On January 2, 2020, Spectrum Pharmaceuticals announced that the FDA had accepted its 351(a) application for a novel granulocyte colony-stimulating factor (G-CSF), eflapegrastim. And no, the name is not misspelled here; the name is a close cousin of pegfilgrastim.
As reported in 2018 by the Center
for Biosimilars, this agent showed promise versus pegfilgrastim. As with
the pegfilgrastim biosimilars, the road to approval for Spectrum has been
bumpy. The manufacturer decided to withdraw its original application for
approval in 2019 after FDA required more information on manufacturing of the
Not a follow-on agent or a biosimilar, eflapegrastim is
intended to be introduced as a new innovative brand. As the early results
hinted at somewhat greater potency than Neulasta®, the current
application cites clinical data that supports noninferiority of eflapegrastim to Neulasta in terms of preventing
febrile neutropenia. The study
objective was to demonstrate noninferiority, not superiority. The phase 3
RECOVER investigation also found no significant differences in terms of safety
between the agents.
One might ask, what’s the point of this product if it isn’t
an improvement over pegfilgrastim? Well, it may be proven to be superior in
some future study (though no further comparator investigations are currently
listed on ClinicalTrials.gov).
It might possibly be an example of corporate inertia. Pfizer
went through with its FDA approval of Ixifi™ (infliximab) even though it knew
that it would not be marketing this biosimilar in the US. When Spectrum first
submitted its application in December
2018, there were already two approved pegfilgrastim biosimilars, and one,
Fulphila®, was being marketed. One wonders why Spectrum may have
believed another branded G-CSF could still be an important player at that time.
Or the pharmaceutical company understood the small portion
of marketshare that eflapegrastim could obtain, in the face of competition with
three biosimilars and two forms of Neulasta in the long-acting G-CSF market. Even
a small slice will be a difficult reach for Spectrum, especially since it will
have to contend with actively lowering prices for the pegfilgrastim category.
The Food and Drug Administration set a PDUFA date of
September 24, 2020 for eflapegrastim.
In a significant coverage move, UnitedHealthcare
(UHC) has signaled that its commercial and Medicaid medical policies on infliximab
and pegfilgrastim have changed direction in favor of the reference drugs.
Effective July 1, 2019, approximately 22.5 million
commercial and 6 million Medicaid UHC members will not be able to access these
biosimilars without trying the reference agents first (virtually eliminating biosimilar
use). Both infliximab and pegfilgrastim are covered generally under the medical
benefit as office-based infusions, and preferring Remicade® and
Neulasta® (including OnPro®).
This move is important for a few reasons. First, it reverses
UHC’s previous position, which preferred the biosimilars over the two
Second, it promotes a prior
authorization practice that makes little
sense—since the biosimilar and reference products are expected to work in
the same way and produce similar outcomes, why would a patient who fails Remicade
then be given Renflexis® instead of a different biologic medicine
like adalimumab, ustekinumab, or others?
Third, it implies that both manufacturers have further
reduced the net cost of these drugs to UHC and its customers, undercutting the
current deals offered by the biosimilar manufacturers. If accurate, this is a
positive development in that infliximab and pegfilgrastim prices are continuing
to come down due to competition. It would also indicate that Amgen, maker of
the pegfilgrastim originator Neulasta, is beginning to defend its prefilled
syringe market more aggressively. This is significant, because Amgen had been
more focused on defending the marketshare of its on-body injector (Onpro), which
is dominant. Alternatively, Amgen may be bundling its filgrastim and
pegfilgrastim products more effectively. Coherus
and Mylan had previously announced pricing that would be one-third less
than the list price of Neulasta. Coherus had specifically indicated that it
would be seeking targeted
deals with payers to ensure at least parity position for its prefilled
syringe product Udenyca®. It did not, however, mention UHC as one of
Fourth, this move puts a further dent into the
sustainability of the US biosimilar market. Obviously, preferring the
originators will make access to their biosimilars considerably more expensive
for patients. It can only promote greater price cuts by the competing brands
and thus reduce profit margins for the biosimilar manufacturers. In the US, biosimilar
makers need a little encouragement to stay in the market, as very
few have had positive experiences to date (e.g., Pfizer,
to name a few).
No one denies the benefits of the increased competition
meaning a halt to price increases and significantly lower net costs, but those
benefits need to be extended across other biologic categories. Without a viable
biosimilar industry, access to lower-cost biologics can only happen through
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.
BR&R: Do you
think interest by manufacturers in biosimilars is gaining or waning at this
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
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
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
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%.
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.
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?
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
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.
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
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.
With the Food and Drug Administration (FDA) approval today of Coherus Bioscience’s Udenyca™ (pegfilgrastim-cbqv), the second pegfilgrastim to compete with Amgen’s Neulasta®, much attention will be now focused on the company’s November 8 earning call.
