Biosimilars lining up to compete with Herceptin – opportunity knocks

Abstract

Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer.

Keywords::

• biologics (biological drug products)
• biosimilars
• FDA
• Herceptin®
• monoclonal antibodies
• patents
• trastuzumab

Approved in the United States in 1998, trastuzumab is a monoclonal antibody marketed in the United States by Genentech, Inc. (now owned by Roche) under the trade name Herceptin. The United States FDA has approved Herceptin for: i) the treatment of human epidermal growth factor receptor 2-positive (HER2+) early-stage overexpressing breast cancer; and ii) for the treatment of HER2+-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma [1]. Herceptin is approved for use alone or as a combination therapy to treat adjuvant and metastatic breast cancer, and as a combination therapy to treat gastric cancer. Different from traditional therapies such as radiation or chemotherapy, trastuzumab is a targeted therapy that works directly on HER2 in the breast or stomach.

HER2 is a membrane-bound receptor protein that in normal cells is activated by epidermal growth factor to promote cell growth and division. Strict regulation of HER2 is important to control cell growth. In some cancers, especially certain aggressive types of breast cancer and gastric cancer, HER2 is overexpressed in the cancer cells. Overexpression of HER2 promotes uncontrolled cell proliferation leading to cancer. Approximately 20 – 25% of invasive breast cancers exhibit overexpression of HER2 [2]. These cancers are often faster-growing and have a higher recurrence rate than tumors that do not overexpress HER2.

Trastuzumab is a monoclonal antibody specifically targeted to HER2. By recognizing and binding to subdomain IV of the HER2 membrane-bound protein, it is believed that trastuzumab inhibits downstream cellular signaling, and also marks HER2 cells for destruction by the immune system [3]. Thus, trastuzumab stops proliferation of cancer cells overexpressing HER2 and generates an immune response against those cancer cells.

While Herceptin has become a leading treatment for many of the most aggressive types of breast cancer, the treatment is expensive. Herceptin can cost over $4500 per month, or over $50,000 for a full course of treatment [4]. Herceptin has achieved over $10 billion in US sales since its launch in 1998 [5,6]. Its worldwide sales in 2013 were almost $7 billion [7]. With an approval pathway now in place [8], development of reduced-cost biosimilar versions of biologic therapies such as trastuzumab is now an attractive addition to a company’s product portfolio. This article looks at how Roche may respond to biosimilar competition in the United States to Herceptin.

1. Herceptin background and biosimilar competition

Biosimilar competition for Herceptin® is a near-term reality. While the biosimilar approval pathways in countries in Europe and Asia differ in some respects from each other and from the pathway that is established in the United States, ultimately all of the approval pathways essentially require that there be a lack of significant or meaningful differences between the biosimilar product and the reference product in terms of quality, safety, and efficacy. In addition, all companies that have a biosimilar approval pathway require some amount of clinical testing. Biosimilars for Herceptin have been approved, or are on the verge of approval, in several European and Asian countries. The sponsors for these foreign biosimilar versions of Herceptin have experience formulating their respective products, running them through the gamut of analytical and clinical studies, and in working with regulatory bodies to obtain approval for their products. And as these companies are becoming more familiar with the US biosimilars pathway, Herceptin is likely to face the prospect of biosimilar competition here in the United States as well.

In November 2013, Mylan and its Indian biologics partner, Biocon, received regulatory approval in India for a biosimilar trastuzumab product. Roche stated that it would not defend its patent rights in India, after the Indian government took steps to implement compulsory licenses for Herceptin. In February 2014, the same week, Mylan launched its product, Roche filed suit in the Delhi High Court arguing that the approvals of Biocon’s and Mylan’s products were invalid because the companies did not properly follow India’s 2012 guidelines for approval of biosimilar products [9]. The court agreed and enjoined Biocon and Mylan from selling their products. At least for now, Roche has successfully fended off biosimilar competition in India. This is a cautionary tale for those entering the biosimilars arena. Just because Roche gave up on the patent front, it did not mean that it was not going to fight the battle somewhere else, this time on the regulatory front, to fend off potential competitors.

In January 2014, Celltrion received approval from the South Korean Ministry of Food and Drug Safety for its biosimilar trastuzumab product [10]. Celltrion’s product, which will be marketed under the tradename Herzuma, is Celltrion’s second biosimilar product to receive approval in South Korea. Herzuma is the first oncology biosimilar monoclonal antibody product to be approved based on global clinical trial studies – Celltrion conducted trials involving 558 patients in 18 countries at 115 sites from August 2009 to December 2011 [10]. Celltrion expects to launch its biosimilar trastuzumab product in 2014.

