Fujifilm Gains Further Exposure in Biosimilar Partnerships

The biosimilar industry continues to make strange bedfellows. In July 2016, I reported in the Center for Biosimilars that a subsidiary of the Japanese camera maker, Fujifilm, had jumped into the biosimilar field. The Indian pharmaceutical company Biocon announced that it has launched its new insulin glargine biosimilar in Japan. Fujifilm Pharma Co, Ltd was named as the partner in this endeavor to commercialize the product in Japan.

Fujifilm Pharma is a producer of diagnostic and therapeutic radiopharmaceuticals, in addition to contrast media. This makes sense, as the parent is in the imaging business. Medical imaging can be a very natural extension of this activity. But biosimilars?

To reaffirm its strategy, Fujifilm announced a new partnership.  Its Fujifilm Kyowa Kirin Biologics subsidiary will manufacture a adalimumab biosimilar in the EU (filed for approval in the EU only) and will be commercialized by Mylan if approved. There is no information about whether Fujifilm will seek authorization to market this biosimilar in the US down the road.

Fujifilm Kyowa Kirin AstraZenecaTo further its chances of commercializing this biosimilar in the EU, Fujifilm Kyowa Kirin Biologics joined a lawsuit in April 2017 with Samsung Bioepis and its partner Biogen. The lawsuit, filed in the UK, sought to invalidate Abbvie’s two remaining adalimumab patents, and the UK court ruled in favor of the plaintiffs, opening the door to marketing next year in Europe. Fujifilm also has a bevacizumab biosimilar (FKB 238) in phase 3 clinical investigation.

The parent company has over 200 subsidiaries, and it can be complicated to track which ones are directly involved. For example, another Fujifilm company, Fujifilm Diosynth, does contract manufacturing of biologics. Yet, the phase 3 trial being carried out on FKB238 is sponsored by Centus Biotherapeutics Limited, which is a joint venture between Astra Zeneca and Fujifilm Kyowa Kirin Biologics. Centus seems to be involved only with the bevacizumab biosimilar, not with the adalimumab agent. Despite this web of intrigue, Fujifilm is not likely to be overexposed in the biosimilar marketplace. It is also unknown whether their efforts will be affected by the recent difficulties of its partners Biocon and Mylan with getting its pegfilgrastim biosimilar approved. It has been reported that Biocon will also benefit from this latest Mylan collaboration.

With the Samsung Bioepis Deal, Abbvie Tightening Its Grip on the US Adalimumab Market

Samsung Bioepis and Biogen has reached a deal with Abbvie that would enable it to market its biosimilar adalimumab (should it be granted approval) in June 2023. This is the second deal Abbvie has made with a potential competitor, confirming the solidity of its patent wall. The European patent expires in October 2018, and competitors will be able to sell biosimilars over the pond unhindered at that time.

However, without competition, most expect unencumbered price increases until a US biosimilar introduction. In other words, biosimilars will not make an appreciable impact on the cost of adalimumab in the US market, unless another biosimilar manufacturer decides to launch at risk in the near future.

A Deal Prior to FDA Approval

The agent, SB5 has not yet been filed for approval in the US. Samsung filed its application for approval in the EU in July 2016 and was authorized by the European Medical Agency in August 2017. Biogen will market the agent for Samsung, whenever it is launched.

Amgen inked a deal with Abbvie in September 2017, effectively ending its patent battle. This deal gives Amgen a jump on other competitors that reach settlements with Abbvie, by allowing a launch in January 2023. In addition, other manufacturers are working on adalimumab biosimilars, including Coherus and Sandoz. The biggest question though is Boehringer Ingelheim’s move, as they have the only other FDA-approved adalimumab biosimilar approved on the marketplace (but also unlaunched). Boehringer responded to our request but declined to comment on its plans mAbbvie produces Humira (adalimumab)oving forward with the product, including a targeted launch date.

Without Competition, Expect 45% Jump in WAC Price 

As addressed earlier in this space, the time to effective competition for a US biosimilar adalimumab is crucial. Abbvie’s annual global revenue on the product may reach as much as $21 billion, with the last price increase registered in January, at 9.7%. Assuming Abbvie sticks to its pledge of no more than one

10% price increase per year, that would result in a wholesale acquisition cost (WAC) of more than $52,000 at the close of 2022, or a 45% jump from today’s WAC. This figure does not reflect individual negotiated rates (including rebates) that health plans and insurers actually pay. Yet, it does roughly indicate what type of discount will be necessary when biosimilars reach the market to simply attain the cost paid in 2018—that is, no more savings. Without competition before 2023, this may be the one area where payers pray for a rapid and bracing race to the bottom on price once 2023 rolls around. With Abbvie’s hand continuing on the tiller, don’t plan on it.

