Humira Biosimilars Face Complex Asia Outlook As Launches Edge Closer
Executive Summary
The Asia Pacific region presents large potential opportunities for the development of biosimilar versions of big-selling original biologics as these come out of protection in the major markets. However the regulatory, reimbursement and commercial situation varies greatly country-by-country, presenting a complex mix of factors affecting the overall market outlook for these up and coming biosimilar products.
The situation for global blockbuster AbbVie Inc.'s Humira (adalimumab) presents a revealing case study of how the variation in these local influences can affect the advent and likely progress of biosimilar competition for a major biologic product, and complicate the outlook beyond a simple consideration of sheer potential market size.
With global sales of around $16 billion last year, mostly in rheumatoid arthritis, Humira is steadily being opened up to biosimilar competition worldwide, with Europe providing most of the early challenges to the original product and initial sales erosion that AbbVie has conceded has been greater than expected.
With further patent expiries happening or coming up around the world, Informa Pharma Intelligence's Asia-Pacific editorial team takes a look at how things stand in four major markets in Asia, assessing the current commercial state of play, and regulatory, policy and pricing factors that are set to influence biosimilar competition for the world's biggest-selling biologic therapy.
Pricing A Key Factor In India
Commercial/Pipeline Situation
Zydus Cadila got approval for the country's (and what it claimed was the world's) first biosimilar adalimumab in September 2014, launching it that December, in a market where local manufacturers have generally employed more aggressive pricing strategies for many first-to-market follow-on products. Zydus initially said its version, Exemptia, would cost one-fifth of the price charged for Humira, which itself as the original branded product is not sold on the Indian market.
Exemptia claimed to be a "fingerprint match" with the originator product in terms of safety, purity and potency, and it was followed by Torrent Pharmaceuticals Ltd.’s version of adalimumab (marketed as Adfrar), which launched in 2016.
2018 saw the arrival of Hetero Drugs Ltd.’s biosimilar Humira, marketed as Mabura, while Glenmark Pharmaceuticals Ltd. sealed a licensing pact with Zydus to launch another adalimumab brand, Adaly. Cipla Ltd. too has since jumped into the fray with an in-licensed version of adalimumab, Plamumab. Some online pharmacies also list the availability of Envira (adalimumab) from local firm Emcure Pharmaceuticals Ltd.
Zydus' Exemptia is said to hold a market share of 65% in the adalimumab segment, significantly ahead of the other players. There are also signs of an expanding patient base for Exemptia; the company's 2016-17 annual report noted that more than 7,000 patients have been on the product.
Access Issues
India remains a low-income, self-pay market, and even follow-on biologics remain beyond the pocket of many Indian patients. Lower prices have boosted access to a number of biologics, however, and with follow-on products capturing a significant share of sales, the country's market for biosimilars was worth approximately $250 million by 2015.
Experts note how the Indian biosimilars market in general has been evolving – in recent years multiple such products for individual innovator biologics, especially the high value monoclonal antibodies such as adalimumab, bevacizumab, trastuzumab and rituximab, have all been approved.
“Competition triggered by the availability of multiple biosimilars not only provides more options to the prescribers and patients, but also helps bring down the prices. These are definite steps towards better access and maturing of the market,” Dr. Charu Manaktala, senior medical director and head of Asia Pacific Biosimilars Centre of Excellence, IQVIA, said.
On the regulatory side, in 2012 India outlined its first set of guidelines on similar biologics, lending much-needed clarity to the approval pathway for such products; the guidelines were then revised in 2016.
Pricing Matters
Interestingly, as for pricing, most Indian players appear to have aligned the levels for their adalimumab biosimilars in the region of INR22,000-25,000 ($320-364) except for the Cipla brand, which is priced at around INR16,072. Typically, though, the price to patients is believed to be much lower, given various patient assistance programs and other discounts.
Zydus confirmed that for patients who are on a patient assistance program through doctor referrals, the actual cost of Exemptia ranges from INR11,000-14,000. Cipla’s Plamumab is believed to be available at prices lower than Exemptia, though the Mumbai-based company declined to comment on product-related issues or pricing.
Some experts, however, suggest that the trade discounts seen in the Indian biosimilars space typically come with a caveat – the offer is valid only if you buy a minimum quantity of the product. “I think these discounts/offers will continue, driven by competition and duration of the therapy. For chronic it will be higher,” said Dr. Subita Srimal, partner at ProGrow Pharma Partners, an Indian life sciences advisory firm. The India biosimilar adalimumab prices are also a fraction of Humira’s price internationally.
