When Pfizer announced its intention just more than a week ago to begin marketing its rituximab biosimilar Ruxience® in January 2020, industry watchers wondered when we might hear a response from its sole approved competitor. The wait was over quickly: Teva and Celltrion will begin shipping their own rituximab biosimilar Truxima® on November 11.
Truxima was approved in October 2018 for the cancer indications of Genentech’s reference product Rituxan®. In a joint press release issued by both companies, Brendan O’Grady, Teva’s Executive Vice President and Head of North America Commercial Operations, stated, “We are excited about the first FDA-approved biosimilar to rituximab in the US. Teva’s commitment to biosimilars is focused on the potential to create lower healthcare costs and increased price competition. This focus is consistent with Teva’s mission of making accessible medications to help improve the lives of patients.”
The press release also mentioned a key detail of the partners’ patent settlement with Genentech. Specifically, Celltrion and Teva will be able to market the autoimmune indications (rheumatoid arthritis, granulomatosis, with polyangiitis, and microscopic polyangiitis) in the second quarter of 2020, assuming they receive approval from the Food and Drug Administration for the broader indications. Ruxience is not currently indicated for these same autoimmune disorders.
The partners announced that the wholesale acquisition cost (WAC) for
Truxima will be just 10% below that for Rituxan, which will be subject to
further discounts and rebates negotiated with individual payers. That
works out to a WAC of $845.55 for 100 mg vial (or $4227.75 for 500 mg vial).
Teva will be responsible for marketing Truxima in the US.
Pfizer has not yet announced their intended WAC for Ruxience’s launch in January.
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™
The approval for Hadlima covers the following indications:
Juvenile idiopathic arthritis
Crohn’s disease in adults
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.
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.
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®.
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
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,
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
biosimilars) very shortly.
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
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
2006, US drug sales of Herceptin have been greater than $1 billion
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.
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%
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.
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 HER2–positive 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.
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,
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.
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.”
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
In other biosimilar news… A January 10 story in The Pink Sheetreported 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).
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
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
(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).
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.
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
billion worldwide in sales in 2017.
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
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.
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
In other biosimilars
news…Sandoz seems to be entering the biosimilar insulin marketplace, with
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®).