On December 6, 2019, the US Food and Drug Administration
(FDA) gave Amgen its approval
to market the fourth biosimilar infliximab medicine.
Dubbed Avasola (infliximab-axxq), a launch date was not
announced, but one can assume that Amgen intends to launch this agent as soon
as possible. This infliximab biosimilar was approved for all of the autoimmune
indications of the reference product Remicade®.
Avasola will be the third infliximab biosimilar agent to be
marketed, as Pfizer’s Ixifi®, though approved, is not sold in the
US, as it would compete directly with another Pfizer-marketed biosimilar
(Inflectra®). Pricing for the Avasola was not yet available.
Avasola was approved based on
clinical studies involving patients with inflammatory bowel disease, rheumatoid
arthritis, and other indicated conditions (over 4,800 patients taking the drug),
including a phase 3 investigation pitting the biosimilar against the reference
product in patients with rheumatoid arthritis.
The US market for infliximab
is shrinking somewhat, based on falling sales numbers caused by biosimilar
competition and prescriptions lost to other biologics. According to Johnson &
Johnson, parent of Remicade’s manufacturer (Janssen Biotech), US
revenues shrank 24% (to $1.14 billion) in the third quarter of 2019
compared with the same quarter of 2018.
The Institute for Clinical and Economic Review (ICER) released a report this week that highlighted seven pharmaceuticals with “substantial price increases on top of already high current spending.” According to ICER, these seven agents accounted for billions in unnecessary expense in 2017 and 2018. AbbVie’s Humira® and Genentech’s Rituxan® topped the list, with Neulasta® coming in at number 5. The first two are not that surprising, because relatively high price increases (even net rebates or other considerations) are common reactions of pharma companies to imminent new competition. This has been typical for small molecule brands facing patent expiration and generic challenges. In 2017 and 2018, AbbVie may have been more concerned that it could not reach a settlement with the several biosimilar manufacturers working on adalimumab agents. Genentech also faced similar conditions with Rituxan. On the other hand, Amgen was already facing strong competition from Zarxio® and Granix®.
ICER specified, “Net price increases for the seven drugs unsupported by new evidence were responsible for increasing total US drug spending by more than $5.1 billion from 2017 to 2018. The drug whose price increases accounted for the greatest single impact on spending was Humira. Humira’s average US price increased 15.9% over this period.” I emphasize, this was net price not list price increases.
In a presentation at the Drug Information Association (DIA) annual meeting, Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research, stated that 83 biosimilar development programs were now ongoing, for a total of 38 different biologics. This implies that biosimilar interest in several new classes of biologics remains strong from established and prospective manufacturers.
Tanvex BioPharma announced in late September that its TX-01 filgrastim biosimilar candidate was not approved by the FDA. According to Tanvex, the FDA’s complete response letter did not cite any data deficiencies that might require additional studies. This leads one to suspect that production facilities problems may be the issue. The soonest Tanvex can expect a new FDA decision is 6 months from its new application submission date. As a result, Zarxio® and Nevistym® remain the only two biosimilar filgrastim agents (plus the follow-on product Granix®) to compete with Amgen’s Neupogen.
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.
First reported
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
date).
Imagine this interesting and perhaps very real-life scenario.
It could have several implications for the present biosimilar marketing
picture.
A reference manufacturer, we’ll call them Arby, signs
multiple licensing deals with biosimilar manufacturers, to launch their
products sequentially in 2025. The licensing deals all conclude outstanding
patent litigation between the parties. But one biosimilar manufacturer doesn’t
sign. We’ll call them Brooklyn Industries (BI for short).
Despite Arby’s contention that its patents on the reference
product Yultira are valid until the year 2045, BI decides to launch at risk in July
2020. According to the phased launch schedule, another manufacturer, Thousand
Oaks, was supposed to have the first biosimilar available on the market, with a
three-month jump on the other seven competitors. Does that really give BI a
five-year start over all of its competitors? And what if BI had an
interchangeable biosimilar designation? Would that enable them to lock up the
marketshare?
