Pfizer Receives Approval for Trazimera, the Fourth Trastuzumab Biosimilar

A fourth trastuzumab biosimilar has been approved by the US Food and Drug Administration (FDA). Pfizer’s biosimilar version of trastuzumab-qyyp (Trazimera) gained approval on March 11.

The principal phase 3 study tested Trazimera against the EU-licensed version of Herceptin®. The REFLECTIONS B327-02 study found no relevant differences in the clinical and safety outcomes for patients with HER2positive metastatic breast cancer, who also received paclitaxel. A second study tested Trazimera versus EU-licensed Herceptin in combination with docetaxel and carboplatin as neoadjuvant therapy, again demonstrating similar outcomes. The FDA’s approval covers both indications approved for Herceptin (treatment of HER2-overexpressing breast cancer and metastatic gastric/ gastroesophageal junction adenocarcinoma).

Pfizer first filed for approval of its trastuzumab biosimilar in the third quarter of 2017, and received a rejection from FDA in April 2018. Resubmission in June 2018, with additional information requested by the FDA, resulted in the current approval. The product was approved by the European Medicines Agency last year.

As with the other approved biosimilar versions of trastuzumab (Herzuma, Ogivri, and Ontruzant) in the United States, Trazimera is not yet available for prescription. Pfizer signed a licensing agreement with Herceptin’s maker Roche in December 2018, but a launch date is not yet available.

In other biosimilar news…Biocon’s biosimilar manufacturing plant has received a second citation from the FDA. The new Form 483 specified two issues, one involving sanitizing a type of barrier system and problems in tracking rejected vials.

Comparing Biosimilar Approval Progress by the FDA and EMA

It is widely reported that European biosimilar development is way ahead of that in the US. In a number of ways, this is true. However, when talking about biosimilar development in the EU compared with the US, we really should take a look at the bigger picture.

First of all, let me specify that I’m talking about biosimilar approvals, not launches. In the latter case, the US is way behind, not even viewable in the distance.

Obviously, the US lags because it got a later start, first in promulgating the BPCIA in 2010, and then in developing the biosimilar regulatory pathway. The US system then tried to shoot itself in the foot with the “patent dance,” which also does not exist in the EU. Even America’s inability to master the steps of the patent dance did not deter initial interest in biosimilars, from inside and outside the nation. Overall, the US failed to take great advantage of the pioneering work of European policy makers in divining a regulatory pathway for biosimilars, and has been playing catch up ever since. In a sense, however, the US’s regulatory machinery has caught up, and perhaps exceeded the pace of the European Medicines Agency (EMA) in approving biosimilars.

Biosimilar approvals

This is a complicated comparison, outside of numbers alone. The chart below offers a view to the Food and Drug Administration’s (FDA’s) 17 current approvals, all accomplished within seven years of the pathway being available (and the seventh year, 2019, is still young). An analysis of information from the Generics and Biosimilars Initiative demonstrates that only 13 biosimilars were approved in the EU seven years after the pathway was implemented.

A closer look reveals a couple of important points: (1) The EU’s first biosimilar approvals were for growth hormone drugs, which were not considered biosimilar products in the US (until 2020); (2) epoetin biosimilars dominated 2007 approvals with five; and (3) filgrastim biosimilars comprised the main approvals for 2008–2010 in the EU. Between 2009 and 2012, the EMA approved only three biosimilars, two of which were filgrastim molecules. In 2013, an impressive array of biosimilars were approved in the EU, including yet another filgrastim and growth hormone, two infliximabs, and follitropin. The EU has made tremendous progress with new molecules over the past couple of years, including the rush of rituximabs in 2017, and pegfilgrastims and adalimumabs in 2018, all corresponding closely with patent expirations. In fact, of the 54 biosimilars approved in the EU (as of December 2018) in its 13 years of experience with biosimilars, 30 (55%) were approved in 2017 or 2018.

That doesn’t mean the FDA hasn’t made missteps—there have been plenty. Remember, the patent dance was not FDA’s doing, that was statutory not regulatory. They do need to admit their responsibility on the four-digit suffixes and the long delay in finalizing guidances, especially on interchangeability. And there are certainly biosimilar drugs that were approved by the EMA but rejected by the FDA.

Overall though, the FDA has not been the reason only seven biosimilars in four drug classes are now available for prescription. Those are uniquely American problems.

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.

A Third Biosimilar Adalimumab Approval in the US and Potentially Huge Humira Price Discount in Europe

The Food and Drug Administration (FDA) announced yesterday the approval of adalimumab-adaz from Sandoz. The new agent, dubbed Hyrimoz™, will not be launched in the US until 2023. The approval of Hyrimoz is the third for Sandoz (but only one, Zarxio®, is available for prescription in the US).

The FDA approval of adalimumab-adaz covered several indications, including adult Crohn’s disease, ankylosing spondylitis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. The drug’s approval was based partly on the findings of a phase 3 clinical trial in patients with chronic plaque psoriasis, in which the biosimilar was found to be noninferior to the originator product Humira® in terms of efficacy (i.e., PASI 75 score) and safety.

