Last week, Eli Lilly and Company (“Lilly”) announced that galcanezumab met its primary endpoint in a Phase 3 study of patients with episodic cluster headaches. Lilly previously announced that galcanezumab met its primary endpoints in three different Phase 3 studies evaluating its effectiveness in preventing episodic and chronic migraine.

The episodic cluster headache study was a two-month Phase 3, randomized, double-blind, placebo-controlled, global trial evaluating the safety and efficacy of galcanezumab (300 mg once-monthly) administered subcutaneously compared with placebo in 106 patients.  According to Lilly, patients treated with galcanezumab experienced statistically significant differences in the reduction of weekly cluster headache attacks compared to patients treated with placebo across weeks one to three of the study.  The safety and tolerability profile was consistent with previous studies evaluating galcanezumab for the prevention of migraine.

Galcanezumab is a monoclonal antibody that is designed to bind to and inhibit the activity of calcitonin gene-related peptide (“CGRP”).  Increased levels of CGRP have been reported in patients during migraine and cluster headache episodes.  Based on the results of the migraine Phase 3 trials, Lilly submitted galcanezumab to the FDA for review, and a decision is expected in the third quarter of this year.  Based on the results of the cluster headache trial, Lilly will no doubt seek to add the treatment of episodic cluster headaches as an indication for galcanezumab.

CGRP antagonists such as galcanezumab have been a focus for a number of companies seeking to develop migraine treatments.  In addition to Lilly’s galcanezumab, two other anti-CGRP antibodies are in late-stage development.  In fact, Teva has already submitted an application for its fremanezumab to the FDA (although manufacturing concerns have delayed FDA approval until at least September), and Alder Biopharmaceuticals is expected to submit an application for its eptinezumab later this year.  In addition, as we previously reported, Amgen and Novartis recently announced that the FDA approved its Aimovig™ (erenumab) product for the preventive treatment of migraine, although erenumab targets the CGRP-receptor instead of CGRP itself.

Last week, Novartis and Amgen announced the FDA approved Aimovig™ (erenumab) for the preventive treatment of migraine in adults.  The FDA granted approval to Amgen; however, Amgen and Novartis have entered into a global collaboration to develop and commercialize treatments in the field of migraine. As part of this agreement, the two companies will co-commercialize Aimovig™ in the U.S.  Amgen retains exclusive commercialization rights in Japan, and Novartis has exclusive commercialization rights in Europe, Canada, and the rest of the world.

Aimovig™ is a monoclonal antibody that targets the calcitonin gene-related peptide receptor.  According to the FDA,“Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks.”  Aimovig™ is self-administered via a subcutaneous injection at a dose of 70 mg once monthly, although some patients may be prescribed a dosage of 140 mg once monthly.

Novartis and Amgen expect that Aimovig™ will be available as soon as this week.  The two companies have also announced that Aimovig™ is expected to cost $575 per month, or $6,900 annually.

According to some experts, the global market for migraine drug sales is around $4 billion per year and is expected to grow to $8.7 billion by 2026.  Thus, it is not surprising that although Amgen is the first to obtain approval for a product that interferes with CGRP signaling, it is not the only company pursing this avenue.  Indeed, Eli Lilly and Company, Teva, and Alder Biopharmaceuticals all have similar products that are either currently under review by the FDA or are expected to be shortly.

As we recently covered, May 15, 2018, saw the FDA granting approval to Hospira (now a Pfizer subsidiary) for its Retacrit injection, a biosimilar to Amgen’s Epogen®. The approval, based on a Biologics License Application dated December 16, 2014, came after Hospira resubmitted its application twice after receiving Complete Response Letters from the FDA, most recently in November 2017.

In addition to the regulatory barriers Hospira has overcome in reaching approval, Hospira has faced legal challenges from Amgen in the form of one of the earliest litigations filed under the Biologics Price Competition and Innovation Act (“BPCIA”). We previously covered that litigation here and here.

Since our last update in early August 2017, there have been several developments in the litigation, including the Federal Circuit dismissing Amgen’s appeal regarding its denied discovery of Hospira manufacturing information on jurisdictional grounds and failure to satisfy the prerequisites for mandamus. However, the most significant development was the five day trial which took place in September 2017.

