The Biosimilar Mabs Have It: FDA Approves Biosimilars for Adalimumab and Rituxumab

In a busy beginning of the week, the US Food and Drug Administration approved new biosimilars for Humira®and Rituxan®. Samsung Bioepis gained approval for Hadlima™ (adalimumab-bwwd), and Pfizer scored with Ruxience™ (rituximab-pvvr).

HADLIMA

The approval for Hadlima covers the following indications:

  • Rheumatoid arthritis
  • Juvenile idiopathic arthritis
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • Crohn’s disease in adults
  • Ulcerative colitis
  • Plaque psoriasis

Formerly known as SB5, Samsung Bioepis secured Hadlima’s approval on the basis of phase 1 and phase 3 studies in rheumatoid arthritis. The phase 3 investigation included over 500 patients, finding ACR20 responses to be equivalent to that of Humira (at 72%). Immunogenicity profiles for the two agents were also similar through 52 weeks of a switching study.

According to its licensing agreement with Abbvie, manufacturer of Humira, Samsung will not be able to market this agent until end of June 2023. This agent joins Samsung’s two other approved anti-TNF biosimilars, Renflexis (infliximab) and Eticovo (etanercept). Only Renflexis is currently marketed in the US.

RUXIENCE

Pfizer’s newest biosimilar entry, Ruxience, has been approved for a subset of indications of reference product Rituxan, including:

  • Treatment of adult patients with relapsed or refractory, low-grade or  follicular B-cell non-Hodgkin’s lymphoma who are CD20-positive and have failed prior treatments
  • Patients who have nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin’s lymphoma and who are stable after receiving a prior chemotherapy regimen containing cyclophosphamide, vincristine and prednisone
  • Patients with CD20-positive follicular lymphoma who are therapy naïve in combination with chemotherapy or who had responded to previous rituximab therapy
  • Patients with CD20-positive chronic lymphocytic leukemia in combination with fludarabine and cyclophosphamide
  • Granulomatosis with polyangiitis in adult patients in combination with glucocorticoids

The biosimilar does not include Rituxan’s labeled indication for rheumatoid arthritis, similar to the other approved rituximab biosimilar.

The application for Ruxience included the results of the phase 3 clinical trial (REFLECTIONS), which included 394 patients with follicular lymphoma. Compared with the EU-licensed version of rituximab (MabThera®), Ruxience was found to provide equivalent clinical and safety outcomes.

Originally designated PF-05280586, Pfizer has not disclosed when Ruxience will be available. Pfizer signed a settlement with Roche (Genentech) over litigation for a key Rituxan patent, but terms of this agreement were not disclosed. The other FDA-approved biosimilar competitor in this space, Celltrion’s Truxima®, is similarly awaiting launch.

Introducing the 21st FDA Approval: Pfizer’s Zirabev, a Biosimilar of Avastin

On June 28, 2019, Pfizer announced that it had received Food and Drug Administration (FDA) approval of Zirabev™ (bevacizumab-bvzr), a biosimilar version of Roche’s Avastin®.

Pfizer approval of Zirabev

Based on the evidence provided by Pfizer, including its phase 3 trial comparing it to the EU-licensed version of Avastin, the FDA approved Zirabev for five cancer indications, including:

  • Advanced, metastatic, or recurrent nonsquamous non–small cell lung cancer
  • Metastatic colorectal cancer
  • Recurrent glioblastoma
  • Metastatic renal cell carcinoma
  • Metastatic cervical cancer

This approval does not include ovarian cancer, which is an additional indication for Avastin. Belonging to a class of biologics called vascular endothelial growth factor (VEGF) inhibitors, these agents work by preventing new development of a tumor’s blood vessels, helping to choke off growth.

Zirabev’s approval marks the 21st FDA approved biosimilar agent and the second approval for a bevacizumab biosimilar. Mvasi®, to be manufactured by the partnership of Amgen and Allergan, obtained approval in September 2017. However, this product is not yet marketed.

