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.
Amgen now has company as the second biosimilar competitor to
Herceptin® has launched. On December 2, 2019, Mylan and Biocon announced
the availability of Ogivri in the United States.
A price for the new biosimilar was not announced, but it is
assumed that they will need to meet or beat Amgen’s initial offering, which was
below the average sales price of Herceptin. Mylan and Biocon have a licensing
agreement with Genentech; it is unknown as to whether Amgen’s launch in July
2019 prompted an earlier-than-expected launch for Mylan/Biocon.
Ogivri is available in single-use vials in doses of 150 mg
and 420 mg.
This marks the second biosimilar launch for the partners,
the first being their pegfilgrastim product Fulphila® in 2018.
In other biosimilar news…The Food and Drug Administration released in November its long-awaited draft guidelines for approval of biosimilar insulin agents. March 1, 2020 is the date FDA set for transitioning insulin copies, among other products (e.g., growth hormone) to the 351(k) approval pathway. The guidelines outline a key update to the expected regulations. Studies proving immunogenicity characteristics of the biosimilar insulin agents will likely not be necessary, which should lower the cost of entry and entice some prospective manufacturers. In its justification, FDA asserted that if the analytical assessment requirements are met, there would be very little risk of immunogenicity caused by the new biosimilar insulin.
This may be good news for partners Mylan and Biocon: Two bills are circulating on Capitol Hill that can alter the transition of insulins to biologic agents in March 2020. However, the timing for passage of these bills is questionable.
The Senate’s Affordable Insulins Approval Now Act (S.2103),
a bipartisan bill that was introduced by Senator Richard J. Durbin (D-IL) in mid-July,
has 13 cosponsors to date. It was referred to the Committee on Health, Education, Labor, and Pensions,
where it awaits review.
Under this bill, a pharmaceutical company may file a 505(b)2 application for an insulin product before January 1, 2020 and still be evaluated via the abbreviated new drug approval pathway beyond the March 20, 2020 transition date. These filings are regulated under the Food, Drug, and Cosmetic Act, which governs the approval of nonbiologic drugs.
If S.2103 is passed, Mylan/Biocon, which received a complete response letter from the Food and Drug Administration September 25 for its follow-on insulin product, would not have to refile for approval under the 351(k) pathway as a biosimilar. Under the terms of S.2103, the insulin would only be transitioned to biologic status and regulated under the Public Health Services Act once approval has been obtained (regardless of when that occurred).
A separate House bill (HR.4244) was introduced in September by Representative Michael Kelly (R-PA). This proposal takes a different approach towards encouraging insulin copy development—completely removing the mandate to transition insulin copies to the 351(k) approval pathway. This bill, which has been referred to the House Committee on Energy and Commerce, does not have any cosponsors at present. Under Representative Kelly’s proposal, insulin copies would be carved out and continue to be regulated under section 505 of the FD&C Act.
The timing and
current status of these bills make it seem unlikely they would be signed into
law before the transition date of March 20, 2020. However, it is possible that
actions of this type can be attached to other legislation that is further
along. Companies like Mylan and Biocon certainly hope so, otherwise valuable
time (having to wait until March 24, 2021 to apply as a biosimilar) will be
lost in this regulatory “dead
Biocon received a second complete response letter relating to manufacturing plant problems in Malaysia. This may seem like a straight forward issue that could hamper its efforts to produce an insulin glargine follow-on agent, but it can become a major problem barring a very quick resolution.
In the filing Biocon made to the India Stock Exchange, the company said, “The CRL did not identify any outstanding scientific issues with the application. We remain confident of the quality of our application and do not anticipate any impact of this CRL on the commercial launch timing of our insulin glargine in the US.” However, that may be a fairly optimistic opinion.
Insulin copies are part of the class of biologics designated
“transitional products” that will be approved only through the 351(k)
biosimilar approval pathway after
March 2020. The latest rules issued by the Food and Drug
Administration (FDA) specify that if a product in this drug class (and others
like growth hormones) does not receive approval by this date, the manufacturer
must submit an entirely new biologic licensing application (for approval as a
full-fledged biosimilar). That would require completing all of the necessary
developmental steps—proving the physiochemical and pharmacodynamic equivalence to
what would now be termed the reference product—Lantus®.
The FDA rules for transition products do not exempt agents that have already received complete response letters and may still be in the FDA’s queue. This is relevant because neither of Biocon’s rejection letters (the first issued in June 2018) pointed to problems with the scientific evaluation of its insulin glargine. Rather, both involved failed inspections at the plants at which Biocon was going to manufacture the agent. The drug was approved by the European Medicines Agency and is currently available by prescription in the EU.