In other biosimilar news…Celltrion acknowledged that it is seeking to rectify the manufacturing plant issues that torpedoed its FDA approval of biosimilars for trastuzumab and rituximab. In the statement, it noted, “Celltrion is confident that the issues raised by the FDA will be resolved in a timely manner.

We can confirm that the resubmission will be in-place relatively soon. Then, we are expecting approvals in 6 months after resubmission according to regulatory timeline.”

More Clinical Study Evidence That Biosimilar Switching Carries a Low Risk

A literature review published this past weekend in Drugs reaffirms what most parties interested in biosimilars suspect—that switching from a reference product to biosimilar is not a significant clinical concern. Biosimilar switching was not generally associated with poorer outcomes.

The study evaluated the results of 90 clinical studies comprising more than 14,000 patients with 14 diseases or conditions. The authors from Novartis (and its Sandoz subsidiary), the Oregon Medical Research Center, Rocky Mountain Cancer Centers, IBD Center of Humanitas Clinical and Research Hospital (Milan), and Avalere Health stated that “the great majority of the publications did not report differences in immunogenicity, safety, or efficacy [as a result of biosimilar switching]. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone.” In addition, they reported, “Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar.”

In this evaluation, the biosimilars tested included those for infliximab, epoetin, filgrastim, growth hormone (which has not been considered a biosimilar in the Ubiosimilar switchingS), etanercept, and adalimumab. Infliximab was the subject of the majority of the clinical studies.

Of the 90 studies, two were outliers, suggesting potential safety issues associated with biosimilar switching. One was described as a 2016 retrospective study of a claims database from Turkey, which found a much higher discontinuation rate with the infliximab biosimilar compared with originator product in patients with rheumatoid arthritis.

The authors correctly note that the vast majority of the studies reviewed involved a single biosimilar switch, and that multiple switches may result in additional safety signals. However, they also point out that “patients have already been exposed to de facto multiple switches for many originator biologics when product quality attributes changed after one or more manufacturing process modifications were introduced.”

The question arises as to whether multiple switch studies are truly necessary outside of the requirement to prove interchangeability between a biosimilar and a reference product. There is a practical reason for doing so—the possibility (actually, the likelihood) of a patient enrolling in a new health plan one year, which covers the biosimilar but not the reference product. If the patient’s health plan changes once again one or two years later, that person may well be required to switch back to the reference product or yet another biosimilar.

This will heighten the importance of collecting real-world evidence and accumulating more experience outside of the clinical trial environment in terms of switching. Efforts such as those at the Biologics and Biosimilars Collective Intelligence Consortium should fill this gap over the next several years.

 

What Will Cost Savings on 2023 Adalimumab Biosimilars Really Be Worth?

AbbVie executives are sticking to their pledge to restrict annual price increases on Humira® below 10%, but even payer price protections won’t mitigate the increasing expenditures before adalimumab biosimilars hit the market. In 2023, when adalimumab biosimilars become available, the savings biosimilars represent may not be real savings at all.

Pharmaceutical companies generally seek to lock in preferred coverage status for their agents through the use of rebates, which lowers the net costs. Typical in these contracts is a price guarantee, which shields the payer from annual (or more frequent) price increases for the duration of the contract. The contract life is one or two years, after which the health plan, insurer, health system, or pharmacy benefits manager must renegotiate—that means significantly higher costs for each successive contract renewal.

Humira adalimumab

Drug price increases for self-injectable medications like adalimumab, are reported on top of its wholesale acquisition cost (WAC), or the list price. Rebates are applied to WAC pricing. Therefore, if for example, a manufacturer announces 9% price increase to drug X, that applies to the WAC price and does not include consideration of rebates or price guarantees secured by a payer. Rebate information is notoriously difficult to obtain, as payers and pharmaceutical companies consider them proprietary.

