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.

Merck Sharply Discounts Its Infliximab Biosimilar

In news that will likely be cheered by payers, Renflexis™, Merck and Samsung Bioepis’ entry into the infliximab marketplace, will launch at a significant discount, according to Merck.

Approved by the US Food and Drug Administration on April 21, 2017, Merck’s second-to-market biosimilar will be available immediately. What was truly noteworthy was the pricing: $753.39 per dose, which represents a 35% savings over the current list price of the originator product Remicade® (Janssen Biotech), and about 13% less than the list price of Inflectra®, the first biosimilar infliximab to be launched.

It appears that Merck is gambling that this pricing will help jumpstart marketshare, and perhaps gain serious consideration to payer coverage. It is, in fact, the first biosimilar of the 3 now available that has broken through the 15% discount (relative to the originator product) floor.

Some industry observers believe that this could be the start of a “race to the bottom,” similar to that seen in the multisource generics industry, but the biologics manufacturers may be more reluctant to engage in pricing wars that could result in 70% discounts. The key question will be how Janssen and Pfizer reacts to the introduction of infliximab-abda. According to our sources, Janssen has matched the net price of Inflectra by increasing its rebates to payer customers, retaining its preferred positioning.  [ERRATUM (7/31): In the original published version of the article, we indicated that Pfizer had preferred positioning deals for Inflectra with UnitedHealthCare and CVS Health. This is incorrect. UHC and CVS have given preferred positioning to Zarxio and Basaglar, not at present to Inflectra. We regret this error and hope it does not cause our readers any inconvenience.]

In a quirk that can only be imagined in the biosimilar arena, Merck owns the marketing rights for Janssen’s Remicade in Europe, so it is dedicated to defending an originator brand overseas while cutting this brand’s marketshare in US.

Our database on biosimilar filings indicates that no other infliximab 351(k) applications have been submitted (at least publicly announced), so it is reasonable to expect that no new market entrants will change the competitive dynamic before 2019.

UPDATE (7/26): An article in Bio-Pharm Reporter by Dan Stanton quoted Pfizer executives who say that Inflectra’s allowable ASP level to $753.40–the pricing level of Renflexis, essentially equaling the 35% discount relative to Remicade. However, the WAC price of Inflectra currently stands at 19% (not 15%) below that of Remicade.

 

Patent Litigation Delays Release of Second Follow-on Insulin Glargine

The US Food and Drug Administration gave its approval on July 20 to Merck’s version of insulin glargine. Although not technically a biosimilar, it is suffering a fate like that of multiple biosimilars—approved but in launch limbo owing to patent litigation issues.

Merck applied for approval of its insulin product under the 505(b)(2) pathway (not the 351[k] biosimilar pathway), which essentially makes it another biologic brand, not a biosimilar. The first insulin glargine follow-on product, Basaglar® (Lilly), utilized the same abbreviated pathway to approval; however, Lilly agreed to a patent settlement with the originator manufacturer, Sanofi, allowing Lilly to launch Basaglar in December 2016. Merck performed separate clinical studies to prove its product’s noninferiority to Lantus®, as well as relying on Lantus data in its application.Image result for Lusduna

Under Hatch-Waxman Act rules, Merck will have to either wait for the final positive ruling by the US District Court in Delaware on the patent litigation or 30 months after the initial filing of Sanofi’s lawsuit (in September 2016), whichever is earlier. This could potentially result in a launch in 2019, providing a compelling incentive for Merck to come to a licensing agreement with Sanofi.

In another connection with biosimilars, Merck developed the drug along with its biosimilar partner Samsung Bioepis.

Whenever the launch takes place, Merck will brand their insulin glargine drug Lusduna Nexvue, which will be available as a prefilled syringe.

A Profile of a Lesser-Known Player in the Biosimilar Space: Pfenex

On occasion, we profile some biosimilar manufacturers with whom our readers may not be as familiar as the big pharma players. In this post, we highlight a San Diego company, named Pfenex (pronounced FEE-nex, as in the city).

Pfenex was founded in 2009, the result of a spin-off from The Dow Chemical Company, whose business was based on its proprietary protein production platform. Called Pfenex Expression TechnologyTM, “it combines an extensive toolbox of expression components with a robotically-enabled high-throughput parallel strain screening technology, delivering unprecedented speed and success in identifying protein production strains capable of producing large amounts of soluble, actpfenex-254_(2)[1]ive product,” according to Pfenex’s website.  The company believes that use of this recombinant protein production platform could enable the avoidance of process related intellectual property that challenge other biosimilar manufacturers.