In the United Kingdom, Hospira gained an important patent victory and is now on the verge of providing a biosimilar trastuzumab product in the Unite Kingdom. In April 2014, the UK Patents Court in the High Court of Justice held two of the European Herceptin patents invalid: one directed to dosages for treatment with anti-HER2 and the second directed to compositions of anti-HER2 having particular purity levels [11]. A third patent, unchallenged by Hospira, just expired on July 28, 2014.

Each of these companies have already developed a biosimilar trastuzumab product that has made its way through the regulatory process in at least one country and are likely candidates to seek biosimilar approval in the United States. Hospira has already publicly stated that it is committed to the successful adoption of the biosimilars approval pathway in the United States, and has demonstrated itself as a global leader in the biosimilars space [12]. In addition to the companies that have already pursued biosimilar approval for trastuzumab across the globe, competition is also possible in the United States from other players with experience manufacturing biosimilar products. Joint development or licensing deals involving biosimilar trastuzumab are likely as companies are increasingly entering into biosimilar production and marketing agreements. Companies are also developing new and more cost-effective ways of producing biosimilars, including biosimilar versions of Herceptin, which may result in competition in the United States. For example, PlantForm, a Canadian company with a US office, includes in its pipeline a biosimilar version of Herceptin that is made from plant cells [13]. PlantForm’s product has demonstrated efficacy in mice, is in the human clinical testing stage, and is purportedly produced at a significant cost savings. PlantForm states that it expects to launch its biosimilar trastuzumab product, in partnership with a pharmaceutical company, in worldwide markets in 2017.

Finally, biosimilar competition for trastuzumab is also possible from traditional branded pharmaceutical companies as well. Amgen, in partnership with Actavis, is in the midst of an 808-patient international Phase III study [14,15]. In July 2014, Amgen verified information on the ClinicalTrials.gov website that the study began in April 2013 and is expected to be completed by December 2016 [16]. Pfizer has also begun Phase III studies involving its version of trastuzumab in an international study that includes sites in the United States [17,18]. Pfizer’s study is to be completed in October 2017 [19].

2. How Roche may respond to Herceptin competition in the US

Roche will undoubtedly seek to protect the considerable investment it has made to build Herceptin into a $7 billion annual product. And when it comes to protecting market share for biologics such as Herceptin, everything old is new again in terms of life-cycle management. Roche will likely use many of the same strategies to protect its Herceptin market that brand pharmaceutical companies have traditionally used to try to protect branded products from generic competition. Specifically, brand pharmaceutical companies have used patent protection, citizen petitions, and development of product line extensions in order to protect their brand share.

Patents are typically a first-line defense for protecting branded market share. So far Roche has been unsuccessful in asserting patent protection for Herceptin. In the United Kingdom, the primary composition patent expired in July 2014, and the patents with later expiration were held to be invalid, thus paving the way for biosimilar competition. In India, Roche elected not to even assert its patent rights, likely motivated at least in part by compulsory licenses the Indian government put in place for Herceptin.

In the United States, patents related to Herceptin have expiration dates extending through 2019. The base patents covering a monoclonal antibody that specifically binds to the extracellular domain of HER2 expire in 2014 [20]. But Genentech has additional evergreen patents extending the patent life, with further patent applications still pending that were all from the same patent family as the patents recently held invalid in the United Kingdom [21-25]. These later patents claim anti-HER2 antibody having particular purity levels and methods of treatment following certain dosing schedules. While these patents are an impediment to bringing a biosimilar based on Herceptin to market in the United States, competitors are likely to challenge these patents, either through patent litigation or in the US Patent Office.

As evidenced by Roche’s lawsuit against Mylan and Biocon in India, regardless of the availability of patent protection, Roche can always turn to regulatory requirements and hurdles to stave off biosimilars. In the United States, brand pharmaceutical companies have frequently used citizen petitions to at least delay the onset of generic competition. Petitions have asked FDA to refuse to accept applications for myriad of reasons. For example, Abbott recently filed a citizen petition asking FDA to refuse to accept any application for a biosimilar version of Humira (adalimumab). Abbott argued that allowing a biosimilar applicant to rely on Humira data for approval of its product is an unconstitutional taking that would have been impermissible when Abbott filed for Humira because at that time there was no biosimilar approval pathway.