Hyrimoz is the third  approved adalimumab biosimilar, none of which have been marketed due to patent litigation.  Abbvie has signed licensing agreements with Amgen and Samsung Bioepis to delay US launches.

HUMIRA PRICE DISCOUNT IN THE EU

This biosimilar is being marketed in the EU, competing with several others for the Humira marketshare overseas. However, signs of real competition are heating up in Europe, as Abbvie has offered a Humira price discount of as much as 80%.

According to an article published in Fierce Pharma, Abbvie is hoping to squash the biosimilar competition and prevent it from gaining valuable European experience ahead of US launches in 2023. The article cited a report by Bernstein analyst Ronny Gal, indicating that even at an 80% discount, Humira will still be profitable for Abbvie. “The objective is to defend the US market by denying the biosimilars in-market experience [in Europe] and then arguing the Europeans ‘chose’ Humira over the biosimilars for quality reasons beyond price,” according to Gal’s report.

On the other hand, this puts the biosimilar makers in a tight spot on the continent. They need to earn back their R&D costs and may be unwilling to face an immediate low-profit reality. Revenues within the EU for Humira are $4 billion. Even if it offered tenders of 80% for every member country (and they were accepted), revenues would still be in the range of $800 million. This would drastically reduce the size of the revenue slices for the European biosimilar competitors. It could be possible that some may drop out of the market, at least until the time of the US launches.

Phase 3 Studies in Biosimilars: Do They Tell Us Enough to Be Useful?

The argument for the elimination of the need for phase 3 studies in biosimilars is pretty simple: They cost a great deal but what do they add to our knowledge about the safety and efficacy of biosimilars? One of the primary tasks of the Food and Drug Administration (FDA), in educating health care professionals, media, the public, academia, and manufacturers, was to deemphasize the importance of the clinical trial in the totality of evidence approach they use to evaluate biosimilars.

Do we need phase 3 studies in biosimilars?The health care professional community, academia, and patient advocates may take another view: They are complex biochemical medicines and we cannot be sure of their safety and efficacy without carefully controlled studies in large populations. We have been ingrained for 40 years with the need for randomized, phase 3 clinical investigations that it may be very uncomfortable indeed to approve a drug without them.

Phase 3 Studies in Biosimilars: Statistically Speaking

At least one pharmaceutical company (Adello) is seeking FDA approval without phase 3 trials that study large groups of patients with the disease indication. In biosimilars, FDA is willing to extrapolate approvals without any clinical studies in other indications, and indeed, payers and providers are willing to accept this.

Furthermore, the FDA has taken many steps to speed access of biosimilars to approval. Other than altering the intellectual property and exclusivity timelines, what action can save more time in the process (much less money for the biosimilar developer) than the elimination of phase 3 studies in biosimilars?

In a phase 3 clinical trial of the originator biologic vs. a biosimilar, what do we expect to see? Since the expectation is that the physiochemical characteristics of the two molecules are exceedingly similar, and phase 1 trials should have proven equivalent pharmacodynamics, we don’t expect big differences in outcomes by phase 3. If phase 2 studies have been performed successfully, we believe this more emphatically.

At worst, we expect to see clinical effects that are on the edges of anticipated norms for the originator drug but within the range expected. One French investigator wrote this month in BioDrugs that typical phase 3 studies with 600 to 1000 patients are not statistically powered to detect more than major differences in safety. What is the real implications of 2 versus 5 drug withdrawals in patients taking medications that are much more alike than they are different? This author believes that well-designed phase 1 trials in volunteers can sufficiently detect the formation of antidrug antibodies and other immunogenicity differences between biosimilars and their originator drugs. This may be particularly true in patients with autoimmune disorders. When patients are routinely given methotrexate (another immunosuppressant) concomitantly with the biologic therapy, reliable evaluations of immunogenicity of the study medications are very difficult. Finding that hidden safety signal may not be possible.

More Pressure on Postmarketing Surveillance

In other words, it is easier to determine whether a biosimilar drug is “noninferior” to a reference product in clinical testing. The range of expected values is small (and there is little or no expectation that a biosimilar will demonstrate superiority). I’m no statistician, but I’d expect that to detect clinically significant differences among outcomes in this type of comparison, one would need study populations far exceeding that of the typical phase 3 study in biosimilars. Unlike in a clinical trial of a study drug versus a placebo or other standard therapy, large differences may be seen, and population sizes may be less important (hence, phase 2 trials of 100 patients may reveal red flags or lack of effectiveness).

Without the use of phase 3 trials in biosimilars to attain comfort and security, the post-marketing surveillance machinery becomes that much more important. The observation of safety issues based on real-world prescribing and utilization will be a front-line defense, not a backstop, to identify unintended pharmaceutical outcomes. This means that more of the onus will fall on the conduct of registry trials, FDA’s Sentinel program, and notably the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), which is in the process of preparing for its first comparative-effectiveness studies in long-acting insulins (Q4 2018) and granulocyte colony-stimulating factors (i.e., filgrastim, pegfilgrastim).