Biosimilar Licensing
Deals: The Acceleration Effect
This scenario is actually playing out today with Amgen’s
launch announcement of its trastuzumab and bevacizumab biosimilars (Kanjinti®
and Mvasi®, respectively). Other manufacturers, including Pfizer,
Samsung Bioepis, Mylan/Biocon, Teva/Celltrion have licensing agreements in
place with Genentech (a subsidiary of Roche) for launch of their Herceptin®
biosimilars. Only Amgen’s Mvasi and Pfizer’s Zirabev® are approved (so
far) to compete for the bevacizumab business. The details of the licensing
deals signed by Roche have not been released publicly, so we do not know when
the first “authorized” biosimilars were supposed to launch. Conjecture abounded
that it would be in 2019, nevertheless.
How does Amgen’s Kanjinti launch affect the licensing agreements
that were signed with Roche? Does it mean that Amgen gets a substantial head start
on the competition? Do the licensing contracts consider this possibility?
According to Kevin M. Nelson, JD, at the Chicago-based law firm Schiff Hardin, this scenario is considered in a typical pharmaceutical licensing arrangement. “Typically, settlement agreements in the pharma space include what are called acceleration clauses. Such clauses will allow an agreed-upon launch date to be accelerated to an earlier date in the event the patent or patents are invalidated or found not infringed in another litigation, or if a competing product or authorized competing product comes on the market before that agreed-upon date.”
Kevin M. Nelson, JD
He added that these acceleration provisions “can come in a variety of flavors from a change in royalty rate or structure, a requirement to leave the market if the ‘unauthorized entrant’ leaves the market, or perhaps agreed damages.”
Accelerating Clauses Are One Thing. Accelerating Launch Is Another Matter
The
fact that Amgen has announced its immediate launch may present more pragmatic
problems for the other manufacturers, Mr. Nelson pointed out. Let’s say that
you were a member of the Mylan/Biocon team. Your product was approved more than
18 months ago (the first one approved). Let’s also say that your licensing
agreement with Genentech allowed you to launch after November 1 (a purely
speculative, arbitrary date). Finally, assume that your licensing agreement was
generous: it allowed you to launch as soon as possible after another competitor
jumped the starter’s gun. Is it feasible to launch immediately, perhaps four months
early?
“The biosimilar companies cannot just fire up the machines and have product ready tomorrow,” stated Mr. Nelson. There are all of the logistical issues surrounding a launch that must be considered: “Manufacturing, packaging, sales, and distribution all take time,” he said. “And you don’t want inventory to go bad—especially not this type as it is expensive. They may have some reserve lots or made small batches just in case, so we could see a trickle into the market.”
Remember,
also, that payer and health system contracts are not arrived at overnight. Even
if the Mylan/Biocon team did have lots available for shipment, they might not
have places in the US to ship, other than to a group purchasing organization or
distributor’s warehouse.
Typically,
payers will not cover pharmaceutical agents outside of medical exceptions
before the Pharmacy & Therapeutics Committee review, and this can happen anytime
between 60 days and 9 months of the launch. And this is not a product that will
revolutionize therapy or immediately fill an unmet clinical need. Only large
discounts can move the needle here, and establish a contract quickly. Therefore,
the anticipated short window of opportunity that Amgen may have in launching
Kanjinti may get a little shorter but perhaps by not much.
When I mentioned the Arby, er Abbvie, scenario, Mr. Nelson agreed that it would be an entirely different ballgame. Had Boehringer Ingelheim decided to enter the market (as an interchangeable or not), their launch “would have caused absolute chaos.” Imagine trying to pull forward launch date plans of seven manufacturers by three years!
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
reach commercialization.
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
contracts.
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
April 2018.
On the trastuzumab side, Amgen/Allergan’s product was the most
recently approved biosimilar (in June 2019).
In their
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.”
On occasion, we profile some biosimilar manufacturers about whom our readers may not be as familiar as the large players like Sandoz, Amgen, and Pfizer. 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 updated post, we highlight a German company, Formycon AG, which has eyes on the US marketplace.
Formycon
acquired Scil Technology GmbH in 2012, and hired a new CEO the following year.
Carsten Brockmeyer, PhD, has extensive experience in the biosimilar field,
previously helping Hexal Biotech to develop EPO and filgrastim biosimilars for
the European market.
