The US Food and Drug Administration (FDA) announced on January 18, 2019 the approval of a new biosimilar version of trastuzumab. Produced by Samsung Bioepis, this agent was dubbed Ontruzant (trastuzumab-dttb).
This is the third trastuzumab biosimilar approved by the FDA, following those by Mylan and Biocon in December 2017 (Ogivri®) and Teva and Celltrion last month (Herzuma®). As with biosimilars other than Herzuma and the reference biologic Herceptin®, this agent is approved for use in the treatment of HER2-overexpressing breast cancer and the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Herzuma is not approved for the latter indication.
As with Renflexis®, Samsung Bioepis’ first FDA-approved
biosimilar, Merck will market the product in the US when launched. No launch
date has yet been revealed.
Mylan and Biocon had signed a licensing agreement with
Roche, the manufacturer of Herceptin, which ended their patent fight, but which
delayed launch. Teva and Celltrion have not yet disclosed whether a similar
deal has been reached with Roche. Pfizer has an investigational trastuzumab
biosimilar, and they too have signed
a licensing agreement with Roche.
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.
Go big or go home, seems to be the message of Coherus’ President Dennis Lanfear. At the JP Morgan Investor Conference yesterday in San Francisco, he outlined what he considers a “full-on branded launch” for the biosimilar maker’s key product. Udenyca was officially launched on January 3.
In preparation for the launch of Udenyca, Coherus Bioscience
$75 million in financing to shore up its cash position and to support its
The First Payer Deal
More than half of the current pegfilgrastim claims are reimbursed
by commercial payers, with Medicare accounting for an additional one-third. Mr.
Lanfear announced a couple of important payer developments that should benefit
sales immediately. He said that Coherus “inked a deal with Anthem Blue Cross
Blue Shield last week,” but did not elaborate on the terms. Although he alluded
to a press release on Coherus’ website, none had been posted at the time of
this writing. He also mentioned that Aetna and Blue Cross Blue Shield of South
Carolina had independently begun “requesting Neulasta users to step through
Fulphila or Udenyca before filling those claims.”
The group purchasing organization (GPO) market “is highly
focused,” said Mr. Lanfear. “About a dozen players account for 95% of the
market. 340B hospitals represents around $963 billion in annual revenue.
Vizient accounted for $824 million in Neulasta sales last year (about 35% of
the non-340B market), and welcomed us to the market.”
Greatest Pegfilgrastim Market Opportunities
He believes, “Biosimilars with pass-through status can
provide significant value in non-340B settings. They may be the lowest price
side of the market, but most motivated.” According to Mr. Lanfear, these facilities’
efforts at cost recovery is expected to drive the market.
Udenyca and Fulphila are priced
identically at $4,175 or at a 33% discount to Neulasta Udenyca’s 33% WAC
discount per syringe to avoid payer disincentives. Specifically, after discounting
and rebates, Amgen’s ASP for Neulasta was $4,422, which gives the payer an
immediate ASP discount. In previous biosimilar launches, their manufacturers’ smaller
discounts had actually resulted in higher ASP costs than the reference
product. In those cases, payers were reluctant to encourage biosimilar use, at
least until the biosimilar had sufficient time in the marketplace where its own
ASP could be calculated. “Having our unique HCPCS code results in an ability to
control our own ASP,” said Mr. Lanfear. This is the direct result of the
current administration’s efforts to fix the original
Further, he believes that Coherus can take advantage of
Udenyca’s reimbursement opportunity in the buy-and-bill sector. At present, Neulasta
is reimbursed at ASP – 22.5%. [Non-340b] pass-through status will be designated
in April 1, 2019, and Udenyca will be reimbursed at ASP + 6% for at least 2
years from that date. (Fulphila currently has pass-through status). This
prevents biosimilars from being disadvantaged from the provider perspective.
