Lupin’s biosimilar plans are reaching a crucial inflexion point, with recent positive global Phase III results of its etanercept biosimilar for rheumatoid arthritis. As research on other biosimilars in its pipeline picks up pace, Lupin is now a serious contender in this space
This February, Lupin moved a crucial step closer to the launch of its first biosimilar for the global market, when its joint venture, YL Biologics (YLB) announced positive outcomes of a global Phase III clinical trial of its etanercept biosimilar (YLB113).
Speaking at the launch, Dr Cyrus Karkaria, President, Lupin’s biotech division, indicated that the company would be be filing for regulatory approval for YLB 13 in Q1FY19 in Japan and the EU, while India would follow in Q1FY19 or Q2FY19.
YLB is a JV between Lupin and Japan’s Yoshindo, formed in April 2014, and etanercept biosimilar, developed by Lupin’s Pune-based Biotechnology Research Group, was the first product to be licensed for clinical development to YLB.
YLB113’s efficacy and safety was compared against Enbrel (of Amgen/Pfizer) which has a global market of $11 billion (IQVIA MAT Q3 2017). Etanercept is used to treat rheumatoid arthritis (RA) and other autoimmune disorders.
The Phase III study of YLB113 was a multinational randomised double-blind controlled trial of 52 weeks duration which included more than 500 patients with RA in 11 countries. More than half of the patients (260) were Japanese, recruited from 62 rheumatology clinics in that country, which according to company officials, is quite unusual for a global RA trial in Japan. The remaining 48 rheumatology clinics were from Europe and India.
According Dr Dhananjay Bakhle, Executive VP, Medical Research, Lupin, the primary endpoint was an equivalent improvement in RA, as measured by American College of Rheumatology 20 (ACR20) response rate. The ACR20 response rate of YLB113 was found to be within a pre-defined equivalence margin that is expected by most advanced regulatory agencies for marketing authorisation. In addition, safety and immunogenicity (antibody formation) of YLB113 was also found to be similar to Enbrel indicating therapeutic equivalence.
Given the number of patients from Japan, company representatives seemed confident that the Japanese regulator Pharmaceuticals and Medical Devices Agency (PMDA) would approve the biosimilar. If the filing is completed as targeted in FY2019, estimating a year for regulatory review by PMDA, Lupin is looking at a launch in Japan in FY2020 or later.
Enbrel’s patent expired in 2012 but continues to November 2028 in the US, after the originator Amgen was granted a new patent. According to a presentation by Vinita Gupta, CEO, Lupin, at the JP Morgan Healthcare Conference (JPMHC) this January, the company targets to file in the US by Q3FY20.
The JPMHC presentation also details Lupin’s strategy as the only Indian player and the sixth largest generic pharma player in Japan. It is evident that biosimilars is a key part of its strategy to have a hybrid portfolio, evolving from its current focus on mature brands to complex generics, to biosimilars and finally to speciality business.
Complex research
The positive late trial results on etanercept are a significant achievement as R&D related to developing the biosimilar had many complexities, points out Karkaria. Etanercept is a biopharma compound whose mode of action in the treatment of autoimmune diseases is to interfere with the tumour necrosis factor (TNF, a soluble inflammatory cytokine) by acting as a TNF inhibitor.
The Lupin-YLB clone consists of an extracellular ligand-binding portion of the human (p75) TNF receptor, linked to the Fc portion of a human immunoglobin (IgG1) antibody. The mechanism of action involves competitive inhibition of soluble TNF-alpha binding to its receptor. According to Bakhle, despite the complexity of engineering of this molecule, biosimilarity to Enbrel was established by totality of evidence starting from analytical similarity, pre-clinical study comparisons, Phase I studies in India and Japan and finally through a global phase III study. As he puts it, “Ultimate proof of the pudding is in the eating,” hence phase III in a large number of patients suffering from moderate to severe RA was the platform for comparing therapeutic equivalence of Lupin’s product.
Development challenges of the Lupin-YLB clone included 21 changes in the manufacturing process of the reference drug. The upstream process involved choosing a clone with high productivity, controlling post-translational modification and refolding, scale up associated changes, and controls related to raw material, process, impurities and costs. Downstream challenges included those related to virus inactivation and clearance, impurity clearance, yield clearance and consistency, process controls and inprocess stability. Formulation of the trial product presented challenges like accurate composition, aseptic manufacturing, stability, device function and cold storage and shipping. Challenges on the clinical side included PK/PD, bioequivalence, immunogenicity, and injection site reactions.
