Rituximab Biosimilars Shown to Be Safe and Effective

Roxanne Nelson, BSN, RN

July 28, 2017

Clinical trial data showing that two biosimilar rituximab products are comparable to the reference product, Rituxan (Genentech) (in Europe, MabThera), were published online July 13 in the Lancet Haematology.

"The results of these two trials will certainly promote the introduction of rituximab biosimilar into daily, clinical practice in the immediate future," write editorialists in an accompanying commentary.

"Rituximab biosimilars have potential cost-saving benefits for health care, and can also improve the accessibility of rituximab-containing treatment worldwide," write the editorialists, Shinichi Makitaa, MD, and Kensei Tobinaia, MD, both from the Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

Both of the biosimilar rituximab products in the two published trials have recently been recommended for approval in Europe, as have several others.

One is CT-P10 (Truxima), from Celltrion Healthcare, which is the first biosimilar rituximab to be approved in Europe. It was recommended for approval in December 2016. This product is awaiting approval in the United States.

The other is GP2013 (Rixathon, Riximyo), from Sandoz, which was recommended for approval in Europe in April 2017.

Three other biosimilar rituximab products (Blitzima, Tuxella, and Ritemvia), all marketed by Celltrion Healthcare Hungary Kft, were recommended for approval in Europe in May 2017.

Important Drug, and a Best-seller

"Rituximab is expected to remain an important drug in the treatment of B-cell malignancies for the time being," the editorialists comment.

The product is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. It is widely used in the treatment of B-cell non-Hodgkin lymphoma, including follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic lymphoma, as well as in immune-related diseases, such as rheumatoid arthritis. It has become a global top-selling oncology drug; in fact, it was the best-selling oncology drug in the world in 2013, with nearly $8 billion in sales.

Approved in November 1997 by the US Food and Drug Administration and by the European Medicines Agency in June 1998, rituximab came off patent in Europe in 2013 and in 2016 in the United States.

The patent expiry has paved the way for the development of biosimilars. Several such products have already appeared in Europe.

European oncologists have been enthusiastic about the coming of biosimilars. The main attraction is their potential to lower costs.

In a position paper released earlier this year, the European Society for Medical Oncology (ESMO) said that in Europe price discounts of 20% to 40% for biosimilars could be reached in Europe, with potential savings for healthcare systems of €50 billion to €100 billion ($53 billion to $107 billion) by 2020.

"Biosimilars are an excellent opportunity to have good, valid drug options that improve the sustainability and affordability of cancer treatment in various countries," Prof Josep Tabernero, MD, PhD, chair of the ESMO Cancer Medicines Working Group, from the Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Spain, commented in a statement at the time.

It is as yet unclear what impact the advent of rituximab biosimilars will have on price, but the hope is that it will bring down the overall cost of treatment. That this is needed is clear from a finding highlighted recently in an editorial published in the July issue of the Lancet Haematology. "An investigation into prices and availability of on-patent cancer medication in different European countries by van Harten and colleagues (Lancet Oncol. 2016;17:18-20) revealed a difference in list prices of important cancer treatments of up to 92%," write the editors. "In the case of rituximab, the monoclonal antibody used for treatment of non-Hodgkin lymphoma, the official price of a single dose varied from €217.47 in Norway to €691.62 in Germany, with some countries unable to access the drug at all."

Comparable Overall Response and Pharmacokinetics

The study of CT-P10 (Celltrion) was a phase 3 trial designed to assess the noninferior efficacy and pharmacokinetic equivalence of the biosimilar compared with reference product rituximab (Rituxan, MabThera) when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma.

The cohort included 140 patients with stage III-IV disease. The patients were randomly assigned to receive CVP plus intravenous infusions of 375 mg/m2 CT-P10 or rituximab on day 1 of eight 21-day cycles. The primary endpoint for efficacy was the proportion of patients who had an overall response over eight cycles.

Of patients who received CT-P10, 97% (64/66) achieved an overall response. Of patients who received rituxmab, 93% (63/68) achieved an overall response. This extrapolated to a 4.3% difference between groups (one-sided 97.5% confidence interval [CI], 4.25%). This difference "lay on the positive side of the predefined non-inferiority margin using a protocol-specified point estimate difference of -7%," say the researchers.

Pharmacokinetics of CT-P10 and rituximab were also found to be equivalent, and treatment-emergent adverse events were similar between groups. In the CT-P10 arm, 83% (58/70) of patients experienced events vs 80% (56/70) of patients the rituximab arm.

The results of this study support previous preclinical and clinical data showing the biosimilarity of CT-P10 to rituximab, note the authors, led by Won Seog Kim, MD, of Sungkyunkwan University School of Medicine, Seoul, South Korea.

Efficacy, noninferiority, and pharmacokinetic equivalence were shown for patients with advanced-stage follicular lymphoma, "supporting extrapolation of biosimilarity across indications," write Dr Kim and coauthors.

The availability of CT-P10 might increase access to this important therapeutic option. Dr Won Seog Kim and colleagues

"CT-P10 represents the first rituximab biosimilar approved by the European Medicines Agency," they add. "Because biosimilars are generally more affordable than innovator products, the availability of CT-P10 might increase access to this important therapeutic option."

Expect Similar Efficacy

The study of GP2013 (Sandoz) compared the biosimilar with the reference rituximab product in combination with CVP in patients with follicular lymphoma.

This phase 3 trial included 858 patients who were randomly assigned to receive either GP2013 (n = 312) or rituximab (n = 315) for eight cycles (combination phase). This was followed by monotherapy maintenance therapy for a 2-year period in patients who experienced a response.

The primary endpoint of overall response was similar for both groups ― 271 patients (87%) in the GP2013 arm and 274 (88%) in the rituximab arm (difference, -0.40%; 95% CI, -5.94 to 5.14).

Adverse events and serious adverse events occurred at similar frequency in the two groups. A total of 289 (93%) of patients in the GP2013 group had an adverse event; 71 (23%) had a serious adverse event. In the rituximab group, 288 (91%) patients had an adverse event, and 63 (20%) had a serious adverse event. The most common event experienced in both groups was neutropenia.

The authors, led by of Wojciech Jurczak, PhD, from Jagiellonian University, Krakow, Poland, say their findings "confirm the similarity of the proposed biosimilar of rituximab with reference rituximab.

Physicians and patients should expect the same efficacy, safety, and tolerability with this biosimilar of rituximab. Dr Wojciech Jurczak and colleagues

"The implications of these data, along with all other existing evidence, are that physicians and patients should expect the same efficacy, safety, and tolerability with this biosimilar of rituximab as with the reference medicine, and its availability should increase competition and help to reduce costs, thereby increasing access to appropriate care," they write.

Limitations Noted

The editorialists point out that both studies have similar limitations. "The primary endpoint of overall response is not a robust endpoint to evaluate the efficacy of therapeutic modalities for previously untreated follicular lymphoma," they note, although the regulatory agencies in Europe and the United States will accept it in the evaluation of a biosimilar product.

They also point out that CVP is not a commonly used treatment for patients with follicular lymphoma, and that CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and bendamustine are the standard treatments.

There are no data on tumor burden, and maintenance data are yet immature, they note.

The Kim study was funded by Celltrion Inc; several coauthors have disclosed relationships with industry, including employment at Celltrion. The Jurczak study was funded by Hexal; several coauthors have disclosed relationships with industry, including employment at Sandoz.

Lancet Haematol. Published online July 13, 2017. Kim et al, Abstract; Jurczak et al, Abstract; Commentary

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