At the conclusion of trial, the jury found that Hospira had not infringed any claim of U.S. Patent 5,756,349 (“the ’349 patent”), while it did infringe two asserted claims of U.S. Patent No. 5,856,298 (“the ’298 patent”). The jury found those two claims to not be invalid for anticipation or obviousness, and further held that only a portion of the lots manufactured by Hospira fell into the BPCIA’s Safe Harbor Defense. Ultimately, the jury found that Amgen had proven $70 million in damages as a result of Hospira’s pre-approval manufacturing activities.

On September 25, 2017, the Court entered its judgment, awarding $70 million and holding the ’298 patent valid and infringed, and the ’349 patent not infringed. Soon after, the first of several post-trial motions were filed. On October 12, as both parties agreed that several counts by both parties had not yet been ruled on, a stipulated agreement was entered into the case that the judgment was not final and was not immediately appealable or executable, and it additionally stipulated a schedule for briefing post-trial motions.

Both parties then filed their initial Motions for Judgment as a Matter of Law or of New Trial on October 23, 2017. Answering briefs were filed by both parties on November 20, and reply briefs on December 8. The most recent filing in the case took place on December 15, 2017, requesting oral argument regarding the motions. Hospira’s motion requests findings that 1) its 21 manufacturing batches are protected under the Safe Harbor Defense, 2) it did not infringe the claims of the ’298 patent, 3) the claims of the ’298 patent are invalid, and 4) damages should be limited to no more than $1.5 million per batch. Amgen’s motion, meanwhile, requests a finding of infringement of the ’349 patent.

If the judgment at issue currently stands, Hospira will be on the hook for $70 million for its pre-approval manufacturing activities. However, as both the ’298 and ’349 patents are currently expired, none of the current judgment or rulings in favor of either party on their motions will prevent Hospira from bringing its now-approved Retacrit to market, and only modifications or removal of the damages award may occur.

What may remain a difficulty for Hospira, however, is that the court still has not entered judgment as to Count 1 of Amgen’s complaint regarding Hospira’s allegedly giving ineffective Notice of Commercial Marketing as required under the BPCIA. While the latest stipulation entered on October 31, 2017, indicates that the parties recognize that as time goes on, this may become, or already has become, a moot issue,  it is still a factor that Hospira considers in the timing of its launch into the U.S. market.

Earlier this month, Celltrion, Inc. (“Celltrion”) filed a copycat IPR petition directed against U.S. Patent No. 7,976,838 (“the ʼ838 patent”) that is essentially identical to a petition filed by Pfizer, Inc. (“Pfizer”).  The PTAB recently instituted review of the ʼ838 patent based on Pfizer’s petition in IPR2017-01923.  Celltrion’s copycat petition was accompanied by a motion for joinder with the currently pending Pfizer IPR.

Celltrion’s motion for joinder asserts that it contains identical grounds to those presented in the Pfizer petition, and thus would not create any additional burdens on the parties or impact the trial schedule.  Celltrion further explains that it conferred with Pfizer’s counsel and agreed to proceed in a limited “understudy” role, unless Pfizer is terminated from the proceedings.  As part of this understudy role, Celltrion agreed to not produce its own testifying witnesses, file any substantive papers (unless those papers do not affect Pfizer), or participate in the oral hearing.

This is the third time Celltrion has challenged the ʼ838 patent in an IPR.  Celltrion’s first challenge to the ʼ838 patent was via another copycat petition based on Boehringer Ingelheim’s (“Boehringer”) petition filed in IPR2015-00417.  Celltrion filed a motion for joinder in that case but while the motion was pending, Boehringer requested adverse judgment and the IPR was terminated.  Celltrion then requested dismissal of its copycat petition without prejudice, which the PTAB granted.  Celltrion subsequently filed its own IPR challenging the patentability of the ʼ838 patent, but the PTAB declined to institute review.

In Celltrion’s first copycat petition in the Boehringer IPR, Celltrion did not retain an expert of its own to support its petition.  Rather, Celltrion relied on the same exhibits and expert declaration that Boehringer submitted.  However, once Boehringer requested adverse judgment, Celltrion was no longer able to work with that expert.  Without an expert of its own, Celltrion could not proceed in the IPR.  Celltrion apparently learned from this experience, and supported its most recent copycat petition with expert declarations submitted by experts independent of those relied on by Pfizer.

The lesson here for parties filing copycat petitions is that they should consider submitting independent expert declaration(s), even if those declaration(s) are essentially identical to those supporting the petition being copied, to avoid any problem with continuing in the IPR if the first-filing party drops out of the proceeding.