Roche has also developed other products as potential line extensions for Herceptin. Typically for small-molecule pharmaceuticals, when generic or other competition appears on the horizon, a brand pharmaceutical company will often shift the focus of its development, marketing, and promotional efforts from the product about to face generic competition to a different product in its stable that is in the same or similar therapeutic category. Roche has developed a subcutaneous formulation of trastuzumab, which has gained approval in Europe and is in clinical trials in the United States. Roche also currently offers other products that are indicated for the treatment of HER2+ breast cancer that Roche is using to gain position in the oncology market and help maintain Herceptin’s market share: Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine).

Pertuzumab is another monoclonal antibody currently approved for use in combination with Herceptin and docetaxel to treat metastatic HER2+ breast cancer. Like trastuzumab, it targets HER2, but is directed to a different region of the HER2 extracellular domain [26]. Pertuzumab is thus complementary to trastuzumab, and is approved by FDA for use in combination with trastuzumab and docetaxel [27]. More than 85% of surveyed oncologists reported having prescribed Perjeta in 2013 – 2014 [28]. Perjeta is even more expensive than Herceptin, with a price tag upwards of $70,000 for a full course of treatment. For the combination of the two therapies together, the cost is over $100,000 for a single patient [4].

Kadcyla is an antibody–drug conjugate combining trastuzumab with mertansine, a cytotoxic agent. It is designed to target cancer cells overexpressing HER2 but to add a cytotoxic agent that kills the cancer cells while causing less damage to noncancerous cells [29]. Kadcyla was approved in 2013 for the treatment of HER2+ metastatic breast cancer after prior treatment with Herceptin and a taxane [30]. In the 9 months following its approval, >80% of oncologists had prescribed the drug [17]. Kadcyla costs $9800 per month, or nearly $100,000 for a full course of treatment [31].

In developing these line extensions that complement Herceptin, Roche has ensured that it will continue to generate sales even to the extent any biosimilars cut into sales of Herceptin. Doctors will continue to prescribe Perjeta and Kadcyla as part of a combination therapy if a biosimilar version of Herceptin becomes available. Roche has also taken steps to potentially replace Herceptin in its combination therapies with Perjeta and/or Kadcyla. Roche is conducting a Phase III clinical study (the MARIANNE study) investigating the combination of Perjeta and Kadcyla versus Herceptin and taxane in patients with metastatic breast cancer [32]. If successful, this study could help Roche gain approvals for Perjeta and Kadcyla as first-line therapies without Herceptin.

Competition from biosimilars differs from traditional generic competition in that marketing will likely be a major battlefront. Traditionally, in response to an imminent threat of generic competition, a branded pharmaceutical company would shift marketing efforts to later-developed line extension products in an effort to shift prescriptions from an older product to a newer, different product that would not have generic competition. At least as soon as a generic product launched if not sooner, the brand company would stop marketing that product altogether, in large part because of automatic substitution laws.

Automatic substitution laws do not apply to biosimilars – or at least not yet. Therefore, any biosimilar trastuzumab competitors will need to take the unique step of actively marketing their products. In response, Roche may become even more aggressive in its promotion and marketing of Herceptin. In doing so, Roche will likely try to leverage its full stable of breast cancer products, including Perjeta and Kadcyla. In marketing their biosimilar products, companies will likely need to promote the benefits of their products, which will have been found highly similar to Herceptin, but presumably with associated cost savings.

Biosimilars are expected to have a substantial impact to reduce health-care costs for biologics. In 2008, the Congressional Budget Office estimated that biosimilars would reduce total expenditures on biologics in the United States by about $25 billion over a decade [33]. The Congressional Budget Office estimates are based on estimated market penetration up to 35% and price reductions reaching 40% compared to the brand price before biosimilar competition. Other studies, including one by the pharmacy benefit management organization Express Scripts, estimate more optimistic savings based on upwards of 50 – 60% market penetration for biosimilars and price reductions of 25% in year 1 climbing to 50% price reduction after 3 years [34]. While the degree of cost savings from biosimilars in the United States will not be known for some time, there appears to be widespread agreement in the industry that biosimilars offer at least the opportunity for cost savings to health-care consumers.

3. Conclusions

The development of monoclonal antibodies has been revolutionary as a treatment in the war against cancer. Herceptin has been quickly adopted as a treatment for specific, aggressive forms of breast cancer and gastric cancer, but with a hefty price tag. As the base patents covering Herceptin expire and regulatory pathways for biosimilars become more established, opportunities flourish for biosimilar competition for Herceptin. Regulatory approval has been granted for biosimilars in a few countries, and it should not be long before biosimilars follow in other countries around the world including the United States. Accompanying the development of competition from biosimilars are hopes for reduction in health-care cost to patients afflicted with the particular invasive cancers against which trastuzumab is specifically targeted.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.