As indicated in a previous post, pharmaceutical company
interest in insulin biosimilars is fairly low. That may be because of the
approaching transition date.
The question remains, can Biocon correct its Malaysian manufacturing
plant deficiencies, can FDA reinspect, and can FDA issue final approval for
this 505(b)2 agent before February 29, 2020? If not, even if Biocon’s plant
passes inspection in December 2019, that will likely result in years’ long delay before the new BLA can
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.
Since the October expiration of Abbvie’s EU patent, the potential Humira savings seem to be truly mind-blowing. After implementing its contracts for adalimumab, the UK National Health Service (NHS) should save about three quarters of the $514 million (£400 million) it spends each year on this product alone.
In a fixed-budgeted system like that in the UK, the real implications of these savings become clear. According to the NHS, this additional $385 million (£300 million) will enable it to pay for 11,700 community care nurses or 19,800 treatments in patients with breast cancer.
And to earn these Humira savings, the NHS does not exclude using the originator product Humira. It has signed contracts (with large price cuts) with Abbvie, as well as with biosimilar manufacturers Amgen, Biogen, Mylan and its partner Fujifilm Kyowa Kirin, and Sandoz.
Could the US see such savings on adalimumab in 5 years? Although the competition may be fierce when the brand loses patent protection in 2023, Abbvie has created a stepped-launch scenario with its licensing agreements. Rather than a jailbreak of competition, as we are seeing in the EU with patent expiration there in October 2018, the timing of the licensing agreements may limit the drop in per-unit price, at least for the first year or so.
After that time, payers will be able to choose from all biosimilar adalimumab manufacturers, which should then drive pricing down (or rebates up) considerably, resulting in long-sought lower net costs. However, this will happen only after years of price increases by Abbvie. Abbvie has not claimed, while it is drastically slashing its price in the EU, that it will be losing money. In part, that is because its US revenues on Humira will continue to be at over $10 billion a year. Furthermore, its revenues largely reflect pure profit on the manufacturing of the product today, as its research and development costs were covered 15 years ago and ongoing marketing costs are a tiny fraction of this figure.
Despite repeated protestations in the US that healthcare resources are not unlimited, our system is not based on a fixed budget. It is not disingenuous to consider savings in the terms posed by NHS. Defining the large savings in terms of other useful expenditures give people a concrete idea of how the money can be better used. The need for savings on drug expenditures is acute in this nation, and biosimilars will eventually lead the way.
Coherus Biosciences surprised many on its third-quarter earnings call late yesterday. It will rely not on a lower price than its biosimilar competitor to gain marketshare after Coherus’ Udenyca launch, but on its ability to pull through on its patient and provider services and supply chain to gain significant marketshare for its biosimilar version of Neulasta®.
This is not to imply that Coherus will not offer contracts to group purchasing organizations (GPOs), hospitals, and payers. The company intends to do so. However, the wholesale acquisition cost (WAC) for Udenyca® will match that of Mylan’s Fulphila®—$4,175 per vial, or a 33% discount from Amgen’s reference product. Denny Lanfear, CEO of Coherus added that the company’s contracting plans “will deliver additional value to payers.”
AWAITING HCPCS CODING
Unlike other biosimilar manufacturers, this is their first product to reach the market. Not only was manufacturing and production a priority, but company infrastructure had to be ready for launch. Although Coherus pointed out that the sales force for Coherus is fully in place, they are holding back the Udenyca launch until the Center for Medicare and Medicaid Services (CMS) designates a Q code for claims and billing purposes. Therefore, the goal is a Udenyca launch date of January 3, 2019.
Jim Hassard, Vice President for Marketing and Market Access, emphasized that “Our overall launch strategy goes beyond pricing, to reliable supply and services. We’re committed to world-class execution and salesforce effectiveness.” The company’s Coherus Complete, patient and provider service site, is operational, and this will include copay support for eligible patients. Mr. Hassard stated, “This price is attractive to payers without diminishing our value proposition. We can deliver significant savings to the health system versus Neulasta.”
CAN UDENYCA GRAB SOME ONPRO MARKETSHARE?
One interesting statement made during the call was the expectation that Coherus will go after some of Neulasta Onpro’s share of the market. Amgen’s on-body injector accounts for about 60% of all Neulasta utilization today, “but this growth has flattened out,” Chris Thompson, Vice President of Sales, emphasized. “We’re looking at the whole market, not just prefilled syringe market,” he said. “We think we’ll be able to sell through the Onpro market,” meaning that their pricing and services will attract some of this marketshare. In fact, Coherus executives believe that biosimilars may eventually garner nearly 70% of the pegfilgrastim market.
