Biosimilar ranibizumab in India- overview of phase 3 clinical trial designs

India was the first country in the world to approve ranibizumab biosimilar. The Drug Controller General of India (DCGI) approved Razumab (Intas Pharmaceuticals Limited, Ahmedabad, India) in 2015 as the first biosimilar ranibizumab [1]. The innovator ranibizumab molecule (Lucentis, Genentech, USA) patent expired in June 2020 (USA) and July 2022 (EU) [2]. This has led to a flurry of new drug applications and approval of biosimilar ranibizumab especially in India. At present India has the maximum number of approved ranibizumab biosimilars. India has eight ranibizumab biosimilar products manufactured by four manufacturing facilities. DCGI has approved these molecules based on the pharmacoequivalence data and brief phase 3 clinical trial data. This manuscript aims to provide an overview of the trials on anti-VEGF biosimilars in India.

Razumab (Intas Pharmaceuticals, Ahmedabad, GJ, India)

Razumab received approval for all indications for the reference drug, ranibizumab. This includes neovascular age-related macular degeneration (n-AMD), diabetic macular oedema (DMO), retinal vein occlusion (RVO), myopic choroidal neovascular membrane (m-CNVM), and proliferative diabetic retinopathy (PDR). Furthermore, it has also been approved for the retinopathy of prematurity (ROP). The first approval was obtained in February 2015.

Phase 3 clinical trial data

A total of 104 participants with n-AMD participated in the study. 104 participants were randomized 3:1 to biosimilar ranibizumab (Razumab), n = 78 and reference ranibizumab (RBZ), n = 26. All the eyes were injected at 4-week intervals up to 12 weeks. For efficacy, the primary endpoint was the proportion of patients who have lost <15 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) at 12 weeks. The mean increase in best corrected visual acuity (BCVA) and central subfield thickness (CST) improvement at 12 weeks was considered as the secondary endpoint. Immunogenicity data was assessed throughout 12 weeks. Both arms were equivalent throughout the study. (Data from file).

Ranizurel (Reliance Life Sciences Ltd, Mumbai, India)

Ranizurel received DCGI approval for n-AMD in March 2020. It was the second biosimilar ranibizumab to be approved in India.

Phase 3 clinical trial data

A total of 160 subjects with treatment naïve n-AMD were randomized in 2:1, 107 subjects in the biosimilar ranibizumab (RanizuRel) arm and 53 subjects in the reference ranibizumab (RBZ) arm, and dose 159 subjects with the study medication i.e. 106 subjects in the RanizuRel group and 53 subjects in the RBZ group. Patients received RanizuRel or RBZ 0.5 mg (0.05 mL of 10 mg/mL solution) as an intravitreal injection once every 4 weeks. The study duration was 24 weeks. Efficacy and safety were found equivalent to the innovator ranibizumab [3].

Ranieyes (Lupin Limited, Mumbai, India)

The third biosimilar ranibizumab molecule (Ranieyes) was approved in India by the DCGI in Oct 2021 for n-AMD, in Apr 2022 for DMO, RVO, and CNVM due to pathological myopia, and submitted the application to the DCGI for extrapolation of indication (PDR and ROP) on Sep 2023.

Phase 3 clinical trial data

A total of 202 subjects with treatment naïve n-AMD were randomized in 1:1, 101 subjects were assigned to the biosimilar ranibizumab (Ranieyes) arm, and 101 subjects to the reference ranibizumab (RBZ) arm. Patients were treated at 4-week intervals for 12 weeks. The primary endpoint to assess the efficacy was the proportion of patients losing fewer than 15 letters (approximately 3 lines) from the baseline BCVA in the study eye by the end of 12 weeks. The predefined equivalence margin for the same was ±8.5%. Efficacy and safety were found similar in both groups [4].

Optimab (Alkem Labs/ Enzene Biosciences, Pune, India)

The fourth biosimilar ranibizumab molecule (Optimab) was approved in India by the DCGI in August 2023 for n-AMD.

Phase 3 clinical trial data

In this study, a total of 152 subjects of treatment naïve n-AMD were randomized in 3:1, 114 subjects in the biosimilar ranibizumab (Optimab) group and 38 subjects in the reference ranibizumab (RBZ) group. Patients received Optimab or RBZ 0.5 mg (0.05 mL of 10 mg/mL solution) as an intravitreal injection once every 4 weeks for the treatment period of 12 weeks. The primary endpoint was the percentage of subjects who lost < 15 letters in visual acuity in the study eye at week 12 compared to the baseline. The non-inferiority margin was set at −20% for the lower limit of the 90% CI for treatment difference. Efficacy and safety were found equivalent. (data in the file).