Industry experts had previously explained that the price advantage of biosimilars is perhaps more valuable in an out-of-pocket market like India, where physicians generally try to "economize" and prescribe adalimumab for around six months to bring down/control the severity of the symptoms, after which the patient can be "tapered off" the biologic and maintained on oral/conventional therapies.
The India pricing dynamics are also interesting in view of general expectations that price erosion for biosimilars is likely to be less dramatic in emerging markets, as regulatory requirements become more harmonized and costs climb. IQVIA’s Manaktala explained that the application of global, harmonized regulatory standards translates into increased development costs. “However, availability of multiple biosimilars for individual biologics is likely to trigger competition and price optimization,” she maintained.
“In self-pay markets such as India, the marketing prowess of leading local manufacturers will rule out the need to compete solely on price, helping to preserve value in the biosimilars sector,” Datamonitor Healthcare analysts predicted in a report in April last year on Biosimilars in Emerging Markets.
Japan Entrants Line Up
Commercial/Pipeline Situation
There had been some predictions that the first biosimilar adalimumab could be launched in Japan for the main rheumatoid arthritis indication in the third quarter of 2018, following the expiry of the local patent in this indication, but as of late November, there were no signs of the first approval, and some companies working in the area are keeping development status close to their chest.
Several firms are known to be developing biosimilars of Humira, including Pfizer Inc., Mochida Pharmaceutical Co. Ltd., and the Fujifilm Kyowa Kirin Biologics Co. Ltd. joint venture, with Mochida's version thought to be among the most advanced. Under a multi-product alliance, the mid-sized Japanese firm is developing LG Chem ’s biosimilar portfolio in Japan including adalimumab, known as LBAL. While Mochida does not publicly disclose the development stage of its biosimilar pipeline, this has been reported to be in Phase III.
Pfizer Japan has said just that it expects to launch "within five years of 2016," while Daiichi Sankyo Co. Ltd. and Amgen Inc. in July 2016 signed a deal for the Japanese development and marketing of nine biosimilars including adalimumab, but as in Mochida's case, the development status of these is undisclosed.
Elsewhere in the commercial sphere, a February 2014 alliance between Kissei Pharmaceutical Co. Ltd. and South Korea’s Alteogen Inc. is developing various biosimilars including adalimumab (current status again not disclosed), and Kyowa Hakko Kirin Biologics is partnering with Mylan NV to commercialize biosimilars in Japan.
More recently, in November 2018, Fuji Pharma entered into an agreement to develop in Japan Alvotech's portfolio of biosimilars, which include adalimumab, although this product was not specifically identified.
The potential commercial field could eventually become crowded, although the overall market is not huge. The current Japanese market for original Humira (co-marketed with Eisai Co. Ltd. in Japan) in its main RA indication is currently estimated to be around JPY30 billion ($264 million) annually at reimbursement prices; the disorder is estimated to affect around 1.2 million people in the country.
Given the expected entry of biosimilars, Datamonitor Healthcare sees branded Humira sales in RA in Japan falling from this current levels to around $112 million in 2025. The total Japanese RA market is expected to fall from $1.3 billion in 2017 to $1.1 billion in 2025, based on a Datamonitor patient forecast.
Access Issues
For new entrants, Japan has the benefit of already having a clear and established biosimilar regulatory pathway, with guidelines issued in 2009. The main differences versus small molecule drugs are requirements for single/repeat dose toxicology studies, and some form of clinical studies in Japanese patients.
The Japanese regulators do allow extrapolation to indications for which the reference product (which must be approved in Japan) is approved, but only if the same mode of action is involved and the safety/efficacy re-examination period for the original's indications has expired. This is why biosimilar Remicade (infliximab) was approved in only three settings (RA, ulcerative colitis and Crohn's disease).
Abbreviations of data requirements are also allowed if sufficient similarity and clinical equivalence can be shown, and with no dose-setting study required at Phase II for example, and an abbreviated Phase III program. But comprehensive post-marketing surveillance studies are usually required, particular where pre-approval data are limited.
The regulations are seen as providing a clear framework and few practical barriers to biosimilar entry, as evidenced by approvals for a range of other biosimilars.
Pricing Matters
While the regulatory situation is positive, uptake is largely down to comparative pricing and reimbursement under Japan's national health insurance system.
Biosimilars are usually priced initially at 70% of the original product’s current reimbursement price, in line with regulations for such follow-on products, either generic or biosimilar, theoretically giving them a modest – although not huge – pricing advantage over the original.
However, under rules that have been discussed this year, pricing of a follow-on biologic manufactured to be made to the same standards and process as the original product would be considered a "standard" generic under Japan's reimbursement pricing scheme, and therefore reimbursed at 50% of the current reimbursement price of the original product, in line with standard chemical generic drugs.
