study was registered with the clinical trial registry (CTRI/2017/04/008338) retrospectively.

Ethics committee name and address

Institutional Ethics Committee Situated at M/s. King George Hospital, Vishakhapatnam- 530002, Andhra Pradesh. ECR/197/Inst/KGH/2013
Ethics Committee St. Thereas’s Hospital Erragadda Santhnagar Hyderabad – 500018, Andhra Pradesh. ECR/230/Inst/AP/2013
Bodyline Hospital, Institution Ethics Committee opp Annapurna Hall, Nr. Dev Status, Vikas Gruh road, Paldi, Ahmedabad, Gujurat. ECR/476/Inst/GJ/2013
Medilink Ethics Committee, Basement Medilink Hospital, Shyamal Cross Road, 132 ft. ring Road, Satellite, Ahmedabad-380015. ECR/344/Inst/GJ/2013
Ethics Committee GSVM Medical College, Opp. CRS Complex GSVM Medical college, Kanpur-208005. ECR/680/Inst/UP/2014
Fortis Hospital Ethics Committee 154/9 Bannerghatta Road, Opp IIM-B, Bangalore-560076, Karnataka. ECR/378/Inst/KA/2013
Care Hospital Care Convergence Centre, H. No. 8-2-595/2/B, Road No. 10, Banjara Hills, Hyderabad-500034. ECR/94//Inst/AP/2013
Ethics Committee Rajiv Gandhi Institute of Medical Sciences & RIMS Government General Hospital Situated at Srikakulam-532001, Andhra Pradesh, India. ECR/492/Inst/AP/2013
Institutional Ethics Committee, Jeevan Jyoti Hospital & Research Centre, 1625, Bai Ka Bagh, Lowther road, Allahabad 211003. ECR/285/Inst/UP/2013

Consent for publication

Not applicable

Availability of data and materials

Data supporting the findings are presented within the manuscript and additional datasets used are available from the corresponding author on request.

Competing interests

SD, VB, BB, PT, SC, LT, SK, PD and SS are the employees of Hetero Biopharma Limited, India and involved from conception of study to the approval of the manuscript. All the authors declare no other competing interests.

Funding

This study was sponsored by Hetero Biopharma Limited, India including the study related materials and study drugs. The study was designed and executed by Hetero Biopharma Limited, India in line with local and international regulatory requirements. The publication of this manuscript is funded by the Hetero Biopharma Limited, all the authors are the employees of the Hetero and were involved in the design of the study and the collection, analysis, and interpretation of data and writing the manuscript.

Authors’ contributions:

Concept and design of trial, SD, VB, BB, SC, PT: Overall project management, data collection, statistical analysis, data interpretation and conclusion analysis, drafting of manuscript, revising manuscript: SD, SC, PT, LT, SK, PD, SS, corresponding author: PT. All authors read and approved the final manuscript

Acknowledgements

Authors would like to thank Darbepoetin investigator group (Dr. Ramesh Chandra, Dr. B. Sudhakar, Dr. Javed M. Vakil, Dr. Bhavin Mehtalia, Dr. Vishal Kumar Gupta, Dr. R. Sreedhara, Dr. P. Vikranth Reddy, Dr. P. Sarat Jyostna, Dr. Anurag Singh) for conducting this study. Authors would also like to thank all the study subjects for their valuable participation in this study.

Author details

¹Clinical Development and Medical Affairs, Hetero Group, Hetero Corporate, 7-2-A2, Industrial Estates, Sanath Nagar, Hyderabad, Andhra Pradesh, India.

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Safety and tolerability of prescribed usage of Derise® (Darbepoetin Alfa, Hetero) in symptomatic anemia: A Post Marketing Surveillance Study

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