Celltrion Bounces Back, Resubmits for FDA Approval of Rituximab Biosimilar

Anticipating that its issues with the Incheon, South Korea, manufacturing plant will be resolved, Celltrion has resubmitted its biologic license application for a rituximab biosimilCelltrion rituximab biosimilarar (CT-P10).

In the April 2018 complete response letters sent by the Food and Drug Administration (FDA) on CT-P10 and the trastuzumab biosimilar CT-P6, FDA cited aseptic practices at the manufacturing plant that it announced in January. The resubmission should mean that a decision will come within six months of the application date, keeping it in the race for the first rituximab biosimilar.

Celltrion, in its announcement, also affirmed that it intends to resubmit its application for its trastuzumab biosimilar in June. In its press release, Celltrion stated, “Celltrion has made progress addressing the concerns raised by the FDA in the warning letter and is committed to working with the Agency to fully resolve all outstanding issues with the highest priority and urgency.”

This marks the quickest turnaround seen yet for reapplication following an FDA rejection of a biosimilar. Truxima® is the brand name of Celltrion’s rituxumab biosimilar that is approved in Europe.

In other biosimilar news…The European Commission announced a proposal that would enable biosimilar manufacturers to produce and export their products before EU full intellectual property rights terminate. This would obviate Special Protection Certificates, which were created in 1992. Under these certificates, intellectual property rights continue for 5 years after EU patent expiration. The announced change would be implemented by end of this year. It will mark the end of special compensation to pharmaceutical industry for the extended period required for research, development, and regulatory approval.

Sandoz biosimilars

Sandoz’s biosimilar version of infliximab has been approved by the European Medicines Agency. Dubbed Zessly™ this agent was the fourth infliximab biosimilar approved in Europe.

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.

Teva and Celltrion Receive Rejections on Trastuzumab and Rituximab Biosimilars

Celltrion and its partner Teva were dealt a significant blow today, as the Korean manufacturer announced that the latest two biosimilar candidates were rejected by the Food and Drug Administration (FDA).

Celltrion logo1As first reported by Dan Stanton in the Biopharma Reporter, the FDA issued complete response letters as a result of inspection problems uncovered at Celltrion’s manufacturing facility in Incheon, Korea. Celltrion initially receive the negative inspection report in January of this year, which highlighted deficiencies in aseptic practices and processing, and failure to investigate variations in batches.Teva

Under the partners’ pact, signed in 2016, Teva would commercialize the two biosimilars. Teva has a separate concern, however, in that the same Celltrion plant cited by the FDA has been tabbed to produce its CGRP-inhibitor fremanezumab for migraine prevention. This migraine prevention antibody, which also has the potential to reach sales of $1 billion, has a PDUFA date of mid-June.

In a statement published by Mr. Stanton, a Celltrion spokesperson said, “Celltrion is making progress addressing the concerns raised by the FDA in a Warning Letter issued in January and is committed to working with the agency to fully resolve all outstanding issues with the highest priority and urgency.”

The issuance of the CRLs may be extremely poor timing for the partners. Although Mylan signed an agreement with Roche to delay the launch of its approved biosimilar version of Herceptin® until at least 2019, the other competitors have not. Amgen/Allergan expect word on their 351(k) submission within the month, and Samsung Bioepis should hear in the fourth quarter. On the rituximab front, Sandoz should receive word early in the third quarter.

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.

Biosimilar Rituximab Under FDA Review

Celltrion announced June 30, 2017 that it has submitted its 351(k) application to the Food and Drug Administration for approval of its biosimilar version of rituximab. This represents the first biosimilar application for rituximab, a monoclonal antibody to CD20.

The product, known during investigations as CT-P10, was approved in the European Union in February, and has been launched there as Truxima in late April. Clinical data have been presented on this biosimilar’s efficacy and safety in treating rheumatoid arthritis and advanced follicular lymphoma, a form of non-Hodgkin lymphoma

If approved, Celltrion will market this product with Teva in North America, which signed a partnership agreement with Celltrion in October 2016 for this biosimilar agent to treat cancer and for CT-P6 (trastuzumab). The FDA application for trastuzumab is expected to be filed this summer. It is currently partnered with Pfizer to market its product Inflectra® (infliximab-dyyb) in the US and Canada.

Also in June, Sandoz received approval from the European Medicines Agency to market its own version of rituximab, called Rixathon™.

In other biosimilar news…Coherus Biosciences, which took hits from the FDA and its investors in the rejection of its pegfilgrastim biosimilar in June, laid off 51 workers (about 30% of its workforce) in an effort to cut costs. Coherus is working towards addressing the issues outlined in FDA’s Complete Response Letter on pegfilgrastim. In its letter, FDA did not require additional clinical studies. In the meantime, Coherus still is seeking to file its biosimilar etanercept for approval in Europe later this year, and its version of adalimumab in the US in early 2018. However, John Carroll reported that Coherus’ clinical development partner on etanercept in Japan, Daiichi Sankyo, has decided to pull out because of concerns that Coherus will not be able to manufacture the product.