Why
you may be hearing more about this company: Formycon has two principal
biosimilar targets, ranibizumab and ustekinumab. The company disclosed
that “it successfully completed a Type IV
pre-submission meeting with the US Food and Drug Administration (FDA) in
December 2018 and clarified other pivotal issues. The filing with the FDA
for the approval of FYB201 is expected at the beginning of the fourth quarter
of this year.” A filing for the European Medicines Agency is planned for 2020. A phase 3 clinical trial of
this agent was completed in June 2018. In the development of this agent,
Formycon partnered with Bioeq GmbH, but it is unclear whether a marketing
partner exists for a possible US launch.
The patent for ustekinumab (Stelara®) expires in 2023 (US) and 2024 (Europe). It is partnered with Aristo Pharma GmbH on the manufacture and testing of this interleukin 12/23 inhibitor (also known as FYB 202).
Formycon is
in the early stages of developing a phase 3 trial for its biosimilar version of
Eylea® (aflibercept or FYB 203), the next generation of macular
degeneration treatment. It is partnered with Santo Holding GmbH on the
development of aflibercept.
In other biosimilar news… Amgen decided to pull its EMA application for its infliximab biosimilar, likely due to market competition. The company has not taken similar action with regard to an FDA application for the same product, ABP 710. Considering that neither Samsung Bioepis or Pfizer failed to gain traction in the US marketplace for infliximab, Amgen must think that some biosimilar infliximab marketshare growth in the US is still possible.
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
Recurrent glioblastoma
Metastatic renal cell carcinoma
Metastatic cervical cancer
This approval does not include ovarian cancer, which is an
additional indication for Avastin. Belonging to a class of biologics called
vascular endothelial growth factor (VEGF) inhibitors, these agents work by
preventing new development of a tumor’s blood vessels, helping to choke off growth.
Zirabev’s approval marks the 21st FDA approved biosimilar
agent and the second approval for a bevacizumab biosimilar. Mvasi®,
to be manufactured by the partnership of Amgen and Allergan, obtained approval
in September 2017. However, this product is not yet marketed.
At a recent annual meeting of the Academy of Managed Care Pharmacy,
a specialty
drug pipeline expert expressed hope that Mvasi would be launched in July of
this year. Its manufacturer has been embroiled in patent litigation with Roche,
but the key patents are expected to expire in the immediate future.
Pfizer has not announced a launch date for Zirabev. Yet, it
could be the second cancer-treating biosimilar category to enter competition (with
Herceptin
biosimilars) very shortly.
Five trastuzumab biosimilars have been approved for
marketing in the US, and the composition-of-matter patent for the reference
product, Herceptin®, expires June 30, 2019. That doesn’t mean we’ll
see a jail break of competition, like that seen in the EU last October with
adalimumab’s patent expiration. Yet there has been heavy interest in capturing
a slice of Herceptin’s $2.9
billion US sales (in 2018).
Three manufacturers have signed licensing agreements with
Genentech (subsidiary of Roche). In March 2017, Mylan signed the first
agreement for its product Ogivri®.
Its marketing partner is Biocon. In December 2018, Pfizer
followed suit for its recently approved agent Trazimera®.
None of the parties have indicated when a biosimilar agent will be launched. At
the end of December, Celltrion and Teva came to a similar agreement on its
Herzuma® biosimilar.
According to Goodwin’s Big Molecule Watch, Roche’s infringement
claims against Samsung Bioepis (Ontrusant®) and Amgen/Allergan (Kanjinti®)
are still being litigated. For Genentech v. Samsung, the bench
trial is slated to begin December 9, 2019. In addition, Samsung Bioepis is appealing
the Patent Trial and Appeals Board ruling regarding the validity of Herceptin’s
method of use patents. Separately, Genentech is challenging the PTAB’s decision
that two other Herceptin patents were invalid. There’s a whole lot here that
needs to be resolved (or settled).
In the case of Amgen and Allergan, Genentech originally
brought suit claiming 38 patents were infringed (in June 2018). In July 2018,
Genentech reduced this figure to less than half (17). A month later, Amgen responded
to the suit. Little information is available on timing of next steps.
Based on this information, it is difficult to know just when
the first trastuzumab biosimilars will be launched. If Genentech followed
Abbvie’s example in its 2023 sequencing of adalimumab biosimilars, one might
expect Mylan’s product to be available first, perhaps as early as this summer,
with Pfizer’s and Celltrion to follow perhaps six months later.
