FDA Approves Celltrion and Teva’s Herceptin® Biosimilar

On December 14, the US Food and Drug Administration gave its approval for a new trastuzumab biosimilar (Herzuma™). Manufactured by Celltrion and marketed in the US by Teva, this agent has been designated trastuzumab-pkrb.

The decision marks the second trastuzumab biosimilar approval, and the 16th biosimilar agentthat has made it through the 351(k) regulatory pathway.

Herzuma was approved for a single indication: the treatment of HER2-overexpressing breast cancer. Unlike the other trastuzumab biosimilar, Ogivri®, and Herceptin, Herzuma does not carry the extrapolated indication for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

Originally submitted for approval by Celltrion in July 2017, the FDA issued a complete response letter because of plant manufacturing issues. A year later, after addressing these problems, Celltrion refiled its 351(k) application (June 2018).

Celltrion has launched Herzuma in Europe and elsewhere with marketing partners other than Teva. Neither Celltrion or Teva have announced at this time when the US launch may occur or how it will be priced. Partners Mylan and Biocon, makers of Ogivri, and Pfizer, the manufacturer of a potential competitor, have signed licensing agreements with Roche, makers of the reference product to delay launch.

Pfizer Signs Licensing Agreement With Roche on Trastuzumab Biosimilar

With Pfizer expecting to hear back on its 351(k) resubmission on a trastuzumab biosimilar in early 2019, Genentech and its parent, Roche, may have been getting nervous about their competitor’s intentions. After all, Pfizer was willing to launch at risk with its marketing of Inflectra®, the infliximab biosimilar manufactured by partner Celltrion. In fact, it is the only biosimilar manufacturer that has gambled on an at-risk biosimilar launch.

According to a report in the Pink Sheet, a district court filing on December 4 noted that the two parties signed a settlement that will put an end to their patent litigation, and presumably allow Pfizer to market its biosimilar trastuzumab in the US at a future date. As in previous agreements signed by Roche, the terms are confidential, and launch dates and licensing fees are unknown.

trastuzumab biosimilar

A similar confidential agreement was completed between Mylan and Roche, for Mylan and partner Biocon’s Ogivri®, the first trastuzumab biosimilar approved by the Food and Drug Administration (FDA) in April 2017.

Three other trastuzumab biosimilars are also trying to reach the market. Amgen and Allergan received a complete response letter in June 2018, and have not yet announced when it might resubmit its 351(k) application. Samsung Bioepis is awaiting its initial decision on its trastuzumab biosimilar, filed in January 2018. Teva and Celltrion seem to be on the cusp of an FDA decision, after receiving their initial rejection in July 2017.

Roche has it covered, though. It filed patient litigation against Samsung Bioepis in September 2018 and partners Celltrion and Teva as well.

This is the very situation that the federal government, payers, and patients want to try to avoid, however. Licensing fees paid to the reference manufacturers may work to significantly inflate the drug’s price to the health system. The lack of transparency characterizing these agreements and the associated delays in launch are being decried by those patients and entities who can benefit from access to biosimilar competition. Herceptin was first approved in 1998. No one envisioned Genentech having 20+ years of marketing exclusivity.

In other biosimilarnews… MomentaPharmaceuticals, which signed an Abbvie licensing agreement for its biosimilar adalimumab, said in a statement that it will delay FDA filing M923 beyond 2019, which will help reduce its corporate expenditures. This delay should not impact the expected commercial launch date of November 20, 2023, according to the company.

Celltrion announced that it has filed an application for European Medicines Agency approval for its subcutaneous form of its infliximab biosimilar Remsima (US brand name, Inflectra®). This would provide the first subcutaneous injection formulation of infliximab.

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.

Pfizer’s Anticompetitive Suit: A Slippery Slope to Competitive Bidding?

When Pfizer first announced its lawsuit against Janssen’s parent Johnson & Johnson in September 2017, it pointed to exclusionary contracting, “anticompetitive” behavior of Remicade®’s maker as the reason for its very limited market access.

The lawsuit claimed that Janssen has withheld or threatened to withhold rebates if payers do not keep Remicade in an exclusive preferred position. The degree to which health plans knuckled under to these demands may only be inferred from the 3% marketshare Pfizer’s Inflectra® now holds. For these drugs, which are still typically covered under the medical benefit, “nonpreferred positioning” usually means no coverage. For drugs covered under the pharmacy benefit, this is not the case.

In August, the Eastern Court of Pennsylvania ruled against J&J in its request that the lawsuit be dismissed. While discovery in the case may be ongoing, we could not find mention of a resolution date for the suit.exclusionary contracting

For the sake of argument, let’s say that the Eastern Court of Pennsylvania rules in favor of Janssen. In other words, exclusionary contracting was not an anticompetitive behavior. That means the status quo is intact, but some factors may affect this situation going forward. These include the Center for Medicare and Medicaid Services’ desire to move part B drugs (the medical benefit) to part D (the pharmacy benefit) for Medicare beneficiaries.