Earlier this month, the Patent Trial and Appeal Board (“PTAB” or “the Board”) denied institution of Sandoz’s petition for inter partes review of Abbvie’s patent, U.S. Patent No. 9,512,216 (“the ’216 patent”), directed to methods for treating moderate to severe chronic plaque psoriasis with a human anti-tumor necrosis factor α (TNFα) antibody.[1] The petition, filed on October 2, 2017, asserted that claims 1-16 of the ’216 patent were unpatentable under 35 U.S.C. § 103(a) as obvious over a Humira 2003 Label and a Humira 2002 Label, in combination with other references. The institution decision ultimately hinged on whether the labels constituted prior art “printed publications” under 35 U.S.C. § 102(b).

As the Board explained in its decision, the petitioner has the burden to establish a reasonable likelihood that it will prevail on the merits, which, inter alia, includes putting forth sufficient arguments and evidence to show that the petitioner would establish public accessibility of the reference by a preponderance of the evidence over the course of the trial.[2] Whether a reference qualifies as a “printed publication” is a case-specific inquiry, with the key factor being a satisfactory showing that the reference was “sufficiently accessible to the public interested in the art” before the filing date.[3] A reference is considered “publicly accessible” if it was “disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art exercising reasonable diligence can locate it.”[4]

In its petition, Sandoz identified the Humira 2002 Label and Humira 2003 Label as prior art under § 102(b), asserting merely that the labels were “prior art FDA-approval label[s]” and that the drugs were approved by the FDA in December 2002 and January 2003, respectively.[5] In the preliminary patent owner response, Abbvie argued that this showing was insufficient. Specifically, Abbvie pointed out that the issue dates on the face of the labels do not establish “public accessibility,” and although Sandoz attached exhibits which could support an argument that the labels were publicly accessible, including a screenshot of the Humira 2003 label from the WayBack Machine and affidavit from the Office Manager at the Internet Archive, neither was cited or discussed in the petition itself.

In response to the preliminary patent owner response, Sandoz sent an email to the Board requesting, in part, authorization to file a reply to address Abbvie’s arguments regarding the public availability of the Humira labels. The PTAB denied this request, explaining that Petitioner could have reasonably foreseen arguments regarding whether the Humira labels were publicly available before the priority date of the ʼ216 patent, given that a petitioner bears the initial burden of production to establish the existence of prior art that renders the claims unpatentable. The Board did, however, grant Sandoz’s request to file a reply in response to the Patent Owner’s arguments regarding §§ 314(a) and 325(d).

Despite the Board’s limited authorization regarding the scope of the reply, the background section of Sandoz’s reply included arguments addressing the public availability and “printed publication” status of the Humira labels, citing to the WayBack Machines screenshot and the affidavit of Christopher Butler, Office Manager at the Internet Archive, affirming that the 2003 Humira Label was publicly accessible and archived from www.fda.gov on March 31, 2003. This appears to have rubbed the Board the wrong way. In the decision denying institution, the PTAB noted that “Petitioner’s attempt in the Reply to meet its threshold showing that Humira 2003 Label is a printed publication is not only untimely, but also appears to circumvent our Order (Paper 11) denying Petitioner’s request to file a reply on that very issue.”[6]

The PTAB ultimately agreed with Abbvie’s arguments that the Humira labels were insufficient to establish public availability, such that the labels did not qualify as prior art under § 102(b), and the petition was thus denied. While this decision illustrates a hard lesson learned under the old adage “don’t bite the hand that feeds you,” it is also a testament to the need for petitioners to put forth sufficient evidence to establish that a reference relied upon is indeed a prior art “printed publication” in the petition itself. Merely including supporting evidence as an exhibit, without a citation or explanation in the petition, just won’t cut it for meeting the threshold showing of prior art status.

 

[1] Sandoz Inc. v. Abbvie Biotechnology Ltd., IPR2018-00002, Paper No. 13 (PTAB May 3, 2018).

[2] Id. at 6-8.

[3] Id. at 7 (citing In re Lister, 583 F.3d 1307, 1311 (Fed. Cir. 2009)).

[4] Id. (citing Kyocera Wireless Corp. v. ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008) (citation and internal quotations marks omitted)).

[5] Petition at 24.