Policy changes in general have been made over the past few years to encourage the use of generics, such as fee structure changes and the default allowance of substitution unless specified otherwise by prescribers.
The differential with the branded original may also be affected by other factors. For RA, for instance, the co-pay advantage for a biosimilar may be limited, given that original drugs' costs are covered under a high-cost benefit program, although high upfront fees may create patient demand. Outside of this, some surveys have shown high awareness of the higher cost of biologic therapy in the disease, however, suggesting that biosimilars may be able to find their niche.
Of three of the early marketed biosimilars in Japan (somatropin, epoetin alfa and filgrastim), penetration has been decided largely by whether the products are used in inclusive payment DPC (diagnostic procedure combination fixed-cost) hospitals. Given that a fixed reimbursement is provided, an opportunity to reduce the drug cost component within this amount may be attractive.
Pharma companies' market presence and sales power, and physician experience and severity of the indication, are seen as other influencing factors.
In the meantime, original branded Humira continues to be approved in Japan for additional indications, receiving a nod in March 2018 for pustular psoriasis unresponsive to conventional therapies, its 10th use in the country, while a pediatric subcutaneous formulation and a new pen autoinjector are other line extensions, while the product has been filed for new uses including the skin disorder hidradenitis supperativa.
South Korean Korean Players Leverage Strengths
Commercial/Pipeline Situation
On the back of the government’s long push to grow the biosimilar sector and early establishment of guidance on the regulation and approval of biosimilars, South Korea has already approved several biosimilar products, including biosimilar infliximab, trastuzumab and adalimumab since 2012. And similar to the situation in other countries, biosimilar adalimumab is expected to be the most popular and crowded biosimilar market in South Korea when products begin to launch – possibly from 2019, when its patent protection expires in the country.
Several biosimilar versions of Humira are set to compete in the country’s KRW70 billion market, with Samsung Bioepis Co. Ltd.'s Hadlima clearly leading the race by already gaining the approval from the Ministry of Food and Drug Safety in September 2017.
Samsung declined to comment on the timing of the launch, price or other details. It plans to select a separate marketing partner of Hadlima for the South Korean market.
In South Korea, only Samsung’s biosimilar version has received regulatory approval so far, while LG Chem, Boehringer Ingelheim GMBH, Pfizer and Sandoz International GMBH’s versions are in Phase III trials. LG Chem is conducting Phase III clinical trials of LBAL in South Korea and the first of these studies is nearly completed
LG and Mochida have been co-developing Enbrel and Humira biosimilars in South Korea and Japan since 2012. Under the agreement, LG will manufacture the biosimilars in its Osong plant and supply them to the South Korean and Japanese markets.
Boehringer’s BI 695501 has received an IND approval in November 2015 to begin a Phase IIIb clinical trial, Pfizer’s PF-06410293 also received approval in October 2014 to begin a Phase III trial in the country, while Sandoz has received the approval to begin a Phase III study of GP2017 in September 2016.
Meanwhile, Celltrion Inc. is developing a Humira biosimilar in high concentration formulation, but it has not begun clinical trials yet in the country. Separately, the company is now progressing a Phase III clinical trial of an infliximab biosimilar in subcutaneous formulation with a goal to commercialize this in 2019. According to the 12-month data from the PANTS study presented at the 13th Congress of the European Crohn’s and Colitis Organisation in Vienna this February, the results indicate that the safety, clinical effectiveness (by various measures), and immunogenicity of Celltrion's CT-P13 (biosimilar infliximab) in patients with Crohn’s disease is comparable to those treated with reference infliximab as well as those treated with adalimumab.
Other South Korean firms have early-stage adalimumab biosimilar pipelines. South Korean biotech BIOCND is conducting a Phase I clinical trial of BCD100, Aprogen has an early stage adalimumab biosimilar, AP97, while Dong-A Socio Holdings Co. Ltd. is developing DMB-3113 together with Japan’s Meiji Seika Pharma Co. Ltd. through establishment of the joint venture DM Bio Ltd. The two agreed in 2012 to develop Herceptin and Humira biosimilars in South Korea and Japan.
Access Issues/Pricing
South Korea also has a well-defined pathway for biosimilars, with the Ministry of Food and Drug Safety introducing specific evaluation guidelines in 2009 and then revising these in 2014.
Like other biologics, biosimilars are reviewed through the evaluation of quality, preclinical and clinical data, although there are usually fewer documentary requirements that original biologics that need to be submitted to authorities. Biosimilars are compared to their reference product and have to prove their comparability in terms of product characteristics, safety and efficacy.
In a reimbursement system akin to that in Japan under the national health insurance system, Korea had been pricing biosimilars at 70% of the original drug's current price, but in 2016, a revised pricing system was introduced, under which – if the products meet certain conditions – they could be priced at 80% of the original's price for up to three years.