Coherus believes that there is pent-up demand for the biosimilar in the hospital segment today, which is why GPOs may represent promising contracting opportunities. They are seeking parity positioning at the payer and pharmacy benefit manager level.
This sounds fairly reasonable. Yet the vast majority of biosimilar consultants and payers with whom I had communicated had anticipated that Coherus would launch with at least a modest WAC discount relative to Mylan’s Fulphila. On the conference call, the investment banking participants wanting information on the Udenyca launch seemed caught off guard as well.
UDENYCA REVENUE TO SUPPORT COHERUS FOR NOW
Perhaps this strategy gives Coherus ample room for contracting while retaining a respectable net cost. Mr. Thompson said, “We’ll roll out a comprehensive contracting strategy for GPOs in the next week or two. It will be competitive and designed to win.”
It may need to be. Relying on better services and perhaps even a better supply chain (albeit one that is brand new) may not be sufficiently persuasive to hospital and payer P&T Committees. And Coherus needs to generate revenue from its sole product to feed its new sales team, new product development, and hungry investors.
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.
The European Medicines Agency (EMA) has had an extremely busy week in the pegfilgrastim biosimilars arena. In addition to granting marketing authorization to Coherus Biosciences for its pegfilgrastim biosimilar, it has also approved the marketing of Pelgraz®, a pegfilgrastim produced by Accord Healthcare. In addition, the EMA’s Committee for Medicinal Products for Human Use has also recommended approval for three pegfilgrastim biosimilars—from Sandoz, Cinfa, and Mylan.
Mylan is the only drug maker with a marketed biosimilar version of pegfilgrastim in the United States. Its product Fulphila® hit the US market in early July. Coherus’ product, Udenyca™, is awaiting a November 2 decision from the Food and Drug Administration. Coherus is reportedly looking for a partner to market its pegfilgrastim biosimilar overseas, while it intends to market the product internally in the US. This means that Accord may have the first pegfilgrastim biosimilar to reach patients in the EU, though this advantage will be short lived should Mylan in particular gain approval.
In other biosimilar news…Boehringer Ingelheim announced positive results in its clinical study of Cylteza® versus Humira® in patients with moderate-to-severe plaque psoriasis. The study results were announced at the European Society of Dermatology and Venereology.
Samsung Bioepis Co., Ltd. announced that the FDA has accepted its 351(k) application for SB5, a biosimilar to adalimumab. Samsung is the fourth manufacturer seeking to enter the biosimilar market for Humira. Two have been approved (Amjevita® by Amgen and Cyltezo® by Boehringer Ingelheim) but are not yet marketed. A decision on Sandoz’s application is expected later this year.
In reporting lower earnings on its second-quarter revenues, Mylan may have surprised industry observers by offering the possibility of some changes in strategic direction. Although Mylan executives sounded hopeful notes on the company’s biosimilar portfolio, the hints CEO Heather Bresch provided may affect the marketing of the biosimilars as well as its other pharmaceutical business.
Chief Executive Officer Heather Bresch said that Mylan’s generic drug business was the main reason for the declines in overall revenues, with adjusted gross profit from US business down 6% from the previous quarter last year. Sales revenues from North America as a whole were down 22% compared with an increase of 10% for the rest of the world.
On a conference call to announce the earnings, she noted that “our efforts to serve patients in the U.S. have been shaped by the industry’s transformation there, and our results and guidance for 2018 are directly correlated with the ongoing rebasing of the US healthcare environment.”
According to Rajiv Malik, President of Mylan, “This past quarter, Mylan continued to execute on its commitment to expand access to medicine through the advancement of our complex product portfolio across our global diversified platform. For example, we launched Fulphila™, our pegfilgrastim biosimilar, in the US, and CHMP issued a positive opinion for our biosimilar of Humira in Europe.”
The Board of Directors released its own statement, however, indicating that it may take a number of actions that could dramatically change the picture (though not specified, these could include selling off assets, seeking a merger, or restructuring the organization). In a press release, the Board said, “we believe that the US public markets continue to underappreciate and undervalue the durability, differentiation and strengths of Mylan’s global diversified business, especially when compared to our peers around the globe. Therefore, while we will continue to execute on our best-in-class, long-term focused sustainable strategy, the Board has formed a strategic review committee and is actively evaluating a wide range of alternatives to unlock the true value of our one-of-a-kind platform. The Board has not set a timetable for its evaluation of alternatives and there can be no assurance that any alternative will be implemented.”
Observers will be greatly interested in how Fulphila performs in the third quarter and beyond, particularly around the deep discount offered by Mylan. This could be a considerable shot in the arm to Mylan’s US revenues or simply a ratification of its opinion that the US health system is incentivized by higher prices.