The anti-CD20 monoclonal antibody, rituximab, revolutionized the management of non-Hodgkin lymphoma (NHL) and remains the cornerstone of modern NHL management. The high cost of rituximab currently puts it beyond the reach of many eligible patients – but, as its patent expiry approaches, new manufacturers are able to begin developing less costly versions, known as biosimilars. For regulatory approval, a biosimilar must demonstrate similar safety and efficacy to the originator biologic in a head-to-head clinical trial.
Non-Hodgkin lymphoma (NHL) is the 10th most commonly diagnosed cancer worldwide.1,2 In developed nations it ranks as high as 7th, with the greatest incidence in the United States and Europe.1,2 Of the indolent (slow growing) subtypes of NHL, follicular lymphoma (FL) is the most common – comprising around 20% of all cases of NHL3 – while diffuse large B cell lymphoma (DLBCL) is the most common aggressive form.4,5 Over the past few decades there has been a dramatic rise in the incidence of NHL globally, surpassed only by malignant melanoma and lung cancer in women.2 Research is still ongoing to determine the cause of NHL, as well as the reasons for this increase in incidence, although the aging population is a likely factor.3
The introduction of the anti-CD20 monoclonal antibody rituximab significantly changed the management of NHL. Rituximab was licensed in the US in 1997 as Rituxan® and in the EU in 1998 as MabThera®. Its wide range of indications across both oncology and rheumatology make it unique among biologic drugs. The initial FDA approval of rituximab was based on a pivotal study in which it was given as monotherapy to treat relapsed or refractory low-grade FL.6 Subsequent studies demonstrated improved responses when rituximab was administered in combination with CHOP chemotherapy as first-line treatment, and as maintenance therapy following the induction of remission.7
Two decades after the first Phase I clinical trials in the mid-1990s, rituximab remains the cornerstone of NHL therapy.8 The prognosis of FL has significantly improved with the incorporation of rituximab into treatment regimens, in both first-line and relapsed settings, with overall survival increasing markedly.3,8,9 Some experts now think the old paradigm that viewed FL as an incurable condition is becoming outdated.8
Unfortunately, many of the world’s patients with NHL are not able to reap the benefits of rituximab therapy. The reason, of course, is cost. A 2014 study examined access to rituximab within the US, Mexico, Turkey, Russia, and Brazil.10 Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with NHL and also in those with chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab, despite guidelines recommending its use in patients with NHL and CLL. Issues with insurance coverage, reimbursement, and costs to patients were commonly cited as barriers to the use of rituximab.10
“At present, access to existing biopharmaceuticals may be viewed as a greater unmet need than that for more effective treatments.” 7
“Rituximab is like gold dust.” 11
The cost of modern cancer biologics reflects the scientific innovation and the investment required to support biotechnological research and development. But it puts these treatments beyond the reach of many people. Pursuit of innovative new drugs is clearly of great importance, but so is broadening patient access to the treatments we have now. There’s no quick-fix solution – but, as many modern cancer biologics start to approach patent expiry, the opportunity arises for new manufacturers to develop less costly versions of them, known as biosimilars.* No rituximab biosimilars have yet been approved in any highly regulated markets, but a number of candidate products are currently undergoing pre-clinical and clinical testing, with the aim of bringing the benefits of this important biologic drug to many more patients worldwide.
*Also known as follow-on biologics, subsequent-entry biologics, and biocomparables, among others.
Unlike the generics of the chemical drug world, biosimilars are not exact copies of originator biologics, because it is not possible for a new manufacturer to precisely replicate the highly complex and sophisticated production processes. However, regulatory requirements are designed to compare candidate biosimilars with their originators, both analytically and clinically, to establish that quality, efficacy, and safety are all a very close match. By January 2016, 22 biosimilars in a range of therapy areas had been launched in Europe with no adverse clinical consequences compared with their originators,12,13 and have resulted in significant cost savings.14 The US Food and Drug Administration (FDA) approved its first biosimilar (filgrastim) via its new dedicated approval pathway in early 2015.
The extent of the testing required means that biosimilars can’t be as heavily discounted as chemical generics. The average savings are around 20–30%,15 but greater discounts have been secured in some cases. Given the high unit cost of biologic drugs, these savings are meaningful. Biosimilars have already helped increase patient access to essential biologics; in the UK, for example, more physicians are now able to provide cancer patients with granulocyte colony stimulating factor (G-CSF) medication to ward off neutropenia at an early stage.13 In addition, there are instances where the introduction of biosimilar competition has prompted the manufacturers of originator biologics to reduce their prices and to consider investing in innovative new products as they seek new competitive advantages.
QuintilesIMS is actively supporting the development of rituximab biosimilars for NHL and we invite you to join us as a clinical investigator. The patients you enroll in these studies will all receive active therapy, either with Rituxan®/MabThera® or with a rituximab biosimilar candidate at no cost to them or to their insurers.
Our current NHL biosimilar study opportunities are in treatment-naïve patients with indolent, low-tumor-burden follicular lymphoma (FL) who will be randomized to receive induction monotherapy with either branded rituximab or a biosimilar candidate given by intravenous infusion once weekly for 4 weeks. Note: this is not a licensed indication for Rituxan®/MabThera®, which is approved in FL as monotherapy only when patients have relapsed on previous therapy or alternatively as a first-line option in combination with chemotherapy.
In treatment-naïve patients with low-tumor-burden FL, rituximab induction therapy has been shown to achieve longer delays before the next intervention becomes necessary, greater progression-free survival, and improved quality of life compared with watchful waiting, but an overall survival benefit has so far not been demonstrated.3,8 This has meant that some physicians prefer a watch-and-wait strategy for such patients. Even if this is your preferred approach, there are still a number of reasons why you may be interested in participating in a study like this as a clinical investigator:
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11. Daily Mail (UK), 3 February 2014. http://www.dailymail.co.uk/health/article-2550030/Some-mornings-Im-pain-Nicky-dress-Girlfriend-celebrity-hairdresser-Clarke-reveals-struggle-terrifying-immune-disease-lupus.html. Accessed 4 December 2015.
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