Pharmacotherapeutic group: Selective immunosuppressive agents.
Pharmacology: Pharmacokinetic properties reported for Adalimumab: Absorption and distribution of a single 40 mg dose is slow and serum concentration reaches its peak after 5 days upon subcutaneous administration with an average bioavailability of about 64 %. Serum concentrations were dose proportional when single intravenous dose ranging from 0.25 to 10 mg/kg was administered. The distribution volume (Vss) ranges from 5 to 6 litres, clearances range from 11 to 15 mL/hour and the mean terminal phase half-life was approximately two weeks with a single dose of Adalimumab administration. Concentration of Adalimumab measured from synovial fluid of rheumatoid arthritis patients ranges from 31-96% of those in serum.
The mean steady-state trough concentrations after subcutaneous administration of Adalimumab have been calculated from serum of the following patients: RA patients: Approximately 5 μg/mL without concomitant methotrexate and 8 to 9 μg/mL with concomitant methotrexate with a dose of 40 mg every other week.
Serum trough levels at steady-state increase proportionally with dose increase (20, 40 and 80 mg subcutaneous dosing every other week and every week).
Polyarticular juvenile idiopathic arthritis patients of 4-17 years age: 5.6 ± 5.6 μg/mL (102 % CV) without concomitant methotrexate and 10.9 ± 5.2 μg/mL (47.7% CV) with concomitant methotrexate (values measured from week 20 to 48) with a dose of 24 mg/m2 (up to a maximum of 40 mg) every other week.
Crohn's disease patients: loading dose of 80 mg Adalimumab on week 0 followed by 40 mg Adalimumab on week 2 results in approximately 5.5 μg/mL trough concentration; loading dose of 160 mg Adalimumab on week 0 followed by 80 mg Adalimumab on week 2 achieves 12 μg/mL trough concentration; 7 μg/mL trough concentration was observed in patients receiving 40 mg Adalimumab every other week.
Ulcerative colitis patients: loading dose of 160 mg Adalimumab on week 0 followed by 80 mg Adalimumab on week 2 achieves 12 μg/mL trough concentration; 8 μg/mL trough concentration was observed in patients receiving 40 mg Adalimumab every other week.
Adalimumab has not been studied in patients with hepatic or renal impairment.
Pharmacodynamics: Mechanism of action: Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Upon binding to human TNF, Adalimumab either neutralizes the biological function of TNF by blocking its interaction with the cell surface TNF-receptors or modulates biological responses involving changes in leukocyte migration of adhesion molecules (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 0.1-0.2 nM). TNF plays a central role in initiation, maintenance and progression of several inflammatory diseases and treatment with Adalimumab improves the signs and symptoms of these TNF-associated diseases in patients.
Pharmacodynamic effects: Upon Adalimumab treatment, the levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), and serum cytokines (IL-6) declined rapidly as compared to baseline in patients with RA. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after Adalimumab administration.
A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease and ulcerative colitis after treatment with Adalimumab. In patients with Crohn's disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNF-α was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in Adalimumab treated patients.
Clinical Efficacy and Safety: Clinical Trial of CHL's Adalimumab in Indian Patients: A total 162 subjects were screened at 11 investigational sites in India, of which, 120 subjects were enrolled in the study, 60 subjects in each group viz. CHL's Adalimumab and Innovator's Adalimumab. Total 103 subjects were qualified as per protocol (PP) criteria and 119 subjects qualified for intend to treat (ITT) criteria which were included for efficacy analysis, respectively.
Efficacy Conclusions of CHL Trials: The American College of Rheumatology (ACR) response was significantly improved for each group at each evaluation throughout the study. After treatment with CHL's Adalimumab, at Visit 5 (on day 84), 82% of patient had an ACR20, 46% had an ACR50 and 14% had an ACR70. Whereas in Innovator's Adalimumab group at Visit 5 (on Day 84), 79.2% of patient had an ACR20, 43.4% had an ACR50 and 15.1% had an ACR70 response. No statistically significant difference between treatment groups were observed in ACR response.
In addition to swollen joints and tender joints, significant improvement was noted in all ACR core component. The difference in both treatment groups was not significant.
Significant improvement was observed in Disease Activity Score 28 C-Reactive Protein (DAS28 CRP) score from the baseline in both the groups. The DAS28 CRP score in CHL's Adalimumab group was 5.8 ± 0.88 and in Innovator's Adalimumab group was 5.8 ± 0.83. Over a period of 84 days the score was decreased to 3.7 ± 1.12 and 3.7 ± 0.94 in CHL's Adalimumab and Innovator's Adalimumab group, respectively. No significant difference was observed between treatment groups at baseline and end of the study.