Yet, unlike the Abbvie agreements, none of the Genentech licensing
settlements were made public (other than the actual dates of the agreement). Keep
in mind, Herceptin was first approved by the FDA in October
1998. In 2018, the drug’s sales in the US and EU combined was over $4.7
billion. Is 21 years of market exclusivity to anyone’s benefit, other than the
manufacturer? Since
2006, US drug sales of Herceptin have been greater than $1 billion
annually.
If the biosimilar launches do not occur shortly, this may be a good test
case of the Federal Trade Commission’s commitment to clearing patents in the
name of competition.
Only Boehringer Ingelheim remains as a biosimilar maker who
has an approved version of adalimumab but who has not signed on with AbbVie.
United Food and Commercial Workers Local 1500 has filed the suit with the other
manufacturers and AbbVie, claiming that by their actions, they are trying to “divide
the market for adalimumab between Europe and the United States,” according to
the Center for Biosimilars report.
This is an interesting question. The individual motivations of the first companies to come to agreement with AbbVie (Amgen, then Samsung Bioepis) included an end to interminable patent legislation in the US. They wanted the ability to immediately plan launches in Europe (starting in October 2018). The motivations of most other subsequent signees almost certainly was to not forfeit marketshare in Europe, which was needed to help sustain biosimilar development efforts for the US market. In fact, many of these prospective US manufacturers already had received approval in the EU.
AbbVie’s principal patents on Humira® expired in Europe in October 2018. The last of the principal patents are supposed to expire around 2023 in the US anyway. Was it necessary to arrange serial US launches as demonstrated in this link? Would patent litigation have continued well past the supposed patent expiration date? Knowing AbbVie, this is likely. Their several patents involving adalimumab use to treat individual diseases would provide AbbVie a basis for forging ahead with lawsuits that would have gained them additional billions of dollars in sales while the suits meandered toward conclusion.
Does this mean that access to Humira is accelerated through the signing of the royalty agreements, rather than delayed through acts of collusion? That is difficult to say. Although should the lone holdout—Boehringer Ingelheim—decide that it makes business sense to launch at risk, it could topple the carefully orchestrated structure of the agreements. Amgen believes that it will launch the first adalimumab biosimilar, and experience a few months of exclusivity in the US. At that point, Amgen (and every subsequent adalimumab biosimilar maker) would have to decide whether (1) to do the same or risk losing its advantage, (2) start working towards marketing plan B, or (3) cede the initial marketshare and its billions in revenue and wait it out. If Boehringer obtains its sought after interchangeability designation, that may well speed up the process.
Personally, I find it hard to believe that these individual
acts represent premeditated collusion; although the resulting lack of access to
the many biosimilar versions may look to others as an orchestrated maneuver.
Doug Long, Vice
President of Industry Relations at IQVIA (formerly QuintilesIMS), spoke with us
about some of the intracacies of the filgrastim and pegfilgrastim marketplace,
and regarding improving access to biosimilars in general.
Doug Long, IQVIA
BR&R: Do you
think interest by manufacturers in biosimilars is gaining or waning at this
time?
Doug Long: It’s
somewhere in between those two. A lot of people are staying in the game to see
how it plays out. Maybe discouraged most
accurately describes their feelings at this time. They are discouraged, because
there are 17 approved products but only 5 are available. And the uptake of
those on the market is not that great, particularly compared with the uptake in
Europe.
BR&R: I can
see how manufacturers and payers would be discouraged right now. You’re right,
in the European market, we’ve seen a great deal of uptake and significant
discounting as well. So many factors affect biosimilar coverage and uptake. It may
also relate to the individual biosimilar’s disparate marketplace situations.
DISTINCT MARKETS FOR
BIOSIMILAR DRUGS
In the US, based on the utilization numbers seen today, do
you believe the infliximab, filgrastim, or pegfilgrastim markets will best
characterize how other biosimilars (e.g., Avastin® or Herceptin) will
perform when available?
Long: Well, with
the filgrastim molecule, you need to look at both filgrastim and pegfilgrastim,
and their routes of administration (prefilled syringes and on-body injectors).