[6] Sandoz Inc. v. Abbvie Biotechnology Ltd., IPR2018-00002, Paper No. 13 at 12 (PTAB May 3, 2018).

 

Today, the FDA announced that it approved Retacrit (epoetin alfa-epbx) as a biosimilar to Epogen® for the treatment of anemia caused by chronic kidney disease, chemotherapy, or use of zidovudine in patients with HIV infection.  The FDA also approved Retacrit for use before and after surgery to reduce the chance that red blood cell transfusions will be necessary due to blood loss during surgery. The FDA’s approval was granted to Hospira, which is now a Pfizer company by virtue of Pfizer’s acquisition of Hospira in 2015.

According to the FDA, approval “is based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Retacrit is biosimilar to Epogen/Procrit.”  The FDA further noted that although Retacrit has been approved as a biosimilar, it has not been approved as interchangeable with Epogen®.

Retacrit is the first epoetin alfa biosimilar to be approved by the FDA, and just the tenth biosimilar approved overall.  In announcing the approval, Pfizer stated that “[a]s the first approved epoetin alfa biosimilar in the U.S., RETACRIT may provide patients and their physicians with increased access to a high-quality, lower-cost alternative treatment option for anemia and the reduction of allogeneic red blood cell (RBC) transfusions in certain patients.”  Pfizer also stated that “RETACRIT is expected to be available in the U.S. at a significant discount to the current wholesaler acquisition cost (WAC) of Epogen and Procrit.”

The FDA’s approval of Retacrit comes nearly a year after it issued a complete response letter (“CRL”) to Pfizer regarding the then pending application.  As we previously reported, Pfizer stated that the CRL did not specifically relate to the manufacture of Retacrit, but was in response to matters noted in a Warning Letter following a routine inspection of a manufacturing facility that was identified as a potential manufacturing site for its epoetin biosimilar.

Hospira and Amgen are currently involved in litigation over patents that Amgen has asserted over this biosimilar.  Last September, a jury in the District of Delaware found Hospira liable for infringing one of the two patents at issue and awarded Amgen 70 million dollars in damages.  However, post-trial motions filed by both Hospira and Amgen are still pending, and so the judgment is not final.  In addition, the patent that Hospira was found to infringe has now expired.

As we previously reported here and here, Celltrion filed suit against Genentech seeking declaratory judgment that a number of patents relating to Herceptin® (trastuzumab) and Rituxan® (rituximab) are non-infringed, invalid, and/or unenforceable.  In response, Genentech filed a motion to dismiss in both cases arguing that the case was statutorily barred under the BPCIA.  On May 9, 2018, the Court granted both of the motions.

To better understand the parties’ positions and the Court’s ruling, a brief recap of the patent dance portion of the BPCIA is helpful.  Following the FDA’s acceptance of an abbreviated Biologic Licensing Application, the applicant (here, Celltrion) provides the reference product sponsor (here, Genentech) with a copy of that application.  After receipt of the application, the reference product sponsor provides the applicant with a list of patents that it believes to be infringed.  The applicant then sends the reference product sponsor a claim-by-claim analysis of why it believes the asserted patents are not infringed by the biosimilar product, are invalid, or are otherwise not enforceable.  The reference product sponsor then responds to the applicants arguments.  Once those exchanges are complete, the parties must negotiate in good faith to identify the patents that will be subject of immediate patent infringement litigation.  The parties have 15 days to complete these negotiations.  If an agreement cannot be reached, the applicant must identify the number of patents that it wishes to litigate, and that number sets the limit on the patents-in-suit.  The parties then exchange the lists of patents that each party believes should be litigated and the reference product sponsor may then bring suit.

The BPCIA also sets limits on the remedies available to an applicant in the event it does not comply with any of the various steps in the patent dance. For example, if the applicant does not provide a copy of its application to the reference product sponsor, then the applicant cannot bring a declaratory judgment action.  Similarly, the applicant is barred from bringing a declaratory judgment action if it does not serve the various required disclosures, e.g., the number of patents it wishes to litigate or the list of patents it believes should be litigated, on the reference product sponsor.

Returning to Genentech’s motion(s) to dismiss, the thrust of the motions was that Celltrion’s declaratory judgment actions were barred due to Celltrion failing to comply with its obligations during the “patent dance” portion of the BPCIA.  According to Genentech, Celltrion failed to engage in the required good faith negotiations that must occur following Genentech’s initial disclosure of the patents it believed Celltrion’s product would infringe.  Genentech alleged that although it initially identified 40 patents, it subsequently proposed reducing the number of patents it would assert based on Celltrion’s responses.  Genentech asserted that Celltrion responded by stating it wished to litigate all 40 patents and filing the declaratory judgment action.