Similarly, at baseline Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 ESR) score in CHL's Adalimumab group was 6.8 ± 0.78 and in lnnovator's Adalimumab group it was 6.9 ± 0.81. Over a period of 84 days the score was decreased to 4.8 ± 1.04 and 4.8 ± 0.89 in CHL's Adalimumab and Innovator's Adalimumab group, respectively. No significant difference was observed between treatment groups at baseline and end of the study.
An efficacy subset analysis showed no significant difference between the treatment groups with respect to age groups, gender and weight on ACR criteria response and DAS 28 (CRP/ESR).
In this study, no significant difference was observed for anti-drug antibodies detected in samples from CHL's Adalimumab treated and Innovator's Adalimumab treated RA patients.
Anti-drug antibody was observed in two samples of patients treated with CHL's Adalimumab on Visit 5 with titer value of 25 and 800, and one sample of patient treated with Innovator's Adalimumab on Visit 5 with titer values of 200. These results indicate that both the drug products CHL's Adalimumab and Innovator's Adalimumab are similar with respect to immunogenic response in patients. (See Tables 2 and 3.)
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Click on icon to see table/diagram/image
Safety conclusions of CHL Trials: Overall, CHL's Adalimumab and Innovator's Adalimumab were safe and well tolerated in this study. A total of 31 adverse events (AEs) including 3 serious adverse events (SAEs) were reported during the study, which were completely resolved. The distribution of AEs was comparable between the treatment groups. There were 15 AEs (including 2 SAEs) reported by 9 subjects in CHL's Adalimumab treated group, whereas in Innovator's Adalimumab treated group 16 AEs (including 1 SAE) were reported by 11 subjects. Pyrexia, headache and cough were commonly reported in both the treatment groups. The 3 SAEs reported were pyrexia, dizziness and cough. Majority of AEs were mild in intensity and not related to the study drugs.
Three system organ class (SOC) with higher number of AEs were gastrointestinal disorder, general disorder and administration site condition, and infection and infestation.
There were no persistent changes from baseline in laboratory parameters in both treatment groups. General examination showed no significant sign in any treatment group except 2 cases of pallor at visit 3 in Innovator's Adalimumab treated group. No other systemic abnormality was observed throughout the study except musculoskeletal; however, the proportion of abnormality was comparable in both treatment groups.
Toxicology: Preclinical Safety Data of CHL's Adalimumab: The safety profile of CHL's Adalimumab was assessed using a battery of toxicological studies.
Preclinical studies for CHL's Adalimumab were performed as per the recommendations set forth in Schedule Y/ICH guidelines in compliance with GLP standards at Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad. Toxicological studies included independent acute toxicity studies in mice and rats by intended subcutaneous route and by alternate intravenous route of administration. Repeated dose toxicity studies by subcutaneous route comprising weekly dosing schedule over a period of four weeks was performed in rats and rabbits. Local tolerance evaluation was a part of repeated dose toxicity studies and by an independent skin sensitization study in guinea pigs.
In general, CHL's Adalimumab revealed a good safety margin in terms of mortality over the acute dose of 830 mg/kg in mice & 410 mg/kg in rats by both subcutaneous and intravenous routes and were approximately 100 times of the human equivalent dose. No mortality, apparent signs of toxicity, adverse changes in body weights and gross pathological lesions were noticed in both mice and rats when compared to vehicle control groups. CHL's Adalimumab did not induce any dermal sensitization in guinea pigs. No adverse local tolerance effects were noticed at the site of injection in both rats and rabbits.
Repeated weekly subcutaneous administration of CHL's Adalimumab was conducted over a period of four weeks at dose levels of 4.1, 20.5 & 41 mg/kg in rats and 2.1, 10.5 & 21 mg/kg in rabbits. The selected dose levels were 1X, 5X & 10X of the human equivalent dose. A recovery group was maintained for a period of two weeks at 10X of the human equivalent dose. Vehicle control groups were maintained with main study & recovery groups. Innovator's Adalimumab was used at 1X of the human equivalent dose for comparative purpose in repeated dose toxicity studies.
No mortality occurred in both rats and rabbits. No adverse changes were noticed during detailed clinical examination, body weight and feed intake determinations, hematological, biochemical, organ weight estimations, bone marrow examination and gross or histo-pathological evaluation. No differences were noticed in both the groups treated with CHL's Adalimumab and Innovator's Adalimumab in both rats and rabbits. No delayed toxicity was noticed during treatment free recovery period of two weeks. The immunogenic response in CHL's Adalimumab treated groups was comparable to that of Innovator's Adalimumab treated group. No immunogenicity titers were noticed against host cell proteins (HCP) which demonstrates that the product have extremely low levels of HCP contaminants.
NOAEL was considered to be more than 10X of human equivalent dose (41 mg/kg in rats and 21 mg/kg in rabbits) by weekly subcutaneous administration over a period of four weeks.
Thus, the overall pre-clinical profile of CHL's Adalimumab seems to be non-inferior with the lnnovator's Adalimumab and considered to be safe at the recommended dose in humans.