The technology itself was developed in 2001. Patrick Lucy, the Interim Chief Executive Officer, President and Secretary, and Chief Business Officer, has been with the company and its predecessor from the beginning of the platform development. Pfenex is also a founding member of the Biosimilars Council.

Why you may be hearing more about this company: A biosimilar version of ranibizumab (Lucentis®) and a therapeutic equivalent to teriparatide (Forteo®)  are lead products for Pfenex. Teriparatide, although a recombinant protein, is being developed via the 505(b)(2) pathway and the pivotal study is ongoing. Ranibizumab has completed a phase 1/2 trial and according to Mr. Lucy, Pfenex “is considering its strategic options” with regard to advancing the product. Both were produced using its Pfenex Expression Technology, and Pfenex is further leveraging its platform for the development of other products. In 2016, Pfenex completed a $181 million multiproduct partnership with Jazz Pharmaceuticals, which includes an option for Jazz to negotiate a license to Pfenex’s pegaspargase (Oncaspar®) biosimilar candidate.

Interestingly, Pfenex is also using its technology to develop a very different drug candidate, Px563L, a novel recombinant protective antigen-based vaccine to protect against anthrax. This is part of a $143.5 million advanced development contract with the Biomedical Advanced Research and Development Authority (BARDA) of the Department of Health and Human Services (HHS).

FDA Advisory Committee Unanimously Recommends Approval for Avastin® and Herceptin® Biosimilars

It was a good day for biosimilar manufacturers and a bad day for Roche and its Genentech unit. Following a broadly positive FDA staff review of the first products to directly treat tumors, the Food and Drug Administration’s Oncology Drug Advisory Committee took the expected step of unanimously recommending approval for agents from Amgen and Mylan.

In the morning session, Amgen and Allergan’s ABP-215 was convincingly presented as equivalent to Roche’s bevacizumab (Avastin®), based on  pharmacologic, pharmacokinetic, efficacy, and safety evaluations. Clinical studies were performed in patients with non–small cell lung cancer. The Advisory Committee voted 17-0, recommending approval of the drug for all of the originator product’s nonprotected indications:

  • As first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy
  • Combined with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line ABP 215-containing regimen
  • As first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non–small cell lung cancer in combination with carboplatin and paclitaxel
  • For the treatment of glioblastoma with progressive disease in adult patients following previous therapy as a single agent
  • For the treatment of metastatic renal-cell carcinoma in combination with interferon alfa
  • In combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix

Several questions brought up by the Committee involved the glioblastoma indication, and the drug’s passage over the blood–brain barrier. Progressive multifocal leukoencephalopathy was also mentioned, but this did not deter the Committee from its unanimous vote.

Amgen did not apply for approval for Avastin’s other orphan indications, which are “protected,” according to FDA. If they did want to obtain approval for those, an additional data package would need to be submitted.

Immunogenicity studies did not reveal any material differences between the biosimilar and originator product. In a minor twist, Amgen did the clinical testing of its biosimilar against the EU-licensed version of Avastin, and it had to conduct bridging studies to demonstrate the similarity between the EU version and the US-licensed originator drug.

In the day’s second session, Mylan’s MYL-1401O, a biosimilar version of Roche’s Herceptin (trastuzumab), was evaluated. The totality of evidence, according to the FDA staff review documents, supported the 351(k) application by Mylan. The Advisory Committee agreed, voting 16-0 to recommend the biosimilar for approval for use in Herceptin’s indications:

  • For use as adjuvant treatment of HER2 overexpressing node- positive or node-negative (ER/PR negative or with one high risk feature) breast cancer (1) as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; (2) with docetaxel and carboplatin; or (3) as a single agent following multimodality anthracycline-based therapy
  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
  • In combination with cisplatin and capecitabine or 5- fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

The FDA usually accepts the recommendation of its Advisory Committees in issuing final decisions. However, in late June, the agency rejected Pfizer’s Retacrit despite a 14–1 Advisory Committee vote to recommend, based on potential problems at a manufacturing facility. Mylan’s manufacturing partner Biocon, has recently been cited by French inspectors in connection with its European approval application, for potential problems at its Bangalore plant.