At a recent annual meeting of the Academy of Managed Care Pharmacy, a specialty drug pipeline expert expressed hope that Mvasi would be launched in July of this year. Its manufacturer has been embroiled in patent litigation with Roche, but the key patents are expected to expire in the immediate future.

Pfizer has not announced a launch date for Zirabev. Yet, it could be the second cancer-treating biosimilar category to enter competition (with Herceptin biosimilars) very shortly.

Don’t Expect All-Out Biosimilar Competition for Herceptin—Just Yet

Five trastuzumab biosimilars have been approved for marketing in the US, and the composition-of-matter patent for the reference product, Herceptin®, expires June 30, 2019. That doesn’t mean we’ll see a jail break of competition, like that seen in the EU last October with adalimumab’s patent expiration. Yet there has been heavy interest in capturing a slice of Herceptin’s $2.9 billion US sales (in 2018).

Three manufacturers have signed licensing agreements with Genentech (subsidiary of Roche). In March 2017, Mylan signed the first agreement for its product Ogivri®. Its marketing partner is Biocon. In December 2018, Pfizer followed suit for its recently approved agent Trazimera®. None of the parties have indicated when a biosimilar agent will be launched. At the end of December, Celltrion and Teva came to a similar agreement on its Herzuma® biosimilar.

Herceptin patent litigation

According to Goodwin’s Big Molecule Watch, Roche’s infringement claims against Samsung Bioepis (Ontrusant®) and Amgen/Allergan (Kanjinti®) are still being litigated. For Genentech v. Samsung, the bench trial is slated to begin December 9, 2019. In addition, Samsung Bioepis is appealing the Patent Trial and Appeals Board ruling regarding the validity of Herceptin’s method of use patents. Separately, Genentech is challenging the PTAB’s decision that two other Herceptin patents were invalid. There’s a whole lot here that needs to be resolved (or settled).

In the case of Amgen and Allergan, Genentech originally brought suit claiming 38 patents were infringed (in June 2018). In July 2018, Genentech reduced this figure to less than half (17). A month later, Amgen responded to the suit. Little information is available on timing of next steps.

Based on this information, it is difficult to know just when the first trastuzumab biosimilars will be launched. If Genentech followed Abbvie’s example in its 2023 sequencing of adalimumab biosimilars, one might expect Mylan’s product to be available first, perhaps as early as this summer, with Pfizer’s and Celltrion to follow perhaps six months later.

Yet, unlike the Abbvie agreements, none of the Genentech licensing settlements were made public (other than the actual dates of the agreement). Keep in mind, Herceptin was first approved by the FDA in October 1998. In 2018, the drug’s sales in the US and EU combined was over $4.7 billion. Is 21 years of market exclusivity to anyone’s benefit, other than the manufacturer? Since 2006, US drug sales of Herceptin have been greater than $1 billion annually. If the biosimilar launches do not occur shortly, this may be a good test case of the Federal Trade Commission’s commitment to clearing patents in the name of competition.

Even Today, Patients and Payers Hold the Key to Biosimilar Uptake Success

Reading the white paper co-published March 19 by the US-based Biosimilars Forum and UK-based Medicines for Europe highlighted for me the importance of an essential roadblock to increased biosimilar uptake in the US.

The white paper outlined structural market changes needed in the US to gain comparable conversion of marketshare in the European market. Without a doubt, barrier number 1 is the patent thicket erected by biologic makers and the resulting patent litigation. This causes barrier number 2: the signing of licensing arrangements that prevent biosimilar makers from entering the market at the earliest possible date.

However, this still doesn’t address the lack of biosimilar uptake for infliximab: Inflectra® has been available for use since 2016. Whereas I placed considerable blame for this on Pfizer, which underestimated payers’ reaction to its initial discount on Inflectra. Today, I place more of the responsibility on the health plans and insurers for lacking the backbone needed to ensure a vibrant biosimilar market for infliximab. The health system can gain the greatest savings by converting to biosimilar infliximab compared with any currently launched biosimilar. With that in mind, let’s consider these agents.