However, in a January piece in the New York Times, the author cites research by SSR Health, which concludes that the price of Humira with rebates rose 100% since 2012 to an average of approximately $38,000. Assuming AbbVie executives hold to their price increase pledge, raising their prices by only 6% per year, by 2023 when patent expirations will bring a rash of biosimilars to market, Humira’s price after rebates would have risen 33.8%, to $50,844. If the price is jacked up 9% per year, that would be an increase of 53.9%, to $58,482. This is assuming of course that AbbVie does not increase the rebate at each contract negotiation to compensate plans to offset the higher net cost. To make this dystopian vision complete, let’s not forget that the full savings will not obtained over a population unless all utilization is fully converted to a biosimilar from Humira. That may require an interchangeable biosimilar product (which has not yet been approved) .

As we reported last year, the Institute for Cost-Effectiveness Research established that to meet accepted thresholds for cost-effectiveness, Humira would have to be discounted 55% from its list price. Rises in the cost-effectiveness thresholds (currently 100,000–150,000 per quality-adjusted life-year) would never keep up with this pace of price increases. By 2023, Humira will be even further off the mark in terms of providing value.

The most important point of this, is that the cost savings of the biosimilars that are finally introduced could be an illusion. If a price war in 2023 for newly available adalimumab biosimilars results in 50% discounts, we may have received little but a roll back in costs to those of today. From the perspective of 2018, that’s not savings. That is price stability.

I wrote in 2016 of the same effect for Enbrel®. Because Amgen had taken multiple price increases in the previous years, the WAC cost jumped 37%. And in 2018, no biosimilar is presently marketed for prescription in the United States. The relative discount by Sandoz (presently the sole US company with an approved biosimilar etanercept) needed to actually save payers money for etanercept will not be realistic.

Sandoz Files 351(k) Application for Adalimumab Biosimilar

Sandoz announced that it has thrown its hat in the ring for another Humira biosimilar. Sandoz filed an European application for approval for GP2017 last year, in the expectation that it will be able to launch soon after the European patent expires in October 2018.

This will be the third application for an adalimumab biosimilar. Versions by Amgen (Amjevita) and Boehringer Ingelheim (Cyltezo) have been approved by the Food and Drug Administration (FDA); however, patent litigation has held up marketing. Amgen had signed an agreement with Humira’s manufacturer Abbvie to postpone marketing until 2023. Boehringer Ingelheim has not signed a similar agreement, but no indication is yet given regarding the US launch of this product.

It is assumed that European revenues will sustain the biosimilar manufacturers until US marketing begins. This is Sandoz’s fifth FDA biosimilar application. It has received approval for Zarxio (filgrastim) and Erelzi (etanercept); its application for rituximab is under review, and it received a rejection for its version of pegfilgrastim.

Are We Now Thinking “Authorized Biosimilars”?

Authorized generics have been around for a couple of decades. They can be a challenge to payers, health systems, and patients who are seeking the price-reduction benefits borne out of normal competition. The Amgen–Abbvie agreementHerceptin on the biosimilar for Humira® seems to be right out of this playbook.

In summary, authorized generics work like this:

  • A brand manufacturer has a product that is nearing patent expiration
  • Rather than ceding its marketshare altogether in the face of multisource products, the manufacturer will come to an agreement with a generic drug maker to produce the first generic of its product, which allows the branded company to earn licensing fees and royalties on the drug
  • The additional royalty or licensing fee means that the price of the authorized generic will likely be higher than if there was no agreement
  • The maker of the authorized generic will get to market sooner (perhaps even prior to patent expiration)
  • Competing generic manufacturers will have to edge their way into the market against not only the authorized generic maker but perhaps the branded manufacturer that is benefiting from the agreement

On September 28, Amgen and Abbvie announced an end to the patent litigation between the companies. The agreement will allow Amgen to market its biosimilar (Amjevita™) in the US (in 2023) and in the EU (in 2019). The dates reflect differences in principal patent expirations for the two major markets. The all-important composition-of-matter patent expired in December 2016, which is why potential biosimilar manufacturers had hopes of marketing their products as early as 2017 in the US. The other patents don’t expire until 2023.

Under the agreement, Amgen acknowledges the validity of Abbvie’s myriad non–composition of matter patents on Humira and gives up the litigation fight to market its version of adalimumab. Amgen will pay Abbvie a licensing fee to market the product, similar to the type of deal for an authorized generic.

