Rituximab Biosimilar Approved by FDA for Cancer Treatment

On November 28, 2018, the Food and Drug Administration (FDA) announced the approval of rituximab-abbs (Truxima™), produced by Celltrion and marketed by Teva.

Approval for this rituximab biosimilar was overwhelmingly recommended by the FDA’s Oncology Drug Advisory Committee by a vote of 16-0 in October. It is the first biosimilar agent approved for the treatment of relapsed or refractory, low grade, or follicular non-Hodgkin’s lymphoma—specifically in adult patients with the CD20+ B-cell variety. The drug makers did not seek approval for the Rituxan’s autoimmune indications, and the FDA did not grant extrapolated approval for them.

rituximab biosimilarAccording to the FDA’s announcement, the most common side effects of Truxima are infusion reactions, fever, abnormally low level of lymphocytes in the blood (lymphopenia), chills, infection and weakness (asthenia). Health care providers are advised to monitor patients for tumor lysis syndrome (a complication of treatment where tumor cells are killed off at the same time and released into the bloodstream), cardiac adverse reactions, damage to kidneys (renal toxicity), and bowel obstruction and perforation.

This leaves a wide open marketing window for Celltrion and Teva, as Sandoz announced in late October that it was halting its effort to bring its own rituximab biosimilar to the market. There is no word as of this writing regarding the launch and pricing of Truxima in the US. This also represents the second FDA approval for Celltrion; its infliximab biosimilar, Inflectra, was approved in 2016.

In Other Biosimilar News… As BR&R reported in our October discussion with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim had decided to forego marketing its adalimumab biosimilar Cyltezo® in the EU. This is likely owing to the highly competitive environment and the huge pricing discounts being signed by European countries. However, Boehringer has now announced its intention to discontinue all efforts to market and develop any biosimilars outside of the US market. This may come as little surprise, as the Boehringer biosimilar pipeline was not aggressively stocked. Instead, it has been focused on seeking interchangeability status for Cyltezo and to launch this product as soon as possible.

FDA Hands Sandoz a Rejection on Its Rituximab Biosimilar

Sandoz announced today that the Food and Drug Administration (FDA) has decided not to approve its biosimilar version of the oncology biosimilar rituximab. The content of the complete response letter was not revealed by Sandoz.

This marks the second rituximab biosimilar rejected by the FDA. Celltrion and Teva’s Truxima™ was also rejected in early April. Both Sandoz’s biosimilar (Rixathon™) and Truxima™ are marketed in Europe and in other parts of the globe. In Europe, Rixathon was approved in June 2017, and Truxima received marketing authorization in February of that year.

Although the European approval for Rixathon was for all of Rituxan/MabThera’s oncology and autoimmune indications, Sandoz was seeking oncology indications only in the US with its rituximab biosimilar.

Sandoz registered early success with filgrastim (Zarxio®) and etanercept (Erelzi®), but was handed a set back from FDA on its biosimilar pegfilgrastim. We’ll report any updates we receive on Sandoz’s progress in resolving the issues in question with rituximab.

Next up is the Allergan/Amgen biosimilar of trastuzumab, which has an FDA PDUFA date of May 28.

Rituximab and Filgrastim Biosimilars Being Reviewed by FDA

Today, Sandoz announced the acceptance by the Food and Drug Administration of its application for a biosimilar rituximab. This biosimilar was approved by the European Medicines Agency in June 2017.

The manufacturer included a phase 3 trial of the agent to treat follicular lymphoma, one of two Hodgkin’s lymphomas for which the originator product is approved to treat. Its pharmacokinetic and pharmacodynamics studies were conducted in patients with rheumatoid arthritis, another major indication.

fdaThis marks the second rituximab biosimilar to be submitted to the FDA; Celltrion’s application for its Truxima™ brand was submitted in June. Sandoz’s Zarxio® has been marketed since 2015, and Erelzi® (etanercept-szzs) was approved in August 2016 but is not yet marketed.