Will Oncology Biosimilars Ease US Access Problems?

Among the broad arguments for the rapid introduction of biosimilars is that they will increase patient access to expensive biologic therapies. This may be true theoretically from a patient cost-sharing perspective. If the biosimilar is priced sufficiently less than the originator product, health plans and insurers may elect to prefer the biosimilar and place it on a more affordable coinsurance or copayment tier.

This is not generally the case for the 2 nononcology biosimilar products launched to date. With shallow discounts for the biosimilars, the originator’s manufacturer can simply match the net cost through deeper rebates; the payer would have little reason to change the formulary tiering of the biologic.

The title is sort of a trick question. It assumes that there is a problem accessing oncology agents in our nation today. A 2015 study of 150 oncologists indicates that this is not the case. None of the respondents reported that obtaining Image result for Truxima imageRituxan for their oncology patients (chronic lymphocytic leukemia or non-Hodgkin’s lymphoma) was a problem. The researchers also surveyed doctors in Brazil, Mexico, Russia, and Turkey. In Russia, 12% indicated that access to Rituxan was indeed difficult, as did 17% in Turkey. The researchers also stated that Russia and Mexico, compared with the other countries included in the study, had the greatest share of patients who did not have any insurance. Of course, it must be noted that the cost of Rituxan is far less in the other countries studied, compared with the US.

Another way in which the introduction of a Rituxan biosimilar could improve access is to alleviate present or future drug shortages. Drug shortages are commonly the result of a couple of factors: manufacturing plant slowdowns or shutdowns (often related to quality issues or the need for maintenance); lack of available drug components, such as its active ingredients or excipients; lack of profit driving generic manufacturers out of the business.

According to the Food and Drug Administration, which is responsible for tracking drug supply shortages, Rituxan has not been subject to any supply notifications, nor have any of the biologicsSupply Chain. However, oncology has not been immune from drug shortages (e.g., daunorubicin liposomal injection, leucovorin injection). In a recent post, I emphasized that the need for anything less than a water-tight drug supply record can torpedo and sink biosimilar marketing efforts. In this instance, one can also make the case that oncology biosimilars like rituximab, trastuzumab, and bevacizumab could serve as a stalwart against potential biologic supply issues.

The outlook for the patient’s ability to pay for expensive medications is cloudier by the day. Access to these drugs is not an issue in the US today, but what about a year from now? How will efforts to change the pre-existing exclusion rules alter the landscape for covering any of the biologic products? Then, biosimilars may be in a real position to maintain or improve access.

The first oncology biosimilars are very close: Decisions from the Food and Drug Administration on biosimilars for trastuzumab and bevacizumab are expected in the third quarter of this year. Celltrion expects to file its 351(k) application for rituximab in June.

Second European Medical Society Endorses Biosimilar Use

A large European medical association has followed on the heels of the European Crohn’s and Colitis Organization, in outlining its support for the use of biosimilars. This time, the European Society of Medical Oncology (ESMO) has endorsed biosimilars for the direct treatment of cancer, seemingly in time for upcoming European approvals. esmo-logoposition paper, ESMO acknowledges that a large number of patents will expire for several monoclonal antibodies by 2020, and that in Europe, price reductions could be as high as 40%.

In a press release from ESMO, President Fortunato Ciardiello stated, “Biosimilars are must-have weaponry in financially sustaining healthcare systems on a global scale as well as significantly improving outcomes for an increasing number of patients throughout Europe and the rest of the world.” He added, “Biosimilars give us the chance to make treatment options for cancer more affordable everywhere.”fortunato-ciardiello-md-phd

Although the European Medicines Agency (EMA) does not have a mechanism for approving the interchangeability of biosimilars with the originator drugs, this decision on drug switching is left to the EU member states. In its position paper, ESMO advises member states to “consider the precautionary principle as well as the potential risks associated with substituting a reference biological medicinal product with a biosimilar when tendering for hospitals. Nine out of 28 Member States completely prohibit automatic substitution of biosimilars for reference products by pharmacists. Six out of 28 Member States restrict substitution to ensure the safety of patients and in particular, avoid unforeseen immune responses. There is no clear consensus among Member States concerning this issue, implying that countries may decide whether to implement policies related to automatic substitution or not.”

However, ESMO advises that automatic substitution should be avoided, and switching allowed only if “(1) the physician is well-informed about the products; (2) the patient is fully briefed by the physician and (3) a nurse is closely monitoring the changes and tracking any adverse events.”

The EMA is currently considering the approval of biosimilar rituximab for its oncology indications in addition to rheumatoid arthritis, and trastuzumab for the treatment of breast cancer.

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.