In its recent earnings call discussing
fourth-quarter 2019 results, Mylan disclosed that the US Food and Drug
Administration (FDA) accepted its 351(k) application for a potential new bevacizumab
The application was submitted
in the late fourth quarter of last year and was not publicized through Mylan’s
communications department. The agent, MYL-1402O, had been subject to a phase
1 human trial, testing pharmacokinetic and pharmacodynamics similarity to
the reference product with 111 healthy volunteers. A randomized study in
patients with metastatic colorectal cancer was also conducted with an Indian
patient population only, but it is unknown whether this study, which was used
to secure approval in India, was included in the 351(k) submission. According to the company, the submission
package included comprehensive analytical data, which in addition to the clinical
study results, adequately demonstrated biosimilarity with Avastin®.
Another clinical study,
testing the product in patients with stage 4 nonsquamous non–small cell lung
cancer had been registered
in 2016 in Europe, but there is no further information on whether this
investigation was completed.
An FDA decision is expected on or before December 27, 2020. If approved, this agent could be the third or fourth bevacizumab available on the marketplace (depending on the status of Samsung Bioepis’ SB 8, which was filed for approval in November 2019).
In other biosimilar news…In the ongoing patent litigation between Sandoz and Amgen regarding Enbrel®, the case was heard in appeals court on March 4. Sandoz and its parent company Novartis have argued that the remaining patents on Enbrel are “obvious” and should be invalidated by the court, allowing a biosimilar to finally reach the market. In a report by FiercePharma, the majority of judges seem to be less than sympathetic to Sandoz, and this could extend Amgen’s market exclusivity through 2029— giving the reference drug an unprecedented 30 years of marketing protection. Sandoz’s biosimilar agent Erelzi® was approved by the FDA in 2016.
Innovent Biologics (Suzhou) Co.,
Ltd., based in China, signed an agreement
on January 13, 2020 that allows Coherus Biosciences to commercialize its
bevacizumab biosimilar when approved by Canadian and American regulators. The
investigational agent is known as IB1305 at present.
Recently completing a phase 3 trial with Chinese patients,
Innovent will need to gather the necessarily analytic comparison data for US
approval. In its press release, Coherus believes that an FDA submission could
be possible in late 2020 or early 2021, based on the Chinese data.
A phase 1 study was listed in ClinicalTrials.gov,
which had an estimated completion date of 2017, but there has not been an
update to this information. Coherus stated that “The Company anticipates
completing a single dose pharmacokinetic clinical study and certain
analytical/bioanalytical exercises to support the U.S. filing.” This could mean
that a new phase 1 study will be undertaken. Coherus also indicated that it
will handle the biologic licensing application process in the US and subsequent
marketing in the US and Canada.
Additionally, the press release announced that Innovent’s
biosimilar rituximab candidate (IB1301) may also be part of this deal. In June
2019, Innovent filed for approval with the Chinese drug regulatory authorities.
According to the terms of the agreement, Coherus has an option to commercialize
this agent in North America. IB1301 has been subject to oncology testing in
China patients (not to treat autoimmune disorders).
This agreement is significant for Coherus, which is trying
to build upon its success in launching the pegfilgrastim biosimilar Udenyca®
in the US. Innovent’s biosimilars represent a new oncology pipeline
for Coherus in the US and Canada, which already includes two
anti-TNF inhibitors (adalimumab and etanercept), and two ophthalmology
biosimilars (although aflibercept is still in preclinical development).
On November 19, Samsung Bioepis announced
that the Food and Drug Administration (FDA) had accepted its 351(k) application
for its bevacizumab biosimilar SB8. This would be the company’s second biosimilar
submission for treating cancer.
Samsung’s trastuzumab biosimilar was approved early in 2019, and it awaits marketing in a crowded market. SB8 would compete with the reference product Avastin® and two approved biosimilars (so far).
The biologic licensing application is supported by a
phase 3 clinical trial of the agent in nonsquamous non–small cell lung
cancer, in which patients received either the biosimilar or reference product
in addition to paclitaxel and carboplatin. The trial resulted in no clinically
relevant outcomes differences between patient groups.
If approved, SB8 would be marketed by Merck in the US. An
FDA decision is expected in Q4 2020.
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®).