According to the white paper, “Full buy-in is needed from payers to sustain a competitive market that values the most cost-effective medicines. This includes proactive incentivizing of biosimilar prescriptions, educating stakeholders on the promise of biosimilars, and requiring commercial insurers to provide access to biosimilars.”

I will take this one step further. Patients need to act on their desire for less-expensive alternatives at the physician’s office. Two things must occur to produce this result: (1) the provision of more accurate, less misleading information to patients relating the quality of biosimilars and their clinical efficacy and safety, and (2) financial incentives for patients to specifically request biosimilars.

There is no question that patients are often confused by the contradictory information they receive on biosimilars. This harkens back to generic–branded drug battles of decades ago. Without accurate education, patients will not reliably consider a biosimilar alternative to products like Remicade® . Much has been published on this issue already, and several biologic makers have been castigated about their contributions to misinformation. This must intensify if the second “pull-through” for biosimilar uptake is to be successful.

Any American patient who has faced high cost sharing or deductibles has considered ways to lower his or her costs. That includes making the decision to not refill their prescription or take their medications as directed. Infliximab is only available today as an office-based infusion, but should a subcutaneous version be approved, this, too, would be more directly in the patient’s hands.

The only way this will occur is if patients are given an appropriate choice by their health plans and insurers: lower cost sharing for biosimilars. This is accomplished easily, through the creation of a specialty biosimilar tier (or assignment of biosimilar agents on a fixed cost, tier 3–type payment). With the reference product strictly on tier 4 or 5 (co-insurance tiers with high dollar maximums), this would be the practical step to move the needle. For Medicare Part D beneficiaries, this could be as high as 33% co-insurance.

With the exception of very few payers, this has not occurred for Inflectra. It did occur for Zarxio®, as early as 2017, but it is not used for a chronic medication. When patients begin asking for lower-cost alternatives and payers provide cost-sharing structures that favor biosimilar use, Inflectra or Renflexis® uptake will begin to increase. That means payers foregoing short-term rebate revenue for longer-term cost savings. But one cannot occur without the other.

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.

A Profile of a Lesser-Known Player in the Biosimilar Space: Bio-Thera Solutions

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight a Guangzhou, China–based company, Bio-Thera Solutions.

Established in 2003, Bio-Thera Solutions “is dedicated to researching and developing innovative and biosimilar therapeutics for the treatment of cancers, autoimmune, cardiovascular diseases, and other serious medical conditions.” It claims several biosimilar and innovative therapies in its pipeline. According to its website, Bio-Thera’s leadership team members spent extensive time in the US. The CEO and Founder Shengfeng Li was also a founder of a California company Abmaxis, which was acquired by Merck, and worked at COR Therapeutics, which became part of Milennium. Chief Medical Officer Li Zhang worked for eight years at the Food and Drug Administration’s Center of Drug Evaluation and Research.  

Why you may be hearing more about this company: Bio-Thera has advanced one of its key molecules, a biosimilar of bevacizumab (reference product, Avastin®) into a phase 3 study against EU-licensed Avastin. The company’s objective is to file a 351(k) application for this product, BAT-1706, with the US FDA and the European Medicines Agency in 2020.

The company announced a new partnership with Mumbai, India-based Cipla Ltd, to market this product in emerging markets. It is not yet known whether Bio-Thera intends to partner with another organization to market in North America or attempt to build its own sales structure.