Celltrion counters that although Genentech proposed narrowing the number of patents in suit, it purported to reserve its right to assert infringement of the other identified patents.  According to Celltrion, this “created unacceptable legal uncertainty” and for this reason, it wished to litigate all 40 patents.  Celltrion also explained that it provided Genentech with a notice of commercial marketing when it brought the declaratory judgment action.  According to Celltrion, service of a notice of commercial marketing triggers a new wave of the patent dance that allows either party to bring a declaratory judgment action to settle any patent disputes remaining at the time of the notice.

The Court disagreed with Celltrion, and found that the declaratory judgment suits were clearly barred by the BPCIA. In both suits, the Court noted that Celltrion failed to identify the number of patents it wished to litigate and failed to exchange a list of patents that it believed should have been in the suit with Genentech.  The Court found Celltrion’s explanation for its actions unavailing.  Celltrion argued that it notified Genentech that it wished to litigate all of the patents originally identified, and thereby simultaneously fulfilled its obligation to negotiate, set the number of the patents in dispute, and rendered a subsequent list exchange redundant.  However, the Court found that because the requirement to negotiate in good faith is in one section of the statute and the identification of the number of patents-in-suit/list of patents exchange is in another, “no single statement or gesture can satisfy the requirements of both sections simultaneously.”  The Court thus concluded that Celltrion had improperly conflated a number of discrete steps and exchanges that are mandated by the statutory framework.  The Court also found that even assuming Celltrion’s interpretation of the statute was correct, Celltrion had erred by presupposing disagreement during the negotiation phase gave it the power to unilaterally terminate the patent dance.  Moreover, the Court concluded that even if negotiations had not been fruitful, the statute requires the list exchange and empowers Genentech, and not Celltrion, to file suit.

The Court also disagreed that Celltrion’s service of a notice of commercial marketing permitted Celltrion to bring the declaratory judgment action.  According to the Court, the BPCIA contains three distinct statutory bars that each apply to a different factual circumstance where an applicant fails to comply with the statute.  Service of a notice of commercial marketing only lifts one of those statutory bars, i.e., where the parties have fully complied with all of the statutory steps.  If the list exchange step (among others spelled out in the statute) is not completed, then a separate bar applies, and the filing of a notice of commercial marketing cannot lift it.

In its order dismissing the case, the Court permitted Celltrion to file an amendment complaint.  However, the basis for the Court’s dismissal was that Celltrion did not comply with certain steps in the statute, and, notwithstanding Celltrion’s explanation of its actions, there does not appear to be a dispute between the parties as to what actions did and did not occur. Meanwhile, Genentech has filed patent infringement suits based on the same Celltrion abbreviated Biologic Licensing Applications in New Jersey and Delaware.

We will continue to keep you updated on future developments.

The Patent Trial and Appeal Board (“the Board”) has decided not to institute inter partes review (“IPR”) on two patents owned by Biogen and Genentech.  Pfizer, Inc. (“Pfizer”) filed two petitions asserting that the patents, U.S. Patent Nos. 8,206,711 (“the ’711 patent”) and 7,682,612 (“the ’612 patent”), were invalid as obvious in view of prior art. Both of these patents relate to Rituxan® (rituximab) and its use in the treatment of chronic lymphocytic leukemia (“CLL”).

Last month, the Board denied Pfizer’s IPR petition for the ’711 patent, finding that all of the claims were not obvious over the cited prior art. Pfizer, Inc. v. Biogen, Inc., IPR2017-02127 (PTAB Apr. 19, 2018) (Paper 10). The Board held that the cited prior art failed “to provide guidance concerning clinical endpoints, treatment parameters, or other information relating to how one would treat CLL with rituximab, or why one would reasonably expect such treatment to be successful.” Id.at 23.