Presumably, Amgen entered into the agreement and did not launch at risk, because it feared that Abbvie would be able to successfully defend its patent maze in court. The agreement would allow Amgen to launch in the European market, which would sustain it during the wait to launch in the US.

However, Amgen is not the only potential maker of an adalimumab biosimilar. Boehringer Ingelheim has an approved product (Cyltezo™), which was approved in January 2017. Several other players are in later-stage trials, including (at least) Coherus Biosciences, Momenta Pharmaceuticals, Pfizer, Samsung Bioepis, and Sandoz. It is too early to tell what this agreement might mean for them. Might Abbvie be willing to make separate agreements with them as well, thereby ensuring itself of a cut of these profits for years to come?

In the biosimilar space, there is no exclusivity for the first biosimilar to market, and if a drug maker sought to launch at risk, the rewards can actually outweigh the potential penalties if they found themselves on the wrong end of ongoing patent litigation. Pfizer took the gamble with its Inflectra® biosimilar of infliximab.

If they have to wait until 2023 for this biosimilar, payers may decide to take action. One way would be to encourage the use of other anti-TNF inhibitors or even other effective biologic classes over Humira, if their pricing made sense. However, Humira is often preferred and significant rebates would be at stake.

Legislators did not account for the possibility of authorized biosimilars. It could be a further obstacle to making biologics more accessible to the people who may most benefit from their use.

FDA Approves New Humira Biosimilar, Bypasses Advisory Board Route

Boehringer Ingelheim Pharmaceuticals, Inc. announced August 29 that it had received approval from the Food and Drug Administration (FDA) for its first biosimilar. Named Cyltezo™ (adalimumab-adbm), a biosimilar to Humira®, it is approved for several autoimmune disorders, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease in adults, plaque psoriasis, and ulcerative colitis.

The FDA approval bypassed the need for an Arthritis Advisory Committee review and recommendation, which the agency suggested may be increasingly common with future biosimilar approvals. One suspects that this is more likely with the licensing of the first biosimilar for a particular originator product, with the assumption of a comprehensive data package on submission.

Like Amgen’s Amjevita®, Boehringer’s biosimilar will likely enter a holding pattern until patent litigation is settled (or the patents expire) on AbbVie’s Humira. In the meantime, Boehringer indicated that it will seek approval for an autoinjector, to stand alongside its newly approved subcutaneous formulation.

Boehringer has also applied for approval with the European Medicines Agency, which is expected to decide on its approval before the end of this year. Samsung Bioepsis and partner Biogen earned its own European approval for Imraldi™ this week, another adalimumab biosimilar.

Boehringer May Seek Interchangeable Designation for Adalimumab Biosimilar

The US Food and Drug Administration (FDA) announced earlier this year its draft standards for assessing the interchangeability of biosimilars with originator products. One biosimilar developer announced on July 27 that it is embarking on a study specifically to prove interchangeability of its biosimilar version of adalimumab.

Initial recruitment of the “VOLTAIRE-X Pharmacokinetics, Safety, Immunogenicity and Efficacy of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis: A Randomized, Double-Blind, Parallel-Arm, Multiple-Dose, Active Comparator Trial” was announced by Boehringer Ingelheim to provide evidence that its investigational biosimilar BI 695501 can be substituted for Humira without significant negative clinical or safety effects. The study will incorporate repeated switching between the originator and the biosimilar agent in 240 patients with plaque psoriasis.

Boehringer’s 351(k) application for BI 695501 was sent to FDA in January 2017. A decision is expected in the fourth quarter. The clinical studies supporting BI 695501 were conducted in patients with rheumatoid arthritis; another is underway in patients with active Crohn’s disease. The VOLTAIRE-X interchange study will not be completed until July 2019; therefore, any FDA decision regarding interchangeability on this biosimilar will be made at least 2 years from now.

A Difficult Road Ahead for a “Pure-Play” Biosimilar Maker

On May 30, 2016, I wrote a profile on Coherus Biosciences for the Center for Biosimilars. Based in Redwood City, California, Coherus was founded in 2010 to solely focus on the development and commercialization of biosimilar agents. It does not have any agreements to manufacture or license existing approved products. The firm refers to itself as a “pure-play biosimilar platform company.”

Like several other biosimilar makers, it paired up with marketing partners on particular products outside the US, but it reserved its US commercialization for itself.