To qualify for this system, products have to be developed by companies that meet certain criteria of innovation, or be jointly developed by domestic and multinational pharma firm, and have undergone a later than Phase I trial in the country.
Complex China Situation
Commercial/Pipeline Situation
In general, biosimilars are expect to grow rapidly in China, give the country now has only a very low (around 2% of total drug usage) market penetration of biologics, partially due to the high costs associated with such products. Biosimilar and conventional generic drugs are both expected to play a bigger role in the country, as the government looks to control rising health costs while improving access.
Biologics in general are often still beyond the pocket of both provincial payers and the vast majority of patients in China. This has limited sales of original biologic brands, and has seen many denied access to national and provincial reimbursement lists.
Some Chinese firms developing biosimilars have also been building out their new drug portfolios, to hedge against concerns that biosimilars will command relatively low pricing power and face limited uptake given the generally poor market penetration of biologics in China. This has been attributed to various factors including their lack of reimbursement under health scheme and relatively higher prices versus conventional drugs.
Companies face a balancing act of pricing enough below the original product to be attractive, while leaving room for further discounting, and educating prescribers about comparability.
A number of companies are developing adalimumab biosimilars, including one of the leading companies in the sector, Henlius, with HLX03. There are about 20 biosimilar versions of various TNF-alpha inhibitors (including adalimumab) currently in development in China, with 3SBio Inc., Hisun and Innovent Biologics Inc. among the companies involved.
Bio-Thera's candidate, BAT1406, was accepted for approval review in August, and the company said this first biologics license application for a biosimilar adalimumab could lead to it gaining the pioneering such approval in the country.
The Chinese company conducted a Phase III non-inferiority trial against the original product, which it said established the same safety and efficacy as Humira.
Access Issues
But there are many hurdles facing biosimilars in China, noted industry experts attending the BioCon China conference in April 2018 in Shanghai. These include: a lack of awareness among physicians and patients; no reimbursement; head-on competition with established multinational originator companies; uncertain pricing; and China's feverish activity to develop innovative biologic therapies, from gene-editing to immuno-oncology drugs to CAR-T treatments.
Some lower-cost follow-on products have been granted reimbursement more widely, however, enabling more patients to access treatment.
On the regulatory side, biosimilars are not subject to an abbreviated approval pathway under official guidelines, and the time to market will largely depend on the results of pharmacology and preclinical comparative studies. The process may take up to seven years. If the early-stage comparability study fails, a biosimilar could be switched to the standard approval pathway of a novel biologic, which can cause further delays.
Interchangeability is another consideration. Although China has a regulatory approval pathway, there are no formal rules on whether originators can be substituted with biosimilars, and no rules on indication extrapolation and how biosimilars will be named. In 2015, China issued its first regulatory pathway for biosimilars, largely adopted from the regulations of the European Medicines Agency, and many believe the naming of biosimilars and interchangeability will be similar to what the EU has in place.
Unlike the US, there are no incentives for a first-to-market biosimilar that is interchangeable with the reference product in China, nor an exclusivity period for pediatric or orphan disease indications. The guidelines, issued by the Center for Drug Evaluation, do not address interchangeability, because Chinese physicians largely prescribe drugs using generic names. If the biosimilar is given the same generic name as the innovative product, then interchangeability is theoretically possible.
Then reimbursement is another key factor. No biologics (biosimilar or otherwise) are currently covered by the China National Reimbursement list, due to their high costs, and biosimilars, like innovative biologics, are unlikely to be included in the Chinese national insurance scheme immediately upon approval. That leaves manufacturers of these products with few choices except to offer patient assistance programs or to seek coverage from local reimbursement initiatives for selected severe conditions.
Even so, some observers see as a huge market for biosimilars in China. While the public hospital sector dominates the Chinese market, opportunities will exist for products that either do not feature on provincial formularies or do not win provincial tenders. Where competition for provincial tenders is particularly fierce, foreign players targeting the Chinese biosimilars market may still be able to generate significant revenues by leveraging extensive trial data and their reputation as manufacturers of high-quality products, seeking opportunities in the high-margin self-pay market rather than the high-volume reimbursement sector, Datamonitor predicts.
As one example, three years after its 2005 launch, CP Guojian Pharmaceutical's follow-on etanercept product for RA, Yisaipu, generated sales worth more than $100 million and around 75% of the RA biologics market, despite not featuring on either national or provincial reimbursement lists. This is due largely to its hefty 40% discount to Enbrel, Pfizer’s original product.
This article is part of the Outlook 2019 series – an annual collection provided exclusively to subscribers of Informa Pharma Intelligence publications.