The FDA approved Udenyca on the basis of a supportive analytical similarity package, but with phase 1 data only. Over 600 healthy subjects were given the agent to test its pharmacokinetic, pharmacodynamic, and immunogenicity safety.
We should learn a great deal by the end of the week about the nature of the competition for the injectable pegfilgrastim marketplace into 2019. In the press release announcing the approval, the company said it will reveal its launch plans, including pricing, during its week’s call. On Monday, November 5, we should hear the first information about whether Mylan’s first-to-market entry, Fulphila®, has gained some traction against the injectable form of Neulasta. Mylan launched Fulphila at the end of July.
In a previous post, we discussed how Amgen’s Neulasta Onpro® patch has already captured upwards of 80% of the pegfilgrastim business. Because of the convenience of the patch formulation, it would be surprising if Onpro’s share of market eroded significantly. However, Amgen must ensure that the net cost difference between the biosimilars and Neulasta Onpro is not noteworthy. Otherwise, payers’ can be expected to try to disadvantage Onpro through step edits or greater patient cost sharing. That would take a sizable bite out of Amgen’s large slice of the $4 billion pegfilgrastim pie.
The FDA approved Udenyca for the following indication: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. It was not approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. This indication language does not differ from that for Fulphila. Neulasta has the additional indication of increasing survival in patients acutely exposed to myelosuppressive doses of radiation.
Undenyca was also approved for sale in the EU, although Coherus has not launched there, awaiting a marketing partner.
On July 20, the US Food and Drug Administration (FDA) approved the second biosimilar version of filgrastim. Pfizer’s filgrastim biosimilar is named Nivestym™ (filgrastim-aafi).
The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio® [filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.
The FDA granted Nivestym the following indications:
To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
Although a launch date was not announced for Pfizer’s filgrastim biosimilar, the company’s press release stated that “Nivestym is expected to be available in the US at a significant discount to the current wholesale acquisition cost (WAC) of Neupogen.”
Rather than competing aggressively for the filgrastim market, Amgen seems to be focusing its efforts on its pegfilgrastim brand, a longer-lasting version. Specifically, it is seeking to move its utilization to the Onpro formulation of Neulasta®. The first biosimilar to pegfilgrastim was approved in June (Mylan and Biocon’s Fulphila™).
The race to bring a pegfilgrastim biosimilar to market officially started on December 17, 2014. The checkered flag fluttered 3½ years later on June 4, 2018, with the Mylan/Biocon team winning on a slow track. The partners earned approval from the US Food and Drug Administration (FDA), becoming the first biosimilar to challenge for this $4 billion market.
Mylan will market the product in the US, and it is assumed that the product will be launched shortly,= to take advantage of their window of opportunity. The drug will be called Fulphila™, and the FDA assigned a formal name of pegfilgrastim-jmdb. The next likely competitor, Coherus, is expected to receive word from the FDA by November 2. Mylan will have the chance to quickly grab marketshare if they produce attractive deals for payers.
We’ve covered the contest to bring a biosimilar pegfilgrastim to market, with considerable depth. The progress and setbacks of Mylan/Biocon, Coherus Biosciences, Sandoz, and Apotex have been tracked. Other drug makers are also working on plans towards 351(k) applications for approval. Eventually—likely sooner than later—one or two will hit the market.
Biosimilar Pegfilgrastim, Neulasta®, and Onpro®
Amgen, maker of the originator product Neulasta®, disclosed in its first-quarter financial report that the total sales for the product in the US is $1.0 billion, $146 million for the rest of the world, for a total of $1.15 billion. This means a US market of approximately $4 billion for one year of sales. Amgen also noted that 62% of its first-quarter Neulasta sales are associated with its Onpro® kit. Although the major patents for pegfilgrastim have expired, Onpro is still protected by patent. Onpro does have some significant advantages in that the patient does not need to go to the doctor’s office for an injection after receiving chemotherapy. The sales figures indicate that doctors prescribe it in preference to the injectable form of pegfilgrastim.
At a current 62% marketshare for Neulasta Onpro, the initial total slice of the pie available for biosimilars may only be $1.5 billion (not considering WAC discounts). If we assume a 20% discount, this may be closer to $1.2 billion. It may not seem logical for Amgen to make great efforts to defend its share of injectable pegfilgrastim because of its successful conversion to Onpro. Also, Onpro does have marketable advantages over the injectable form.
The list price of Neulasta is upwards of $7000 per injection, and Amgen does not charge additionally for the Onpro kit. This stance may prove an incentive to health plans and insurers to not encourage biosimilar use over Onpro.
Will Physicians Resist Moving From Onpro to a Biosimilar Pegfilgrastim Injection?
The $1.2 billion to $1.5 billion estimate also assumes that Amgen cannot convert more patients to Onpro prior to approval of a new biosimilar. That would further shrink the revenue opportunity. Physicians may also resist payer efforts and not prescribe the injectable form if they favor the Onpro kit. To the extent that payers may prefer the biosimilar (or otherwise restrict the use of a more expensive originator agent) when it becomes available, that slice of the pie could increase quite a bit. Furthermore, the picture could also change in a few years as biosimilar manufacturers develop delivery systems that gain the same advantages as Onpro.