Other products in research and development include an adalimumab biosimilar (BAT-1406), for which an application for approval has been filed for the Chinese market, and a phase 1 tocilizumab (Actemra®) biosimilar (BAT-1806) for the treatment of autoimmune diseases. The company’s information does not indicate whether either of these products will be targeted for the US market. In a 2018 press release, Bio-Thera indicated that biosimilars of secukinumab (Cosentyx®), golimumab (Simponi®), and ustekinumab (Stelara®) were also in the pipeline. Regardless of the success of its bevacizumab and adalimumab biosimilars, the company seems to be well-aligned to address patent expirations of next-generation biologics.

In other biosimilar news… Regulatory Focus reported Pfizer’s announcement that the drug maker has reevaluated its biosimilar drug pipeline. It has dropped plans to develop 5 biosimilars in preclinical development. The products themselves were not disclosed and were not listed in earlier available version of Pfizer’s drug pipeline. Five other biosimilars in clinical development will continue moving forward, according to the company. This does not affect biosimilars already approved by the FDA. No reason for the decision was given, other than that this was part of an “R&E investment review.”

Will the Government Shutdown Slow Biosimilar Approvals?

The partial federal government shutdown is having specific effects in various important areas of government, but it may not be particularly troubling for FDA user-fee funded activities.

Scott Gottlieb, MD, Commissioner of the FDA, has been especially busy on Twitter, trying to inform the public how the government shut down is affecting FDA operations. He made it clear that the agency is prioritizing its efforts on ensuring consumer safety.

During an extended tweet storm (the past 7 days), he has not directly addressed the effect of the shutdown on current drug approvals. However, since the pharmaceutical companies have paid into the drug approval activities of the Center for Drug Evaluation and Review, there may be sufficient funds and resources for ongoing approval activities. In a tweet last week, Dr. Gottlieb mentioned that FDA was bringing onto staff several new user-fee funded staffers. Yet, in a January 7 tweet, he promised additional information on how the shutdown would affect biosimilars; this has not yet been addressed.

In terms of biosimilars, two trastuzumab drug makers are expecting FDA decisions this quarter (Pfizer and Samsung Bioepis). However, Pfizer’s biosimilar launch is subject to a licensing agreement with Genentech (Roche), the maker of the reference product Herceptin®. Therefore, if there was a short delay in FDA approval, it will not likely have a material effect on availability for prescription. We anticipate that Pfizer will also be hearing from the FDA on its rituximab biosimilar in the second quarter.

This could raise a secondary problem with the shutdown: Will the current furlough cause a chain reaction of delays in the evaluation of existing biologic licensing applications? How long might it take the full FDA staff to catch up, if that is the case?

In a January 13 tweet, Dr. Gottlieb said, “The lapse in funding represents one of the most significant operational challenges in FDA’s recent history. But as an agency, we’re committed to fulfilling our consumer protection mandate, to the best of our abilities, under our current configuration.”

In other biosimilar news… A January 10 story in The Pink Sheet reported that Leah Christl, PhD, Associate Director of Therapeutic Biologics at FDA intends to depart the agency in the near future (a specific date was not given).

An Update on Potential Biosimilars for Bevacizumab

Embroiled in patent litigation, the partnership of Amgen and Allergan have waited for the opportunity to launch Mvasi® since September 2017. During this time, the competition has not been stagnant, with Pfizer moving towards an FDA decision. The next 6 months may prove critical, but when will providers, patients, and payers have access to Avastin® biosimilars? That may be based more on guesstimates than on fact.

Avastin patent litigation

WHAT DO WE KNOW?

(1) Amgen and Allergan received its FDA approval for Mvasi (bevacizumab-awwb) September 17, 2017. The approval covered all of the reference product’s indications. The drug was approved for use by the European Medicines Agency in January 2018.

(2) In court documents filed during its patent battle with Genentech, Amgen had originally stated that it planned to begin marketing Mvasi once the last 8 patents it considered valid expired on December 18, 2018.

(3) Amgen then revised this potential launch date, according to the court filing, saying that it could launch several months earlier, on April 5, 2018.

(4) In either case, the launch has not occurred. According to the Purple Book, Avastin was first approved by the FDA February 26, 2004. That is approximately 15 years, and counting.