This would still be a significant leap of faith, based on the approvals and limited use of biosimilars today, but I can envision other companies gambling, with FDA’s consultation, on skipping this traditional step to drug approval. I wouldn’t bet against it.

FDA Advisory Committees on Biosimilar Applications: Mylan’s Latest Muddies the Waters Further

When the Food and Drug Administration (FDA) approved the first biosimilar pegfilgrastim (Mylan’s Fulphila™), it broke precedent in more ways than one. Not only was this the first biosimilar member of the pegfilgrastim class to be approved, but its approval did not require an FDA Advisory Committee recommendation.

The FDA has been a bit fuzzy with respect to when an FDA Advisory Committee will be necessary. In the past, however, these AdComms had been required for all first biosimilar approvals to a new reference product. This was the case for filgrastim, infliximab, etanercept, trastuzumab, bevacizumab, adalimumab, and epoetin. Second biosimilars did not always require an AdComm, most recently last September with Boehringer Ingelheim’s Cyltezo®, the second adalimumab approved by FDA.

FDA Advisory CommitteeVarious problems with the 4 pegfilgrastim biologic license applications and resubmissions have provided the FDA ample time to review data and mull the consequences of approval or rejection. This case could be an exception. A greater challenge may be upcoming though.

Not that a great deal was achieved with the biosimilar AdComms. In general, votes for recommended approvals have been unanimous or lopsided. A recommendation for approval does not always result in approval—sticky manufacturing issues have gotten in the way (e.g., for Pfizer’s Retacrit). The FDA Advisory Committee meetings does give the public and other stakeholders a chance to air their views. Generally, this has been not for or against the biosimilar being reviewed but for or against biosimilars as a whole.

In March, I raised the case of Adello Biologics, which is attempting to gain approval of its filgrastim biosimilar without any phase 2 or phase 3 clinical data. This may be the second filgrastim biosimilar approved, so the FDA can avoid an AdComm on this basis. More importantly though, this agent could be the first biosimilar approved without any patient-based clinical testing (phase 1 is usually conducted in healthy volunteers). The next FDA Blood Products AdComm is not scheduled until November 29, 2018, and we do not know if Adello’s product will be part of that discussion. With a submission date of September 2017, one would expect a decision from FDA in the third quarter of this year.

In other biosimilar news… Celltrion resubmitted its 351(k) application to the FDA for its biosimilar version of trastuzumab. The original application resulted in an April 5 complete response letter for the Celltrion/Teva team.

Mylan and Biocon Land First Pegfilgrastim Biosimilar Approval

The race to bring a pegfilgrastim biosimilar to market officially started on December 17, 2014. The checkered flag fluttered 3½ years later on June 4, 2018, with the Mylan/Biocon team winning on a slow track. The partners earned approval from the US Food and Drug Administration (FDA), becoming the first biosimilar to challenge for this $4 billion market.

Mylan will market the product in the US, and it is assumed that the product will be launched shortly,= to take advantage of their window of opportunity. The drug will be called Fulphila™, and the FDA assigned a formal name of pegfilgrastim-jmdb. The next likely competitor, Coherus, is expected to receive word from the FDA by November 2. Mylan will have the chance to quickly grab marketshare if they produce attractive deals for payers.

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.

Pfizer Gets Green Light From the FDA on Epogen® Biosimilar

It has taken a long time, but Pfizer finally earned approval from the U.S. Food and Drug Administration (FDA) on the first biosimilar version of Epogen®. The drug, Retacrit® (epoetin alfa-epbx), had originally been submitted for approval in December 2014. Its much stalled road to approval is finally at an end.

After an initial rejection, the FDA’s Advisory Committee voted overwhelmingly (14–1) in May 2017 to give the product a green light. However, the FDA changed the traffic light to red, issued a second complete response letter in June 2017, citing issues with its manufacturing plant in McPherson, Kansas (a plant Pfizer inherited with its acquisition of Hospira).

Retacrit is approved for the treatment of anemia caused by chemotherapy or chronic kidney disease, for use in patients taking zidovudine for the treatment of HIV infection, and to reduce the need for red-cell blood transfusions before, during, or after surgery.

This is the 10th biosimilar approved by the FDA, and Pfizer is expected to shortly launch only the fourth biosimilar agent. Epogen’s patent has long expired, and it was one of the first biosimilars approved in Europe (in 2007). Retacrit has been marketed in the EU for over 10 years. It is one of four biosimilar epoetin products available overseas.

In other biosimilar news… Mylan’s earnings call on May 9 produced little clarity on the fate of its upcoming FDA decision on its pegfilgrastim biosimilar. Although CEO Heather Bresch believes that its product will represent one of its most important launches of the year, she could not shed any light on partner Biocon’s response to the FDA’s critical review of its manufacturing facility. The PDUFA date is June 4; a positive decision means that Mylan/Biocon will have beaten the competition to the market for this important biosimilar product.

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.