In its earnings report, Amgen indicated the sales of Neulasta have been decreasing, by 5% from the same quarter last year. This may be the result of movement to other, less-toxic cancer chemotherapies or other treatments to prevent neutropenia and its related infections.
The Onpro market for the rest of the world may be given a boost soon, as Amgen also announced that the European Medicines Agency issued a positive opinion for the drug maker to include the Onpro Kit in its EU label.
As reported in BR&R, Coherus CEO Denny Lanfear thought the pegfilgrastim market may be split in a manner similar to that for filgrastim (i.e., 30%/30%/40% shares for 2 biosimilar makers and the originator). That may possibly mean 30% of a $1.2 billion US market (not $4 billion), if payers do not emphasize the use of the biosimilar over Onpro.
When it received a June 2017 complete response letter from the Food and Drug Administration (FDA), the outlook for Coherus Biosciences was cloudy. Its lead product, a biosimilar for pegfilgrastim (CHS-1701), had been cited for the way the drug maker evaluated immunogenicity and for manufacturing plant issues. Upon receiving the news, it cut 30% of its workforce.
Furthermore, Coherus has had little luck in challenging the existing patents of originator products. It was denied inter partes review on a key patent held by Abbvie on Humira® as well as a patent on Enbrel® by Amgen.
Today, Coherus may be on the verge of a turnaround in fortunes
Armed with new immunogenicity data, Coherus resubmitted its 351(k) application with the FDA on May 3, and investors reacted strongly to its new prospects. The company’s stock price soared 17.3% for the day, closing at $14.90. Its previous 52-week low was $8.05. Coherus is a U.S. manufacturer that is focused solely on biosimilar development (a “pure-play” biosimilar maker).
In the company’s announcement, Coherus reported that the new FDA application is “supported by similarity data from analytical, pharmacokinetic, pharmacodynamics, and immunogenicity studies comparing CHS-1701 and Neulasta and integrates new immunogenicity data obtained from using a more revised immunogenicity assay.” Mr. Lanfear said, “The CHS-1701 BLA resubmission marks a significant milestone in our ongoing transition to a commercial company as we tightly focus on execution of our strategic plan.”
In April, Coherus filed for a rehearing of the etanercept inter partes review.
Coherus originally filed its pegfilgrastim biosimilar application with the European Medicines Agency November 29, 2016. According to a report from early in 2018, Chief Executive Officer Denny Lanfear asserted that he hoped to receive EMA approval in the second half of 2018.
According to a Reuters report, Janssen Biotech withdrew its patent lawsuit against Samsung Bioepis on November 10. The suit alleged infringement in the manufacture of Samsung’s infliximab biosimilar.
The action, which was filed in U.S. District Court of New Jersey, means that Merck and Samsung, which launched Renflexis™ in July, is no longer at risk for revenues earned in the sale of its biosimilar. If Janssen had maintained the lawsuit and later earned a victory in the courts, it could have been awarded a large percentage of Samsung’s Renflexis revenues.
In a separate case, an appeals court found that the Southern District of Florida was correct in its decision clearing Apotex Inc of any patent infringement in its development of biosimilars of Amgen’s Neulasta® and Neupogen®. The initial ruling, in September 2016, helped cleared the path for the biosimilars to reach the market. However, the organization’s filgrastim biosimilar was first filed in February 2015, without an approval. Its pegfilgrastim biosimilar was filed earlier, in December 2014, but has not advanced through the Food and Drug Administration’s 351(k) approval process. Apobiologix is the Apotex subsidiary that would manufacturer and market the biosimilars in the US, should they gain approval.
On October 27, Sandoz announced that the European Medicines Agency has accepted its re-application for review of its biosimilar version of Neulasta® as supportive treatment in patients receiving cytotoxic chemotherapy.
Sandoz’s attempt to bring its biosimilar pegfilgrastim to the market was stalled in the US in Q2 2016, when the FDA issued a complete response letter. It had withdrawn its application to the European Medicines Agency in January 2017. However, the new application seems to be bolstered by additional data, according to reports.
Sandoz is expecting to reapply to the FDA in 2019, according to its website.
As noted too often in this space, the journey to approval for a pegfilgrastim biosimilar has been marked by failure and setbacks. However, as shown in the Figure from the MarketRealist, revenues for Neulasta are considerably larger than that for its nonpegylated progenitor, Neulasta (filgrastim). This is a powerful impetus for potential biosimilar manufacturers to succeed. At close to $5 billion in annual revenues, there is little reason to think that a biosimilar pegfilgrastim will not be approved eventually.
Source: The Market Realist.
In other news… AbbVie expects its Humira sales to jump to $21 billion by 2020 from $16 billion today, evidently bolstered by its successful defense of its patents against Amgen.