(5) The US District Court handling the litigation is expressing impatience with the back and forth between the two parties (read the Judge’s concluding remarks). A trial court date was set for June 2020.

(6) Pfizer completed its phase 3 trial for PF-06439535 in nonsquamous non–small cell lung cancer and filed for FDA approval in August 2018. An FDA decision is expected in the second quarter of this year.

(7) In November 2018, Boehringer Ingelheim completed its phase 3 trial in lung cancer for BI 695502.

(8) Samsung Bioepis completed its phase 3 trial in lung cancer in October 2018 (compared with EU-licensed Avastin).

(9) In addition, Centus Biotherapeutics is scheduled to complete its phase 3 trial in June 2019 as well.

WHAT WE DON’T REALLY KNOW

So much for what we know. Here are some things we know less well.

At a drug pipeline update at the Academy of Managed Care Pharmacy in October 2018, Express Scripts’ Aimee Tharaldson, PharmD, Senior Clinical Consultant—Emerging Therapeutics, offered a projected launch date of July 2019. In an E-mail communication with Biosimilars Review & Report, Dr. Tharaldson clarified that this estimate was based on the anticipated expiration of a key patent on Avastin that month.

Bevacizumab Biosimilars
Aimee Tharaldson, PharmD

When we contacted a senior Amgen executive, he stated that the company declined to discuss potential launch dates.

Goodwin’s Big Molecule Watch, which keeps a close eye on biosimilar-related patent litigation, does not list any ongoing suits between Genentech and Pfizer or Boehringer Ingelheim regarding Avastin (which may be surprising in itself).

We would anticipate that Pfizer will launch as soon as feasible, if they receive an FDA approval by June. Pfizer has an established record of moving their biosimilars quickly to market (e.g., Inflectra® [with Celltrion], Retacrit®, and Nivestym®).

Samsung Bioepis has not yet revealed their plans around an FDA filing for their investigational biosimilar of bevacizumab.

Boehringer had not yet filed a 351(k) application for approval of BI 695502. Comments by Molly Burich, Director, Public Policy: Biosimilars and Pipeline, in our interview last Fall, made it clear that the company is laser focused on bringing its adalimumab biosimilar (Cytelzo®) to market. In fact, this bevacizumab biosimilar was no longer posted on their pipeline at that time.

WHAT WE FOUND OUT

Today, Susan Holz, Director, Communications, Specialty Care, confirmed that the company decided that this agent was not in its strategic plans and it simply allowed the study to be completed. She said, “Boehringer Ingelheim made the decision to terminate all activities related to the BI 695502 program, a biosimilar candidate to Avastin. It is important to note that this decision was not based on any safety or efficacy findings with the investigational medicinal product BI 695502. Boehringer Ingelheim continuously evaluates our business portfolio and assesses potential strategic partnerships to help enhance our pipeline and development capabilities.”

Perhaps several of these unknowns will be resolved by the end of July, and the clouds will lift a bit. I suspect at that time, we’ll be much closer to biosimilar access for this biologic, which racked up $7 billion worldwide in sales in 2017.

Coauthor of Hatch–Waxman Act Attacks the Use of IPR Process for Biosimilars

The Hatch–Waxman Act (officially, The Drug Price Competition and Patent Term Restoration Act of 1984) enabled generic medications to be marketed after branded patent expirations. One of the bill’s cosponsor, Senator Orrin Hatch (R-UT), is now spurring a legislative proposal that would protect reference drug manufacturers from use of the inter partes review (IPR) system. This action would result in further delayed access to lower-cost generics and biologic medicines.

Inter partes review is used by makers of generic drugs and biosimilars to challenge weaker patents. It enables the parties to bypass lengthier litigation through the courts, potentially helping less-expensive drugs reach the market faster than otherwise possible.