Granix® and Zarxio® have the majority of the dollar share
on the filgrastim side. It’s too early to tell on the pegfilgrastim side,
though Amgen has a 61% share of that Neulasta® molecule with its
Onpro® formulation. The addressable market for the molecule is
really only the remaining 39%.
You also have to make a distinction between how much of the
market is controlled by the pharmacy benefit managers compared with the hospital
group purchasing organizations (GPOs) or buying groups. Most of the filgrastim
and pegfilgrastim is controlled by the hospital buying groups, and that’s also
going to be the case for the cancer-treating biosimilars. There’s no doubt in
my mind that when Humira® or Enbrel® are available, the
PBMs will embrace the biosimilars. There are just so more complexities on the
hospital side of the market that it makes it more difficult for them to move
towards the biosimilars.
DEEPER INTO THE
FILGRASTIM/PEGFILGRASTIM SCENARIOS
BR&R: There’s
an interesting situation brewing in the filgrastim market. The success of Granix
and really Sandoz’s Zarxio penetrating the market has contributed significantly
to the drop in total sales revenues for filgrastim sales combined. However, how
much of this decrease is attributable to migration to pegfilgrastim, and Neulasta
Onpro in particular?
Long: Sure, look
at their revenues today. Filgrastim is at $611 million in annual sales and
pegfilgrastim is at $4.3 billion. Of that $4.3 billion, Onpro accounts for 61%.
BR&R: At
Coherus’ fourth-quarter earnings conference call, their CEO indicated that he
thought the Onpro marketshare might be vulnerable to the pegfilgrastim biosimilar,
which is available today in prefilled syringes. Obviously, that would mean
selling Undenyca® at a more enticing price, below the 33% discount
currently offered. Do you think that Onpro sales erosion is likely or does the
formulation offer real value?
Long: That could
work, but the thing about Onpro is that when you finish your chemotherapy for
the week, they put the injector on you and you don’t have to go back to the
doctor’s office for a pegfilgrastim injection the next day. That’s one of the
reasons it is as popular as it is—it reduces hospital and doctor expenses at
the end of the day, and is more convenient for the patient.
BR&R: Biosimilar
manufacturers like Coherus have expressed interest in developing its own
on-body injector for its biosimilar. It seems to present distinct advantages. Does
that mean that the biosimilars will be relegated to fighting only for that
prefilled syringe market, the remaining 39% of utilization?
Long: It’s
probably too early to say. Fulphilia® has only been marketed since
July, and the other one [Udenyca] was launched only recently. We’ll have to see
what kind of uptake it gets. Also, we’ll have to see what happens when other
players come to the market. The more drugs you have available, the more share
erosion from the originator you’ll likely see. Yet that did not happen with
Remicade…
BR&R: That
may be more of a special situation, considering the actions taken by Janssen
Biotech to prevent coverage of both Pfizer and Merck’s products.
The filgrastim/pegfilgrastim markets are also different for
that reason: Amgen did not aggressively defend their market share on the
prefilled syringe originator products (i.e., Neupogen® and
Neulasta). Rather, they focused on getting conversions to Onpro. So the
biosimilar manufacturers were not facing aggressive defensive tactics, like those
employed by Janssen.
Long: Yes, but
they will defend Onpro as much as they can.
BR&R: And
Amgen established Neulasta and the Onpro formulation at the same price point.
Long: It made
sense. It was a good defense mechanism.
BR&R: It does
force the biosimilar manufacturers to work harder to gain business.
AN UNCLEAR FUTURE
BR&R: The
Administration has several initiatives that may directly or tangentially affect
the biosimilar market. These include the Medicare International Pricing Index,
the move to place Part B drugs into Part D (and allow step therapy and other UM
tools), the reevaluation of drug rebate safe harbors, and of course, the
individual components of the Biosimilar Action Plan. Do you think this will
ultimately result in artificial price deflation? Would that be helpful or
harmful to biosimilar makers?
Long: That’s a
question that I really don’t have an answer for. Who knows what’s going to
happen? People have started to make moves to reduce WAC prices, like Amgen on their
PCSK9 inhibitor and Gilead on their hepatitis C treatment. Gilead created an
“authorized generic” to reduce its price dramatically.
People are starting to play around with it. Maybe to get
adopted, a biosimilar maker may actually have to raise their drug’s WAC price
higher than the originator, and then give a larger rebate.