A National and
Regional Sales Structure
To support the new launch, Coherus has created a formidable
sales force and structure, including:
67 Oncology account managers
7 Regional sales directors
7 Key account directors
7 Field reimbursement specialists
7 Medical science liaisons
3 Group purchasing directors
4 Payer directors
Mr. Lanfear believes that creation of this extensive sales organization has not been done before with a biosimilar. And he emphasized that they expect to leverage this salesforce infrastructure for its pipeline products, including biosimilar adalimumab, biosimilar ranibizumab, biosimilar aflibercept, and a small-molecule treatment for nonalcoholic steatohepatitis (NASH).
Coherus has ramped up its production, to be able to handle
demand from all its customers, and it has used the LASH Group to develop the Coherus COMPLETE support site for
patients and providers.
Coherus’ plan for a “branded-type” launch for its biosimilar
pegfilgrastim seems to afford benefits in pricing, sales, supply, and services.
We await news of their progress.
The assets of biosimilar drug developer Adello Biologics
were sold to Kashiv Pharma, LLC, the companies announced on January 4, 2019.
The new company will now be known as Kashiv Biosciences, with its headquarters
in Bridgewater, New Jersey.
Adello Biologics had been one of a handful of “pure-play”
biosimilar companies, in that it was not involved with any other pharmaceutical
sectors. Its two biosimilar products in most advanced development (filgrastim and
pegfilgrastim) would be subject to heavy competition if approved. The
acquisition by Kashiv now broadens the pipeline. In a press release, Kashiv cited “As a
result of the acquisition, Kashiv BioSciences’ broad business offering includes
drug delivery platforms incorporating delayed-release technology and gastric
retention systems that improve the efficacy and safety of known drugs; a
505(b)(2) pipeline of seven development products targeting unmet clinical needs.”
It does not appear that any of the 505(b)(2) agents are currently being evaluated
for approval by the FDA.
A privately held company, it had been known as Therapeutic
Proteins International since November 2016. Adello filed for Food and Drug
Administration (FDA) approval for its filgrastim biosimilar in September 2017, with
a decision expected in the third quarter of 2018. The delay in approval lends
speculation to the possibility that FDA issued a complete response letter to
the company. This filing was based on the submission
of phase 1 data only. In March 2018, Amgen filed a lawsuit against Adello
in New Jersey District Court, claiming
patent violations and that Adello failed to follow the necessary biosimilar
development protocol outlined by law.
The company’s pegfilgrastim biosimilar (TPI-120) had completed two phase 1 studies by the beginning of 2018, and it was hoped that the company would submit its FDA 351(k) application before the end of the year. Executive Vice President & Chief Business Officer Pavan Handa confirmed in an E-mail that the pegfilgrastim program “is in active development and we continue to make significant progress towards a filing. ”
Adello’s journey highlights the potential financial problems
that biosimilar-focused companies may face. As a privately owned company, its
capitalization was likely limited, and delays in reaching the market become even
more critical for companies without other revenue-generating products. The deal
with Kashiv breathes new life into the enterprise, but Kashiv, too, does not yet
have an approved biosimilar product (nor approved innovative drugs) to its
credit. Before the acquisition, Kashiv had focused on
“applying novel technologies to
improve the delivery of compounds with otherwise problematic physical and/or
chemical properties” and on abuse-deterrent technologies for opioid
It appears to us that the purchase of Adello by Kashiv, another private company, is an effort at doubling down, to attain more immediate revenue from drug sales.
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®).
You’ve heard the expression, “throwing the baby out with the bath water.” It refers to the problem of unintended consequences of our actions.
On December 14, Texas District Court Judge Reed O’Connor decided that when he ruled that the individual mandate of the Patient Protection and Affordable Care Act (ACA) is unconstitutional, the entire Act is also invalid. If affirmed, this doomsday scenario may well mean that all of the provisions of the Act are to be repealed.
One crucial piece of legislation incorporated into the ACA is the BPCIA—the Biologics Price Competition and Innovation Act, on which the biosimilar regulatory pathway is founded. Yes, if the appeals are upheld and the US Supreme Court affirms the decision, the last 7 years of progress made in creating a competitive environment for biosimilars could be jeopardized.