In addition, Adello Biologic announced that their 351(k) application for a new biosimilar filgrastim was sent to FDA on September 11. No FDA decision date was announced, but assuming a smooth ride through the process, a decision may be expected around the third quarter of 2018.

This is Adello’s first biosimilar brought to FDA application. According to its website, Adello is currently in clinical trials with a pegfilgrastim biosimilar, with preclinical development on a version of adalimumab.

An Eventful Week for Biosimilars

It has been an eventful week in the biosimilar world during a rather uneventful beginning to 2017. The next likely FDA decision on a biosimilar will not occur until reviews of Samsung Bioepis and Merck’s version of infliximab or Coherus Bioscience’s version of pegfilgrastim are completed sometime in the second quarter.

However, the biosimilar world is girding for the opening arguments April 26 in the Supreme Court’s hearings on the validity of the 180-day notification (exclusivity) period. To this end, the Biosimilar Council issued a lengthy amicus brief arguing cogently that Congress did not intend to provide 12.5 years of marketing exclusivity to biologic manufacturers. Several others have petitioned the court with similar arguments, including AARP and America’s Health Insurance Plan. In fact, I would be interested in reading an amicus brief in defense of the notification period.

The Biosimilar Council’s parent organization recognized an opportunity was opening wide, and decided to rename itself. The Generic Pharmaceutical Association is now officially the Association for Accessible Medicines.

The European Medicines Agency handed Celltrion the approval for the first biosimilar of an anticancer monoclonal antibody. Truxima™ is a biosimilar version of rituximab, which will compete against MabThera® (which is also marketed as Rituxan® in the US). Celltrion has partnered with Teva to market the biosimilar in the US, if and when the FDA approves the agent. Celltrion is yet to file for FDA approval. Two other monoclonal antibodies have been filed with the FDA for the direct treatment of cancer—trastuzumab (Mylan/Biocon) and bevacizumab (Amgen/Allergan), both of which are expected to yield FDA decisions in the latter half of 2017.

Finally, a study was published this week that highlighted the overall cost problem for the health care system—the price of cancer medications are persuading significant proportions of cancer survivors to skip their drugs or specifically request lower-cost alternatives. It is well known that cancer diagnoses are one of the most common reasons for medical bankruptcy. An earlier literature review of the financial implications of cancer reported that more than half of cancer survivors were in debt as a result of their cancer treatment, and roughly half of cancer survivors experienced some form of financial distress. These investigators stated that depending on the study, between 4% and 45% of these patients “did not adhere to recommended prescription medication because of cost.”

Celltrion’s Rituximab Recommended for Approval in Europe

Just weeks after Celltrion presented data at the American College of Rheumatology meeting demonstrating that its product CT-P10 is as safe and effective as Rituxan® for the treatment of rheumatoid arthritis (RA), the European Medicines Agency (EMA) received the recommendation to approve the product for use in the EU.

The Committee for Medicinal Products for Human Use sent its recommendation to EMA on December 15. Assuming the regulator grants marketing authorization, CT-P10 will be sold as Truxima and will be indicated for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, RA, granulomatosis with polyangiitis GPA, and microscopic polyangiitis.

The originator product in the EU is MabThera®, which was licensed in 1998. If approved, it will be the first CD20-inhibiting monoclonal antibody to reach the market in a biosimilar version.

In other news from Europe: EMA Launches Consulting Pilot for Biosimilar Manufacturers. In what may be a page taken the US Food and Drug Administration’s (FDA’s) playbook, the EMA is offering scientific advice, starting February 2017, for companies seeking to bring a biosimilar to market. As part of the FDA’s biosimilar development program, it meets with manufacturers at various stages to consult on their analytical and clinical testing projects. The EMA’s pilot initiative does seem to be more limited, however, in that it offers a presubmission consultation. The pilot is said to run for up to 6 requests for scientic advice.