Hatch-Waxman Act
Senator Orrin Hatch (R-UT)

Called the Hatch–Waxman Integrity Act, this amendment to the CREATES Act was introduced December 11, 2018 simultaneously into the Senate and the House (by Representative Bill Flores, R-TX). If passed this amendment could significantly limit the ability of generic and biosimilar manufacturers to use the IPR process to speed patent review and litigation.

Seemingly a contradictory stance by Senator Hatch, he believes that the IPR process may too strongly affect the balance between access to medications and biopharmaceutical innovation.

In any case, this proposal would have a very difficult road to passage. First the administration’s current efforts to make biosimilars available as soon as possible runs counter to this bill. Second, the shift to the Democratic majority in the House could be an insurmountable barrier to passage.

In other biosimilars news…Sandoz seems to be entering the biosimilar insulin marketplace, with its agreement to commercialize three different types (insulin aspart, glargine, and lispro) that will be manufactured by the Chinese company Gan & Lee. Sandoz will be responsible for the US and Canada, the EU and Switzerland, Australia and New Zealand, and Japan. In the US, insulin makers can file applications for biosimilar status as of 2020.

Additionally, Pfizer received good news from Europe, receiving a positive recommendation from the EMA’s Committee for Medicinal Products for Human Use (CHMP) on its bevacizumab biosimilar Zirabev (reference product, Avastin®).

Pfizer Pulls One Biosimilar Adalimumab Application From the EMA

Earlier this month, Pfizer notified the European Medicines Agency (EMA) that it was withdrawing one of its two applications for approval of its biosimilar adalimumab. 

According to Pfizer’s Director of Global Media Relations, Thomas Biegi, the company had submitted two applications for this biosimilar, one for a limited set of indications, and the other for the full array of autoimmune indications of the reference product Humira®. Pfizer has decided to focus on gaining approval for the full slate of indications and withdrew the other application. Under the “skinny label,” the product would have been marketed as Fyzoclad™ in Europe. The potential brand name of the biosimilar if  approved with all of the reference product’s indications was not disclosed. In the US, the biosimilar is still known as PF-06410293 .

Although Pfizer would not confirm its plans for the US filing, phase 3 trial results for PF-06410293 have been published, establishing the biosimilar’s equivalency to Humira in terms of efficacy, safety, and immunogenicity.

PrintPfizer noted in its December 5th letter to EMA that their decision was not related to safety or efficacy. No doubt, Pfizer is surveying the heavy competition for adalimumab in Europe today. Pfizer did not elaborate on why the decision was made to submit applications for both the skinny label and the full set of indications.  

Pfizer signed a licensing deal with Abbvie on November 30 to market this adalimumab biosimilar in the US. It will be the sixth biosimilar to enter the market in 2023, based on this deal. Therefore, Pfizer must believe that a sixth biosimilar entrant to the US market at that time may still yield relevant revenues and marketshare. 

According to EvaluatePharma, Humira US sales estimates (published in 2018) for 2020 will be about $21 billion. By 2024, this company believes Abbvie’s share of the revenue will be a bit more than $12 billion (which is not much different than today’s figures). If this guess is accurate, that leaves $9 billion for seven or so biosimilar makers. If the guess is very inaccurate, and Abbvie is left with far less revenue because of the competition and falling prices, then any number of adalimumab biosimilar manufacturers could attain more than $1 billion in sales. 

In other biosimilar news…Amgen has announced the filing of a new biosimilar version of infliximab. ABP 710 was the subject of a phase 3 trial in patients with moderate-to-severe rheumatoid arthritis; researchers concluded that the drug was equivalent to Remicade® in terms of efficacy, safety and immunogenicity. Today’s filing would put this biosimilar on a path to a late Q3 or early Q4 2019 decision by the FDA. If approved, ABP 710 would be the fourth infliximab biosimilar approved in the United States (Pfizer’s Inflixi® is also approved but will only be sold overseas).

 

This post was updated and corrected on December 18, 2018.