SEVERAL PROGRAMS AT RISK, INCLUDING BIOSIMILAR REGULATIONS
President Trump has stated to reporters that he was happy with the decision of the Texas District Court and hopes that the Supreme Court will not overturn it. His perspective might be different if he thought through the full implications of the action. The repeal will directly affect the 17 million people who receive their health insurance through the ACA, either through the exchanges or expansion of state Medicaid programs.
The unintended consequences of a full repeal of the ACA without any comparable replacement will affect not only work done in biosimilar development and regulation in the US, but also by the Centers for Medicare and Medicaid Innovation (i.e., accountable care organizations and value-based contracting) but closing the Medicare part D coverage gap, the Patient-Centered Outcomes Research Institute (to conduct comparative-effectiveness research), and work done to advance prevention in public health.
In fact, many of the provisions of the ACA are supported by broad consensus. For one, discriminating against people with preexisting conditions, through either exclusions or higher rates. Although the Republicans have not credibly defended this concept by their past actions, they do profess to believe in it.
The potential benefits of a value-based health system is another area where all political parties seem to agree. Hope springs eternal that outcomes-based payments, reimbursements that include shared savings, and bundled or global contracts will improve our care quality and efficiency.
A CONSENSUS ON THE BIOSIMILAR PRESENT AND THE BIOSIMILAR PROMISE
Those who understand the intent of the BPCIA believes that it will result in significantly lower drug costs, at least in the long term. A spokesperson for the Association for Affordable Medicines told BR&R in an E-mail, “As Congress and the Courts respond to last week’s ruling, it’s important to remember that the biosimilars pathway remains one of the least controversial aspects of the Affordable Care Act. All stakeholders agree on the need to maintain this critical aspect of the law. Without it, patient access to biosimilar medicines would be jeopardized.”
Just last week, the trade association America’s Health Insurance Plans applauded the Trump administration for releasing draft guidances that begin moving transitional drugs to biosimilar status in 2020 and for its efforts to reduce biologic drug pricing in general.
Of course, a number of reasonable scenarios may yet occur to prevent the loss of our baby. The Texas District Court ruling may be overturned on appeal, the Supreme Court may overturn it outright, or the Supreme Court may apply it specifically to the individual mandate (allowing all other ACA provisions to remain). The process has already begun—attorneys general from 17 states filed on December 17 for an expedited appeal by the Fifth Circuit Court of Appeals.
The Trump administration has staked much on its promises to improve drug access and lower pharmaceutical costs. However, the President’s positive comments on District Court ruling directly conflict with the actions of the Department of Health and Human Services (e.g., Secretary Alex Azar and FDA Commissioner Scott Gottlieb).
If the worst-case scenario comes true, which I personally believe is unlikely, will new legislation have to be proposed and enacted to preserve our ability to evaluate and approve biosimilar agents? Will the FDA be prohibited, in the meantime, from progressing with existing biosimilar drug reviews? These questions must be considered, because our ideas of what is realistic are being sorely tested. This baby’s health must be protected from this ruling’s unintended consequences.
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.
Pfizer 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.
On December 14, the US Food and Drug Administration gave its approval for a new trastuzumab biosimilar (Herzuma™). Manufactured by Celltrion and marketed in the US by Teva, this agent has been designated trastuzumab-pkrb.
Herzuma was approved for a single indication: the treatment of HER2-overexpressing breast cancer. Unlike the other trastuzumab biosimilar, Ogivri®, and Herceptin, Herzuma does not carry the extrapolated indication for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
Originally submitted for approval by Celltrion in July 2017, the FDA issued a complete response letter because of plant manufacturing issues. A year later, after addressing these problems, Celltrion refiled its 351(k) application (June 2018).
Celltrion has launched Herzuma in Europe and elsewhere with marketing partners other than Teva. Neither Celltrion or Teva have announced at this time when the US launch may occur or how it will be priced. Partners Mylan and Biocon, makers of Ogivri, and Pfizer, the manufacturer of a potential competitor, have signed licensing agreements with Roche, makers of the reference product to delay launch.