Finally, the regulatory challenges pertained to the choice of reference product and the differences in the regulatory requirements across different agencies like the US FDA, EMA, PMDA, DCG(I). For example, various regulatory authorities may judge the criteria for therapeutic equivalence slightly differently as it happened in the case of etanercept. While EMA and PMDA accepted an equivalence margin as 15 per cent, US FDA wanted a tighter margin of 12 per cent. The clinical trial results were then analysed differently according to such criteria and Lupin’s product passed the more stringent criteria of US FDA as well. “The world of clinical research as judged by advanced regulatory agencies is much tougher to meet for complex products such as etanercept and Lupin’s level of expertise got fully tested and validated in the process,” explains Bakhle.
Biosimilar play
As the fifth largest company in India’s pharma market (IQVIA MAT December 2017), and the seventh largest generic company globally, Lupin’s biotech play started a decade back with the establishment of the Pune facility in 2008. Today Lupin’s biotech facility is spread over 22,000 square metres, with a talent pool of close to 300 people, consisting of approximately 11 per cent PhDs and 63 per cent post-graduates. Its first two oncology products, Lupifil and Lupifil-P (biosimilars for Filgrastim and Peg-Filgrastim molecules respectively) were commercialised in India in 2015, marking Lupin Biotech’s first step on the evolution curve. Besides etanercept , another product in the pipeline, ranibizumab has the potential to be in the first wave of entrants across major markets. Additionally, Lupin has novel molecules in various stages of development across diverse indications such as oncology and endocrine disorders.
The establishment of biosimilars in regulated and semi-regulated markets by 2020 will be the second step in its mission to evolve up the biotech value chain. The February announcement of YLB113’s positive results make this target fairly doable. By 2025, Lupin Biotech aims to gain first mover advantage with new generation biosimilars and graduate to novel biological entities (NBEs).
Lupin’s strategy is to choose products that are difficult to make, have an entry barrier and therefore a larger competitive interest in the long run. Though Lupin might be one of the last to join the biologics bandwagon, they do get results, no doubt learning from the missteps of other peers. But will the delay cost them in terms of market share?
February’s announcement came after five and a half years of development, during which two Indian companies, Cipla and Intas Pharma, launched their biosimilars of etanercept. While Cipla launched in April 2013, at a price that was reportedly 30 per cent lower than that of Amgen’s product, Intas Pharma followed two years later, in March 2015.
Explaining how Lupin’s biosimilar strategy differs from other peers in India and the delay in launch, Karkaria says, “When a pharma company develops (a biosimilar) with the India market, the (development) time is less but it has problems in the global market. So Lupin targetted Japan, EU and then India. Studies done in the RoW markets won’t hold in these markets. This is a big advantage of starting late, because you learn from other people’s mistakes. We didn’t jump the gun, instead negotiated with each global authority.” He indicated that they are ”doing the spade work” looking for partners for the US market, but the US launch is still some way off, as there are IP issues as well.
Karkaria indicates that while there will be price erosion, as more players launch their etanercept biosims, Lupin will have a cost advantage as it is made in India. “The small molecule patent cliff is passe. Now companies are tracking the biologics patent cliff.” Though there are five-six biologics losing patent protection in the next few years, he says the difficulty level of replication is much higher than with small molecules. As is oft repeated, with biologics, the process is the product, and even small changes in the process can change the properties of the biosimilar. Doctors thus take longer to be convinced of the safety of biosimilars versus the original molecules. Hence the switch to biosimilars is slower than with generics.
Next steps
The biosimilars road ahead is not without its challenges. Besides global competition from the likes of Novartis which is fighting a patent challenge from Amgen for the etanercept US market, Lupin’s biosimilar will be launch quite some time after its peers in the India market.
But company leaders seem confident of making a strong mark when they do launch. Bakhle points out that both the competitor products have been developed for the Indian market, whereas Lupin’s etanercept has been developed for global markets which puts enormous responsibility on the company to demonstrate totality of evidence from laboratory stage to clinic passing through animal studies as well.
Giving examples, he says, “The number of patients required for a global phase III study were upwards of 500 for Lupin, whereas Schedule Y requirement is around 100 patients. The rigour of doing a global phase III study with half the patients coming from Japan and rest from Europe is a different ballgame for an Indian MNC. The way CMC data is scrutinised by PMDA, EMA and FDA is much more rigorous and challenging for a biosimilar being developed for these advanced markets. Sustaining competition in the global market requires inherent strengths of the product and the clinical research designs and implementation to pass through the technical entry barriers that are tougher than market barriers.”
On the price front like Karkaria, he too refrains from disclosing specifics commenting, “We’ll certainly be competitive but would not like to reveal our market strategy at this stage.”
One of the next steps is to compare Lupin’s mode of delivery with etanercept autoinjectors and demonstrate differences if any. Bakhle reveals that their study is in 150 patients of RA and yet to begin though they have received regulatory approvals. All in all, Lupin’s moves on the biosimilars front, may have been slow but are worth watching more closely in the days ahead. It could be the tortoise that finally wins the race.
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