The scrutiny on rebate contracting coming from several sectors, and lack of transparency, may also independently influence future use of these pharmaceutical company tactics. I helped conduct a market research project recently on a nonspecialty drug. As part of these interviews, we were asked by the client to inquire about the range of rebates they were receiving from competitor manufacturers. Their responses were requested as a range (e.g., 20% to 30%), not specific contract details, and we had no intention of providing reports of individual payer deals, only anonymous, aggregate information. We expected little to no response to that query, and that is exclusionary contractingexactly what we received.

Let’s discuss the other potential outcome, in which the Court rules in favor of Pfizer. That implies that this exclusionary contracting practice is indeed anticompetitive. If this is the case, we may be on a very slippery slope. What is the difference between payers and pharma companies engaging in a “1 of 1” contract when there are multiple potential products and a “1 of 2” contract? In both cases, drug makers are committing payers to anticompetitive behavior (as perhaps defined by the Court’s new precedent).

The preferred drug tier (whether preferred generics, preferred brands or whatever) is supposed to be for products with proven clinical, patient care, or economic advantages. Truthfully, payers rarely place medications in the preferred tier for reasons other than net costs or rebate contracting, which is based on marketshare.

Now add in the potential effects of the Administration’s desired shift to part D, where pharmacy benefit rules can be applied. That exposes injectable products that were shielded under Medicare part B to commonly applied formulary placement practices.

To be complete, Janssen’s strategy was not solely based on Remicade. It may be found to have bundled Remicade with other agents in deals to exclude Pfizer’s products. The Court may also react specifically to Janssen’s contract stipulation that threatens to withhold rebates connected to future use of the product, to increase its leverage.

However, if the Court determines that 1 of 1 or exclusionary contracting with rebates are the root of the anticompetitive behavior, why should 1 of 2 or even 1 of 3 contracts in a drug category with 5 similar agents be less so? This is the slippery slope that could undo rebate contracting, and push us towards a system that more resembles a competitive bidding process like in Europe. Alternatively, it could accelerate the move towards outcomes- and value-based contracting. The result could be a system-wide revamping of the drug formulary and the pharmacy–drug maker relationship.

In other biosimilar news…Sandoz has signed a licensing agreement with Abbvie, allowing it to market its biosimilar version of Humira in 2023. The agreement, as with Abbvie’s settlements with other biosimilar makers, halts all patent litigation with Sandoz in exchange for a licensing royalty paid to Abbvie.

Fresenius Kabi and Celltrion Get Good News

A German manufacturer is considering its options after the successful completion of two clinical studies involving a pegfilgrastim biosimilar (MSB11455).

Fresenius Kabi, which completed its purchase of the biosimilar business from Merck KGaA in September 2017, announced its investigational biosimilar agent had proved sufficiently similar to the reference product Neulasta® in these phase 1 investigations (conducted in healthy participants). These may serve as pivotal investigations for the manufacturer, which said in its release, “Both studies are designed to enable the application for marketing authorization in the EU and US.” This may be the first indication that Fresenius Kabi seeks to be a player in the US.

Fresenius Kabi does not yet have an approved biosimilar on the European market. It hopes that MSB11455 may propel its fortunes on both sides of the Atlantic.

Food and Drug AdministrationIn its first study, the company reported that its biosimilar “met all primary pharmacokinetic endpoints, [maximum plasma concentration], and area under the curve, as well as the primary pharmacodynamic endpoints of absolute neutrophil count (ANC).” Fresenius Kabi added that there were no meaningful differences in the frequency of adverse events in these healthy volunteers. The second study focused on the biosimilar’s potential for immunogenicity, and this was also determined to be no different between the reference drug and the biosimilar. In addition, neutralizng antibodies were not found.

If Fresenius Kabi proceeds with an application for approval in either market, it will find a good deal of competition for pegfilgrastim biosimilars. In Europe, up to 5 biosimilars may be approved (2 already are). In the US, Mylan’s product is the only one to be approved, but another (Coherus Biosciences) is expecting a decision from the Food and Drug Administration (FDA) in early November. Two others (Sandoz and Apotex) are seeking US drug approval.

In other biosimilar news…The Food and Drug Administration’s Oncology Drug Advisory Committee voted unanimously (16-0) today to recommend Celltrion’s CT-P10 rituximab biosimilar for approval. If the biosimilar is approved by the FDA, it will be marketed by Teva….Mundipharma purchased European biosimilar maker Cinfa, which has a pegfilgrastim that has received a CHMP recommendation for approval in the EU.

Celltrion’s Rituximab Biosimilar Earns Positive Review

The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.

The members of the Oncologic Drugs Advisory Committee will review the data and hear public comments before voting to recommend that the FDA ultimately approve or reject CT-P10 for the treatment of non-Hodgkin lymphoma. Celltrion did not perform clinical trials for rituximab’s autoimmune indications. However, if the FDA approves CT-P10, it may extrapolate the approval to other indications as well.