This past week, the Board denied Pfizer’s other petition for the ’612 patent, again finding that the claims were not obvious over the prior art. Pfizer, Inc. v. Biogen, Inc., IPR2017-02126 (PTAB Apr. 30, 2018) (Paper 10). Pfizer argued that the prior art “would have provided an ordinarily skilled artisan with a reasonable expectation of success for methods of using rituximab to treat CLL patients at the claimed doses.” Id.at 11. However, the Board disagreed that the prior art demonstrated that “an ordinarily skilled artisan would have had a reasonable expectation of success in using any dosage of rituximab to treat CLL.” Id. at 10. Rather, the prior art suggested “a rationale for exploring the possibility of treating CLL with rituximab,” but such suggestion amounted “to no more than an invitation to experiment.” Id. at 10.

This is not the first challenge to these two Rituxan® patents. Celltrion, Inc. previously filed three IPR petitions challenging both patents, all of which were denied by the Board. See Celltrion, Inc. v. Biogen, Inc., IPR2017- 01227 (PTAB Oct. 23, 2017) (Paper 10); Celltrion, Inc. v. Biogen, Inc., IPR2017-01230 (PTAB Oct. 12, 2017) (Paper 12); Celltrion, Inc. v. Biogen, Inc., IPR2017-01229 (PTAB Oct. 23, 2017) (Paper 10).

Sandoz announced last week that the FDA issued a complete response letter for its proposed biosimilar to rituximab.  In the announcement, Sandoz stated that it “stands behind the robust body of evidence included in the regulatory submission and is currently evaluating the content of the letter.”  Sandoz further indicated that although disappointed, it “remains committed to further discussions with the FDA to bring this important medicine to US patients as soon as possible.”

Sandoz initially announced that the FDA accepted its application for its proposed rituximab biosimilar on September 12, 2017.  Sandoz’s licensing application to the United States FDA followed the approval of its rituximab biosimilar for all indications in Europe.

Rituximab is an anti-CD20 monoclonal antibody approved for the treatment of non-Hodgkin’s lymphoma (follicular lymphoma and diffuse large B-cell lymphoma) and chronic lymphocytic leukemia, as well as immunological diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

We will continue to keep you updated on further developments.

  • European Medicines Agency approves second trastuzumab and third insulin glargine biosimilars
  • FDA has not approved any biosimilar drug in 2018
  • Only three of nine approved biosimilars have launched in the United States

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top nine branded biologic drugs were estimated to total $63 billion in 2016[1].  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar Omnitrope® was first authorized on April 12, 2006, an additional 39 out of 44 applications have been approved in Europe.  Three of the authorizations have been withdrawn post-approval by the marketing authorization holders (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar Zarxio® received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.   Subsequent to Zarxio®’s approval, only eight other biosimilar drugs have gained U.S. approval to date (Table 2).  As illustrated in the following graph, the EU’s significant head start led to the existent imbalance in the number of biosimilar drugs available in the respective markets.

Currently, sixteen biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of U.S. patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for at least twelve different original biologics are currently navigating the FDA’s biosimilar pathway or are in late stage development (Table 4).  Interestingly, Neulasta® (pegfilgrastin) biosimilars have failed to gain approval in Europe and in the United States despite numerous attempts.  The FDA has rejected pegfilgrastim applications filed by Coherus, Mylan/Biocon, and Sandoz, and there are currently eight pending applications for pegfilgrastim pending in Europe.

On February 9, 2018, the EMA approved HerzumaTM, the second trastuzumab biosimilar to Roche’s Herceptin® in Europe.  The EMA previously approved Samsung Bioepis’ Ontruzant TM in November 2017.  Herzuma is the third biosimilar from Celltrion’s portfolio approved by the European Commission.

On April 23, 2018, Pfizer announced that the FDA had issued a Complete Response Letter (CRL) highlighting the need for additional information for its trastuzumab biosimilar referencing Herceptin®.   On April 5, 2018, Celltrion announced that the FDA had issued CRLs for 2 of its products, CT-P10, a proposed rituximab biosimilar referencing Rituxan®, and CT-P6, a proposed trastuzumab biosimilar referencing Herceptin®.  The FDA has not approved any biosimilars in 2018.

Given biosimilar applicant experience in navigating the EMA process and the EMA’s high authorization rate, the FDA will need to continue to provide useful guidance and streamline the approval process in order to reduce the imbalance.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated May 1, 2018).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on April 17, 2018).

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines updated on April 10, 2018).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. that have biosimilars in the regulatory pipeline.

 

[1] Mullard, Asher. “Bracing for the biosimilar wave.” Nature Reviews Drug Discovery 16.3 (2017): 152-154.