Discussion

Based on the analysis of the aforementioned clinical trial designs, which led to the approval of various ranibizumab biosimilars in India, significant variability is seen in the subject’s randomization ratio apart from overall sample size variability. (Table 1) Furthermore, variability is seen in the overall duration of the trial. Overall, Ranieyes had 1:1 randomization and other molecules had either 3:1 (Razumab and Optimab) or 2:1 (Ranizurel) randomization between innovator and biosimilar ranibizumab. Most of the phase 3 trials for biosimilars fail to detect the risk of adverse events due to these molecules. Regulatory authorities decide the structure of a clinical trial based on the pharmacoequivalence data between the innovator and biosimilar which is generated before the clinical trial phase. This baseline pharmacoequivalence data makes the key comparison data for these molecules from a regulatory standpoint. Challenges are popping up due to the growing number of biosimilars for an innovator molecule as such, India has 8 ranibizumab biosimilar molecules at present, and often the questions arise, which one to prefer? It is not feasible to have efficacy and safety comparisons between different biosimilars of a molecule. Based on the recent biosimilar perception survey by the International Retina Biosimilar (Inter-BIOS) Study Group in collaboration with the Vitreoretinal Society of India (VRSI) (Unpublished data), Physicians believe that the real-world data would help them to make better clinical decisions amongst these molecules. Although it’s the regulatory body that decides to finalize recommendations for a clinical trial design for biosimilar molecules, We feel the symmetry in biosimilar clinical trial designs might help to avoid nocebo perception towards some of these molecules going forward [5].

Table 1.

Key characteristics of phase 3 clinical trial designs.

Biosimilar name/ manufacturing company	Approval indications	Sample size	Primary outcome	Marketed by/brand name	Total study duration	Safety assessment criteria
Razumab/ Intas Pharmaceuticals Ltd, Ahmedabad, GJ	n-AMD, DMO, RVO, m-CNVM, PDR, ROP	104 (Razumab-78) (RBZ-26)	Loss of < 15 letters on ETDRS at 12 weeks.	Intas Pharmaceuticals/ RAZUMAB	3 months	TEAEs ADA
Ranizurel/Reliance Life Sciences Mumbai, MH	n-AMD	160 (Ranizurel-107) (RBZ-53)	Loss of < 15 letters on ETDRS at 16 weeks.	Reliance Life Sciences/ RANIZUREL Cipla Ltd/ VISUMAB	6 months	TEAEs ADA
Ranieyes/ Lupin Ltd, Mumbai, MH	n-AMD, DMO, RVO, m-CNVM, PDR	202 (Ranieyes-101) (RBZ-101)	Loss of < 15 letters on ETDRS at 12 weeks.	Lupin Ltd/ RANIEYES Sun Pharmaceuticals/ OCEVA	3 months	TEAEs ADA
Optimab/ Enzene Biosciences a subsidiary of Alkem Labs, Pune, MH	n-AMD	152 (Optimab-114) (RBZ-38)	Loss of < 15 letters on ETDRS at 12 weeks.	Alkem Labs/ OPTIMAB Ipca Labs/PREVISION Mankind Pharma/RETIZUBA	3 months	TEAEs ADA

Key characteristics of phase 3 clinical trial designs of ranibizumab manufacturers approved by DCGI.

n-AMD neovascular age-related macular degeneration, DMO diabetic macular oedema, RVO retinal vein occlusion, m-CNVM myopic choroidal neovascular membrane, PDR proliferative diabetic retinopathy, ROP retinopathy of prematurity.

DCGI Drug Controller General of India, BCVA best Corrected Visual Acuity, ETDRS Early Treatment Diabetic Retinopathy Study Letters, TEAEs Treatment-Emergent Adverse Events, ADA Anti Drug Antibodies, RBZ Reference ranibizumab, NA Not Available.

Author contributions

AS: conception, analysis, drafting, integrity check, final approval NK, NP, FB, AL, BDK; drafting, revision, analysis, integrity check.

Competing interests

Dr Ashish Sharma: CONSULTANT: for Novartis, Allergan, Bayer and Intas. Dr Francesco Bandello: CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, FidiaSooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. Dr Anat Loewenstein reports other from Allergan, other from Novartis, other from Roche, other from Notal Vision, other from Forsightslabs, other from Beyeonics, other from Bayer Health Care. Dr Baruch D Kuppermann: CLINICAL RESEARCH: Apellis, Genentech Inc, Boehringer Ingelheim, EyePoint, Ionis, IVERIC Bio, Novartis Pharmaceuticals, Regeneron Pharmaceuticals Inc, RegenXBio; CONSULTANT: Aviceda, Allegro Ophthalmics, Allergan/AbbVie, Bausch+Lomb, Boehringer Ingelheim, Clearside, Coherus, EyeBio, Eyedaptic, EyePoint, Genentech Inc, Glaukos Corporation, InflammX Therapeutics, IVERIC Bio, jCyte, Mobius, Neurotech Pharmaceuticals, Novartis Pharmaceuticals, Ocular Therapeutix, Outlook Therapeutics, Regeneron Pharmaceuticals Inc, ReVana Therapeutics, Ripple Therapeutics, Stealth Biotherapeutics, TechImmune, Theravance Biopharma, Visgenx. Dr Nilesh Kumar: None. Dr Nikulaa Parachuri: None.