The orirituximab biosimilarginal 351(k) application by Celltrion in April 2017 resulted in a complete response letter from the FDA. The rejection for this rituximab biosimilar cited multiple deficiencies, including “clinical, product quality, and facility” problems, as well as clinical study issues from the original submission.

According to the FDA reviewers, “In considering the totality of the evidence, the data submitted by [Celltrion] show that CT-P10 is highly similar to US-licensed Rituxan®, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency of the product.”

BR&R will cover the Oncology Drug Advisory Committee meeting and provide updates on its decision. If this rituximab biosimilar is eventually approved by the FDA, Teva would market the product in North America, based on a previous partnership agreement.

In other biosimilar news…Merck has inked an exclusive contract to supply its biosimilar infliximab (Renflexis®) with the US Department of Veterans Affairs. According to a report from Pharmaphorum, it will be the only infliximab biosimilar on the VA’s national formulary.

Is Celltrion Paving a New Road for Biosimilars? A New Route of Administration Being Tested for Infliximab

When payers, patients, or physicians discuss biosimilars, they assume that the biosimilar works just like the reference product. They also assume that the biosimilar is administered in the same way as the originator biologic. Celltrion is actively researching a new subcutaneous infliximab. This could result in a first for the biosimilar industry.

Sponsored by Celltrion and conducted in multiple sites, the research results were announced at the annual meeting of the European Congress of Rheumatology in June. The investigators presented outcomes data on the use of a subcutaneous (SC) form of infliximab-dyyb. Currently, infliximab is only available as an intravenous (IV) infusion at the physician’s office that takes at least 2 hours. Subcutaneous infliximab was given on a biweekly basis.

subcutaneous infliximabThe researchers studied 48 patients with rheumatoid arthritis, finding that outcomes were not clinically different through 30 weeks of follow-up. Three dosages were tested, and in this small study, no ACR20 differences were reported in any subgroup receiving infliximab infusions or SC injections.

Hypersensitivity reactions did occur in one patient each receiving the lowest dose (90 mg) SC and the middle dose (120 mg). None were seen in the group receiving the highest infliximab SC dose (180 mg). Injection site reactions occurred in two patients apiece in the 90 mg and 180 mg dose cohorts. receiving subcutaneous infliximab. The formation of antidrug antibodies was detected in nine patients receiving the standard infusion, but less than half that number in each of the subcutaneous groups.

Currently, infliximab treatment requires a lengthy office visit for each infusion (every 8 wk in the maintenance phase). It is one of the key limiting factors to its use. A self-injectable formulation should result in lower administration costs, and the potential for covering the agent through the pharmacy benefit.

A phase 1, open-label trial of subcutaneous infliximab has already been conducted by Celltrion in patients with Crohn’s disease. That trial found similar outcomes between the SC and IV formulations. Another phase 1 trial is wrapping up, this one evaluating safety and pharmacokinetics in healthy volunteers. Celltrion is also sponsoring a phase 3 trial of more than 300 patients with rheumatoid arthritis. Preliminary results will not be available until December 2018.

It is not yet clear, however, what type of data the Food and Drug Administration would require for approval of a new formulation of a biosimilar. The regulatory agency may decide to treat this as it would a new route of administration for any approved product, which would focus on pharmacokinetic and pharmacology factors. Celltrion seems to be covering all of its bases.

FDA Approval Eludes Amgen for Biosimilar Trastuzumab

Amgen will have to wait a bit longer to market its biosimilar version of trastuzumab . On Friday, June 1, the Food and Drug Administration (FDA) rejected Amgen’s 351(k) application for its Herceptin® biosimilar. biosimilar trastuzumab approvalIn a brief press release, Amgen announced receiving the complete response letter for ABP 980. In the announcement, it also said that the delay in its biosimilar trastuzumab approval should not “impact our US launch plan.” This may signal that even if it received approval, it would not market the biosimilar trastuzumab immediately.

The timing of the FDA announcement on the biosimilar trastuzumab approval contrasted with the near-simultaneous marketing authorization of this same trastuzumab biosimilar by the European Medicines Agency. The biologic will be marketed in Europe under the trade name Kanjinti™.

Mylan/Biocon’s Ogivri™ remains the only biosimilar trastuzumab approved by the FDA. It is not yet marketed, however. Separate trastuzumab biosimilars by Teva/Celltrion and Pfizer have been stalled by the FDA. Samsung Bioepis’s entry is due for an FDA approval decision in the fourth quarter of 2018.

In related biosimilar news… in September 2017, Mylan filed a 505(b)2 application for its insulin glargine agent. The manufacturing duo of Mylan and Biocon received a rejection from the FDA on June 1. The complete response letter specified issues raised by a change in manufacturing site (from one in India to a new facility in Malaysia). As reported by the Economic Times, the complete response letter was expected by Mylan and Biocon. They told the Economic Times, “Together, Mylan and Biocon are already executing on all required activities we had agreed upon with the FDA, and they are progressing according to plan,” the statement said.

Although insulins are not currently approved through the 351(k) biosimilar pathway, they are among the “transitional agents,” which by 2020 will be considered biosimilars by the FDA.

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.