At an earnings call this week, Pfizer’s CEO highlighted the
impending launches of Ruxience®
not long after the previously announced launch of Zirabev®
(bevacizumab) at the end of this year.
The New York–based pharmaceutical manufacturer plans to
begin marketing Ruxience in January 2020, and Trazimera February 15, 2020. This
would make Pfizer first to market with a Rituxan® competitor. Pfizer
follows Amgen to market with Trazimera, as Kanjinti®
launched in July this year.
On the call, Albert Bourla, PhD, indicated that the
company’s infliximab biosimilar (Inflectra®) had grown 8% for the
third quarter of 2019 over the same quarter in 2018 (to $77 million). Inflectra’s
marketshare in the US still remains below 10%, according to IQVIA.
After coming to a settlement agreement (which may have been
prodded by Amgen’s
launch of Mvasi® in July), Pfizer can launch Zirabev®
at the end of this year.
by Aiden Fry at The Pink Sheet and confirmed
by Kelly Davio at the Center for Biosimilars, the settlement
between Genentech and Pfizer was signed September 19. It clears all remaining
patent suits filed by Genentech (and its parent Roche), and if it follows the
standard terms of previous agreements, pays a license to the maker of the
reference product (Avastin®).
Amgen decided to launch Mvasi at-risk, gaining the advantage
of being the first bevacizumab biosimilar available for prescription. The legal
case brought by Genentech against Amgen hinges less on patent infringement but
more on whether 6-month notice of launch was provided (or needed). The next
step in this case is reportedly a trial sometime in 2020.
At least five other
bevacizumab biosimilars are actively being investigated, but none of these
are likely to be approved in 2020 (none have filed 351[k] applications to
The partnership of Amgen and Allergan made a huge splash in the biosimilar market by announcing the simultaneous US launches of the first two biosimilars of anticancer monoclonal antibodies. The agents Kanjinta® (trastuzumab-anns) and Mvasi® (bevacizumab-awwb) were officially made available July 18.
The move occurred almost simultaneously with a court denial
of Genentech’s request for a restraining
order against Amgen. For Amgen, this marks the first two biosimilars to
The launch discounts associated with these two agents is only 15% off of average wholesale price (AWP), but the manufacturers point out that is still significantly below the average selling price (ASP) of the two reference drugs—13% lower than that for Herceptin® and 12% lower than that for Avastin®. This pricing does not include potential rebates or discounts that could further reduce the net costs of these biosimilars.
The launch timing raises the question of when the
FDA-approved biosimilar competition will be launched. Other biosimilars in the
trastuzumab space have signed
licensing agreements with Genentech, the maker of Herceptin. Their launch
dates have not been disclosed. Several biosimilar makers have also signed
licensing agreements with Genentech on their versions of Avastin, and their
launch dates may be upcoming as well.
Assuming the licensing agreements compel the other
manufacturers to pay some percentage of sales or profits to Genentech, this
could give Amgen/Allergan an automatic edge in profitability. It is unknown
whether the launch timing of Mvasi and Kanjinti, have any implications for the
existing licensing agreements. For example, it may be possible that an early
launch by an unlicensed competitor could negate specific clauses of these
The bevacizumab biosimilar class progress had stagnated
through court proceedings and licensing agreements. In a post from January
2019, we had noted that Amgen had notified the court that it was prepared to
launch as early as
On the trastuzumab side, Amgen/Allergan’s product was the most
recently approved biosimilar (in June 2019).
joint press release, they quoted Paula Schneider, CEO of the Susan G. Komen
Breast Cancer Foundation. “The introduction of biosimilars is an important
step in increasing options for treating HER2-positive breast cancers, which
account for about 25% of all breast cancers,” she said. “As patient
advocates, we are working to ensure that patients are educated about
biosimilars and understand that these FDA-approved treatments are just as
effective as the original biologic drugs.”
Apotex has recently made news in Canada, introducing biosimilars and obtaining marketshare there. However, the story of Apotex and its Apobiologix biosimilar subsidiary in the US is less positive.
As we’ve listed in our updated table, Apotex had originally
filed for approval for its pegfilgrastim biosimilar with the FDA in late 2014
and its filgrastim biosimilar in early 2015. In 2019, no announcement has been
made with regard to the filing status of either biosimilar.
In April 2018, we spoke with Apobiologix executives, who told us that the company “were still in discussions with the FDA” about the path forward for its G-CSF biosimilars. Unfortunately, this statement has not changed at all on its website. If there were discussions, they didn’t go far. And so the mystery continues.
There is some support for the view that the parent company is
seeking to shed the Apobiologix subsidiary, and has been actively seeking a
buyer for some time. This would make sense to a degree, as any of its newly approved
biosimilars would be facing a difficult crawl to US marketshare, being the
third or fourth filgrastim or pegfilgrastim biosimilar to launch. Realizing that its marketshare potential would
be substantially limited, why spend the additional developmental dollars?