Fourteen months ago, which can seem like another age in terms of biosimilars, Coherus had extremely positive prospects. It had a deal with Baxalta to market its late-stage adalimumab biosimilar (CHS-0214) in Europe, Canada, and Brazil and with Daiichi Sankyo to market this agent in Asia. Its version of pegfilgrastim (CHS-1701) was nearing FDA application, and its phase 3 clinical studies on etanercept were yielding good results in rheumatoid arthritis and psoriasis. Coherus had a victory under its belt in the continuing patent battle with Abbvie over Humira®. Finally, it had just announced that it would be adding ranibizumab (CHS-3351) and bevacizumaba (CHS-5217) to its biosimilar pipeline. According to the company, it had more than $400 million available to complete its pegfilgrastim FDA application and its ongoing clinical studies for the biosimilar candidates.

Coherus Logo

That was then. In 2016, Shire, which acquired Baxalta, announced that it was returning its marketing rights to the adalimumab biosimilar to focus on rare diseases. As announced in the past week, Coherus laid off 30% of its workforce (51 employees) and lost Daiichi Sankyo as a marketing partner on its etanercept agent, both likely related to FDA’s rejection of its lead biosimilar, pegfilgrastim.

 

 

 

In its March 2017 financial report, Coherus mentions a nonbiosimilar drug candidate for multiple sclerosis in phase 2b studies (CHS-131), which a separate filing indicated that it is seeking another partner to enable the clinical trial program to progress. The latter document indicates that whereas both ranibizumab and bevacizumab are in preclinical development, “Our goal is to advance at least one of these product candidates into clinical trials in 2017.” However, no mention of any of these 3 products are made on Coherus’ product pipeline.

 

Without the ability to utilize revenues from other products to capitalize the biosimilar development and commercialization program, a “pure-play” biosimilar manufacturer is in a precarious position. It is unfortunate that pegfilgrastim was the first Coherus product to reach the approval stage. So far, no other manufacturer (Sandoz or Apotex included) have successfully obtained an approval on pegfilgrastim. In the best case scenario, it may have been able to market pegfilgrastim, which may have provided needed cash if a subsequent product experienced a problem in phase 3 trials or in FDA review. On the other hand, its remaining 2 late-stage products seem promising.

Indeed, it is a difficult road for biosimilar-only manufacturers. Epirus Pharmaceuticals filed for Chapter 7 bankruptcy in July 2016. One can imagine that with Coherus’ assets and progress, a purchase by a major pharmaceutical player could be in the cards. That might be fortunate for Coherus but unfortunate for the health care delivery stakeholders, including consumers, because new, healthy competition in the pharmaceutical arena is needed. I hope that with a new infusion of capital, Coherus can see it through as a stand-alone manufacturer with approved biosimilars to sell.

Biosimilar Rituximab Under FDA Review

Celltrion announced June 30, 2017 that it has submitted its 351(k) application to the Food and Drug Administration for approval of its biosimilar version of rituximab. This represents the first biosimilar application for rituximab, a monoclonal antibody to CD20.

The product, known during investigations as CT-P10, was approved in the European Union in February, and has been launched there as Truxima in late April. Clinical data have been presented on this biosimilar’s efficacy and safety in treating rheumatoid arthritis and advanced follicular lymphoma, a form of non-Hodgkin lymphoma

If approved, Celltrion will market this product with Teva in North America, which signed a partnership agreement with Celltrion in October 2016 for this biosimilar agent to treat cancer and for CT-P6 (trastuzumab). The FDA application for trastuzumab is expected to be filed this summer. It is currently partnered with Pfizer to market its product Inflectra® (infliximab-dyyb) in the US and Canada.

Also in June, Sandoz received approval from the European Medicines Agency to market its own version of rituximab, called Rixathon™.

In other biosimilar news…Coherus Biosciences, which took hits from the FDA and its investors in the rejection of its pegfilgrastim biosimilar in June, laid off 51 workers (about 30% of its workforce) in an effort to cut costs. Coherus is working towards addressing the issues outlined in FDA’s Complete Response Letter on pegfilgrastim. In its letter, FDA did not require additional clinical studies. In the meantime, Coherus still is seeking to file its biosimilar etanercept for approval in Europe later this year, and its version of adalimumab in the US in early 2018. However, John Carroll reported that Coherus’ clinical development partner on etanercept in Japan, Daiichi Sankyo, has decided to pull out because of concerns that Coherus will not be able to manufacture the product.