Biosimilar for ranibizumab clears hurdles in India

Intas Pharmaceuticals of Ahmedabad, India, seems to have overcome the manufacturing problems that led to ocular inflammation in 10% of the patients injected with the first three batches of razumab, a biosimilar for ranibizumab, according to two ophthalmologists who have administered the drug.

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“In our short-term study of a very small study of 94 eyes, we suggest that this new biosimilar razumab is safe and effective for retinal vascular diseases, though long-term data and immunogenicity studies are required,” said Dr Alay Banker of Bankers Retina Clinic and Laser Centre in Ahmedabad, India.

Along with Srinivas Joshi of the Joshi Eye Institute in Hubli, India, Dr Banker travelled to the American Society of Retina Surgeons (ASRS) 2016 Annual Meeting on August 13, 2016, in San Francisco to present data on the experiences of patients treated with razumab.

Like generic drugs, biosimilars are meant to replicate original drugs whose patents have expired, and they sell for lower prices. But since they mimic products made by biological processes, they may differ subtly in their molecular structure. For that reason regulatory agencies generally require studies in which the biosimilar and the original drug are compared.

Intas designed razumab to replicate ranibizumab, the blockbuster anti-vascular endothelial growth factor (VEGF) drug marketed by Roche of Basel, Switzerland, as Lucentis.

It is one of many developed around the world to compete with anti-VEGF treatments including at least two other biosimilars to ranibizumab and others to bevacizumab (Avastin, Roche), and aflibercept (Eylea, Regeneron Pharmaceuticals).

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So far no biosimilars have been approved by European or US regulatory agencies for use in ophthalmic medicine.

Razumab showed statistically equivalent effects on best-corrected visual acuity and central retinal thickness in randomised head-to-head comparison with ranibizumab and won approval from the Drugs Controller General of India in June 2015.

In India, a 10 mg/mL dose of razumab sells for €212 per injection, whereas the same dose of ranibizumab sells for €300. That contrasts with about €900 for Lucentis in Europe.

A brief ban on the use of bevacizumab in India stimulated widespread use of the drug, with 4668 injections administered from July 2015 to July 2016, Dr Banker said.

In the first three batches, about 10% of patients experienced inflammation, said Dr Banker. These symptoms were successfully controlled with steroids, he said. “The main problem with biosimilars is the stability and the batch-to-batch maintenance of the standard of the drug.”

Solving the problem

In response to the problem, Intas introduced an additional filtration step to its manufacturing process and added fresh “ultra-pure polysorbate 20.” From batch four onward, no such adverse events have been reported, according to Dr Banker.

Dr Banker reported his clinic’s experience with 174 injections in 94 eyes, of which 26 had choroidal neovascularisation (CNV), 43 had diabetic macular edema (DME), 13 had retinal vein occlusion (RVO), and 12 had treatment warranted retinopathy of prematurity (ROP).

With a mean follow-up of 15.3 weeks, average LogMAR visual acuity improved from 0.53 to 0.37, which was statistically significant (p<0.05), and central retinal thickness fell from a mean of 359.65 to 298.68 µm, also statistically significant (p<0.01).

The eyes with retinopathy of prematurity achieved resolution of threshold disease.

Electroretinography did not reveal any abnormalities, and there were no significant adverse events

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He showed images of hemicentral proliferative diabetic retinopathy and DME, severe ROP, and oter cases where razumab proved a successful treatment.

In a second presentation on razumab, Dr Joshi presented data on 123 eyes with DME, choroidal neovascular membranes (CNVM), and RVO. Overall, LogMAR BCVA improved from 0.67 to 0.57 in one month, which was statistically significant (p=0.001)

He, too, showed several images depicting improvement in individual patients, and agreed with Dr Banker that the treatment could become a “safe, low-cost therapy for macular diseases in developing countries.”

But Intas seems to have its eyes on the developed world as well. Dr Banker noted that Intas has applied to conduct phase 3 trials with an aim to gaining approval for razumab in the USA when ranibizumab’s patent expires in 2020 and in Europe when its patent there expires in 2022. Dr Banker also noted that a phase 4 study of the treatment is underway.

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In the meantime, two other Indian companies have launched biosimilars to bevacizumab: cizumab by Hetro of Hyderabad and ­bevacirel by Reliance Life Sciences of Navi Mumbai.

Formycon of Munich and bioeq of Hozkirchen, Germany, have begun a phase 3 trial comparing their biosimilar, FYB201, to Lucentis. They planned to enrol 650 patients in 80 clinical centres worldwide. Meanwhile, Formycon has begun work on FYB2013, a biosimilar candidate for aflibercept.

Elsewhere, Pfenex of San Diego, CA, USA, is developing PF582, a biosimilar to ranibizumab. On August 8 it announced that “there were no meaningful differences” in intraocular pressure, BCVA, or central retinal thickness between PF582 and Lucentis in a 3-month phase 1/2 safety and tolerability study of 25 patients.