A final FDA decision is expected for Amgen’s bevacizumab biosimilar by September 14, and for Mylan’s trastuzumab biosimilar by September 3.

Coverage Uptake: Zarxio® Covered by 94% of Employer-Sponsored Plans

An analysis released by Avalere on July 11 showed that coverage of biosimilar filgrastim is the rule, not the exception, by employer-sponsored plans.

Avalere surveyed medical or pharmacy executives from 45 health plans and insurers, representing 183 million lives, about coverage for their commercial products. They found that 94% had placed Zarxio (filgrastim-sndz) on formulary. Forty-two percent of the plans responding to this online survey indicated that Zarxio was a preferred brand. This is on par with the competitors (Granix®, Neupogen®, and Neulasta®), one of which is preferred for 45% of the plans surveyed.

In the report, titled “Policy 360: Biosimilars—US Payer Perspective,” Avalere found that coverage in these same employer-sponsored plans for Inflectra® (infliximab-dyyb) was trailing, with 42% covering the biosimilar but only 7% listing it as preferred on their 2017 formularies. Pfizer has only been available for 7 months, so these numbers are expected to rise over time.

Unsurprisingly, health plans ranked relative cost as the number 1 factor in coverage decision making for biosimilars (95%), followed by efficacy (80%), safety (73%), and existing contracts (53%).

In other news: Mylan and its partner Biocon hit a stumbling block to approval of its trastuzumab biosimilar in Europe (application filed in 2016). French inspectors cited Biocon’s manufacturing facility in Bangalore, India, for a number of violations that need to be corrected before the partners can receive authorization to market from the Europeans Medicines Agency. An inspection of the facility, conducted in March, also revealed problems that could affect the production of Mylan and Biocon’s pegfilgrastim biosimilar. The companies had filed for Food and Drug Administration approval of both products, with trastuzumab being reviewed by the Oncology Advisory Committee on July 13. It is not known whether a potential US-licensed version of the drug will be produced at the same Bangalore plant.

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.

Will Approval of an Interchangeable Biosimilar Mean that Others Are Inferior?

In terms of the biosimilar market and utilization, the US has been at least one full decade behind Europe in every respect but one. Yes, we have the EU beat in a game they avoided playing: The interchangeability gambit. The Europeans never defined interchangeability as a separate concept for biosimilars, thus leaving the individual countries to decide whether to allow unencumbered switching of biosimilars for their originator drugs.

As in other areas of biosimilar policy and regulation, the US started very slowly. Leah Christl, PhD, Associate Director for Therapeutic Biologics, OND Therapeutic Biologics and Biosimilars Team, Food and Drug Administration (FDA) stated last week at the Drug Industry Association’s annual meeting in Chicago that she expects the first interchangeable biosimilar to be approved within about 2 years. This is probably realistic, based on the timeline of the adoption of the agency’s interchangeability guidelines. Comments on the draft guidance are being read by the FDA at this time. Seven years after the passage of the legislation calling for the biosimilar approval pathway. If there were competitors in this game, we’d be desperately trying to catch up!

It seems unlikely that the FDA has any active 351(k) applications seeking the interchangeability designation, although Dr. Christl did not reveal whether this was the case. The application process is confidential; a submitted application is publicized only if the drug maker issues a press release on its ownDeck 1.png. It would seem premature to seek the interchangeability designation before the FDA’s own guidance on what the review entails is released. This may not prevent a biosimilar manufacturer that has already received approval from taking the quick step towards interchangeability, especially if they have conducted a series of switching studies that meet the FDA’s criteria (e.g., NOR-SWITCH).

Payers are chomping at the bit for an interchangeable product in the 36 states (and 3 pending) that have signed legislation allowing pharmacies to automatically substitute a biosimilar for an originator biologic.

Others have pointed out that the interchangeable biosimilar may be a boon to its manufacturer, but it may have negative effect on competitive markets. For example, a noninterchangeable infliximab may be considered by prescribers or patients somehow inferior to the interchangeable version, devaluing this biosimilar. On the other hand, the maker of “infliximab-int” could experience increased demand and boost prices (or avoid decreasing prices in the face of other noninterchangeable biosimilars coming to the market). And this may be justified. No one really knows the manufacturer’s incremental cost of achieving this designation, based on:

  • The cost of conducting additional switching studies
  • The potential cost of responding to FDA requirements for more data
  • The opportunity cost in marketing time, resulting from a delay in the application or approval

The race for a product with this extremely valuable designation drags on at a snail’s pace. I hope I’m still writing about it by the time someone reaches the finish line.