In April 2018, Canada had granted the company approval to market its pegfilgrastim biosimilar (Lapelga™), and in Canada’s provincial systems, it has become a dominant player. Filgrastim was approved in Canada in 2016 (and in the EU in 2014).
According to its website, Apobiologix had been developing
the following products for the US market:
Epoetin alfa (reference drug, Epogen®),
in Phase 3
Darbepoetin alfa (Aranesp®), in preclinical
Bevacizumab (Avastin®), in Phase 1
Rituximab (Rituxan®), in Phase 1
Trastuzumab (Herceptin®), in preclinical
Although the pipeline lists the epoetin, bevacizumab, and
rituximab biosimilars in clinical trials, no mention of any of these specific
investigations can be found on www.clinicaltrials.gov, under
Apotex or Apobiologix as a sponsor. A request for comment from Apobiologix was
not answered by the time of this publication.
If this is the case, it is less the FDA than the parent drug maker who has lost faith in their biosimilars’ potential in the US. We can ill afford fewer active players in this market.
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.”
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®).
The biosimilar industry continues to make strange bedfellows. In July 2016, I reported in the Center for Biosimilars that a subsidiary of the Japanese camera maker, Fujifilm, had jumped into the biosimilar field. The Indian pharmaceutical company Biocon announced that it has launched its new insulin glargine biosimilar in Japan. Fujifilm Pharma Co, Ltd was named as the partner in this endeavor to commercialize the product in Japan.
Fujifilm Pharma is a producer of diagnostic and therapeutic radiopharmaceuticals, in addition to contrast media. This makes sense, as the parent is in the imaging business. Medical imaging can be a very natural extension of this activity. But biosimilars?
To reaffirm its strategy, Fujifilm announced a new partnership. Its Fujifilm Kyowa Kirin Biologics subsidiary will manufacture a adalimumab biosimilar in the EU (filed for approval in the EU only) and will be commercialized by Mylan if approved. There is no information about whether Fujifilm will seek authorization to market this biosimilar in the US down the road.
To further its chances of commercializing this biosimilar in the EU, Fujifilm Kyowa Kirin Biologics joined a lawsuit in April 2017 with Samsung Bioepis and its partner Biogen. The lawsuit, filed in the UK, sought to invalidate Abbvie’s two remaining adalimumab patents, and the UK court ruled in favor of the plaintiffs, opening the door to marketing next year in Europe. Fujifilm also has a bevacizumab biosimilar (FKB 238) in phase 3 clinical investigation.
The parent company has over 200 subsidiaries, and it can be complicated to track which ones are directly involved. For example, another Fujifilm company, Fujifilm Diosynth, does contract manufacturing of biologics. Yet, the phase 3 trial being carried out on FKB238 is sponsored by Centus Biotherapeutics Limited, which is a joint venture between Astra Zeneca and Fujifilm Kyowa Kirin Biologics. Centus seems to be involved only with the bevacizumab biosimilar, not with the adalimumab agent. Despite this web of intrigue, Fujifilm is not likely to be overexposed in the biosimilar marketplace. It is also unknown whether their efforts will be affected by the recent difficulties of its partners Biocon and Mylan with getting its pegfilgrastim biosimilar approved. It has been reported that Biocon will also benefit from this latest Mylan collaboration.
A couple of noteworthy pieces of news have emerged from across the pond on the biosimilar front. The first involves progress for Amgen’s application for its bevacizumab biosimilar at the European Medicines Agency (EMA). Its drug evaluation arm, the Committee for Medicinal Products for Human Use, recommended approval of the biosimilar on November 9.
Assuming EMA final approval is received, however, Amgen and Allergan’s cancer treatment agent will not be marketed any time soon. The principal European patent is not set to expire until 2022.
In the US, Mvasi™ was approved by the Food and Drug Administration in September, but its launch is similarly delayed by patent litigation. The main US patents should expire in 2019 (Roche claims to hold 27 enforceable patents). Amgen had filed suit October 6 challenging the validity of the patents in question, but this case may not be heard until late 2018. Amgen has the option of launching “at-risk,” but it has not indicated that it will go this route. Otherwise, the earliest launch may be sometime in 2019.
In other related news…An announcement will be made on November 20 regarding where the EMA will relocate its headquarters as a result of the Brexit. The Agency will need to complete its move by March 31, 2019, when Britain’s divorce from the European Union is finalized.
The Food and Drug Administration announced today the approval of the first biosimilar for Roche’s Avastin®. The approval of Mvasi™ (bevacizumab-awwb) represents the first biosimilar approved in the US for the direct treatment of cancer. Amgen is partnered with Allergan in the development and marketing of the new biosimilar.
Its approved indications include:
Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate. No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
Metastatic renal cell carcinoma, in combination with interferon alfa.
Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
Like Avastin, Mvasi will carry a black box warning involving gastrointestinal perforations, surgery and wound healing problems, and severe or fatal hemorrhage.
The FDA’s Oncology Advisory Committee had unanimously recommended approval of the agent. No announcement was made by Amgen as to pricing or availability of the new product.