 

US Supreme Court Strikes Down 180-Day Waiting Period

In a unanimous decision, the Supreme Court rejected Amgen’s oral arguments—a biosimilar manufacturer can meet the 180-day notification period requirement by notifying the originator’s manufacturer before receiving approval. In other words, biosimilar launches can occur immediately after approval by the Food and Drug Administration (FDA).

The 180-day notification period was seen as giving the originator a further 6 months of exclusivity, not allowing newly approved products to reach the market until after the period had expired. The argument by biosimilar manufacturers has been that notification of its intention to commercialize the drug can be given prior to approval (e.g., at the time the application is sent to the FDA), without any disadvantage in terms of an examination of whether patents had been infringed.

Sandoz v. Amgen involved Sandoz’s filgrastim biosimilar Zarxio®, which has since launched, but this decision, written by Justice Clarence Thomas, will clear one barrier out of the way to faster access to biosimilars.Image result for justice clarence thomas

The justices decided to punt on a ruling of whether the patent dance is necessary to the states, where unfair business conduct laws may take precedence. The patent dance involves a protocol where the biosimilar applicant must provide to the reference drug maker information on how it plans to manufacture the agent and its actual 351(k) application. The reference drug manufacturer can then evaluate which of its patents it believes will be infringed, and must respond (and counter) within a specific timetable. According to Justice Thomas’ opinion, “There is no dispute about how the federal scheme actually works, supreme-courtand thus nothing for us to decide as a matter of federal law. The mandatory or conditional nature of the [Biologics Price Competition and Innovation Act] requirements matters only for purposes of California’s unfair competition law, which penalizes ‘unlawful’ conduct. Whether Sandoz’s conduct was ‘unlawful’ under the unfair competition law is a state-law question, and the court below erred in attempting to answer that question by referring to the BPCIA alone.

“We decline to resolve this particular dispute definitively because it does not present a question of federal law. The BPCIA, standing alone, does not require a court to decide whether §262(l)(2)(A) is mandatory or conditional; the court need only determine whether the applicant supplied the sponsor with the information required under §262(l)(2)(A).”

Justice Stephen Breyer suggested, in a concurring opinion, that the FDA may play a greater role in deciding the outcome of the patent dance. He stated, “[If FDA], after greater experience administering this statute, determines that a different interpretation would better serve the statute’s objectives, it may well have authority to depart from, or to modify, today’s interpretation.”

FDA Sets Advisory Board Review Date for Cancer Biosimilars

On July 13, the Food and Drug Administration’s Oncology Drug Advisory Committee will meet for 2 sessions to review biosimilars that were submitted via the 351(k) pathway in November 2016 to challenge reference agents manufactured by Roche/Genentech.

That morning, the committee will review Amgen and Allergan’s 351(k) submission for its biosimilar version of bevacizumab (Avastin®), which is used for the treatment of patients with metastatic carcinoma of the colon or rectum; nonsquamous, non–small cell lung cancer; gliobastoma in adults; metastatic renal cell carcinoma; and cervical cancer. Avastin is also used off-label to treat several ocular disorders, including wet age-related macular degeneration.

In the afternoon, the same committee will ruminate on the evidence for recommending Mylan/Biocon’s biosimilar version of trastuzumab (Herceptin®) for approval. This agent’s proposed indications include HER2 overexpressing breast cancer (early treatment and metastatic) and metastatic gastric adenocarcinoma.

Final decisions on the approval of these agents are expected in the early third quarter of this year. Recommendations for approval by the Advisory Committee of either or both products would likely result in the launch of the first biosimilars for the direct treatment of cancer.

In other news…This week’s Digestive Disease Week scientific sessions yielded additional positive results in switching studies on Pfizer/Celltrion’s infliximab-dyyb (Inflectra® in the US). In the first, a phase 3 double-blind, controlled trial of 220 patients with Crohn’s disease from 16 countries, found no significant difference in efficacy and safety results compared with the originator product. The second investigation reported extended (2-year) results of Norway’s well-publicized phase 4 NOR-SWITCH study, which comprised 481 patients with inflammatory bowel disease.