The Center for Biosimilars Staff

1. Pfizer’s Humira Biosimilar Shows positive 

: Pfizer’s second proposed inflammation biosimilar and the third proposed biosimilar pipeline    molecule to report positive top-line results within the past four months.The Pfizer biosimilars pipeline consists of eight distinct biosimilar molecules in mid to late stage development, and several others in early stage development.

2. Non-Proprietary Naming of Biologics and Biosimilars: 

: FDA will change Zarxio’s nonproprietary name from filgrastim-sndz to “filgrastim-bflm." And Amgen's Neupogen (filgrastim) would be changed to "filgrastim-jcwp."

3. FDA to review Biocon and Mylan's biosimilar 

: The US Food and Drug Administration (FDA) has accepted Mylan’s biologics license application (BLA) for the biosimilar, MYL-1401O, for review through the 351 (k) pathway.

Articles

Today's top healthcare news with a focus on the biosimilars industry.

News and Views in Healthcare: Today's Top 3 Reads

According to an amicus brief filed by the Generic Pharmaceutical Association's Biosimilar's Council (GPhA), a rumble may be brewing that could delay the approval process of biosimilars in the US by six months.

As part of Obamacare, the Biologics Price Competition and Innovation Act (BPCIA) states an expedited approval pathway can be used and appropriately marketed only when--and after--the reference biologic is in market for 12 years.

The US Food and Drug Administration (FDA) will only accept biosimilar filings (351(k)) five years after the original biologic is licensed by the FDA, and after the filing is accepted, biologics and biosimilars manufacturers are expected to exchange patent and manufacturing information to continue the “patent dance" and work out any conflicts. The problem is the provision in the BPCIA that directs biosimilar makers to provide a 180-day notice to biologics manufacturers prior to marketing the biosimilar, but only after a biosimilar is licensed by FDA.

In August, Amgen announced Apotex had provided it with a copy of its biologics license application (BLA) for a biosimilar of the neutropenia treatment Neulasta (pegfilgrastin) and exchanged information on the biosimilar's manufacturing and Amgen patents that the biosimilar could infringe on.

Amgen sued Apotex because Apotex argued that by complying with the information exchanges it was allowed to opt out of providing the 180-day notice of marketing.

In early December a federal judge in Florida ruled against Apotex and found that the 180-day notice provision is actually mandatory, though Apotex appealed that decision.

The only other case to deal with such a scenario involves 

of Amgen's Neupogen, which is the first US biosimilar approved under the BPCIA. That biosimilar’s launch, approved as Zarxio, was delayed for 180 days after FDA approval because of the notice provision, although those companies did not engage in the so-called patent dance as Apotex and Amgen did.

Six months in delay may equate to millions of dollars for development organizations -- and time for patients to be given another medicinal option.

The New Wrinkle in the US Biosimilars Approval Process 

From FDA Approval to Medicare and Medicaid Payments: 6 Things to Know

1. Effective July 1, 2015, for biosimilars reimbursed under Medicare Part B, which generally covers services provided in physician offices and clinics (including clinics operated as hospital outpatient departments), CMS set the stage for its coding policy to group all biosimilar products of a single reference product under the same HCPCS code. For Zarxio, CMS established a temporary billing code, HCPCS code Q5101 (“Injection, Filgrastim (G-CSF), Biosimilar, 1 microgram"). Effective Jan. 1, 2016, the billing code for the reference product was revised to expressly exclude biosimilars. HCPCS code J1442 now reads: “Injection, Filgrastim (G-CSF), excludes biosimilars, 1 microgram.” CMS left the door open for future coding decisions to separate some or all biosimilars into their own codes.

2. Although CMS established a single HCPCS code methodology for the biosimilar payment calculations, the agency acknowledged a need for a better understanding of products being dispensed or administered. Mandatory modifiers, therefore, which identify the manufacturer of the administered biosimilar, must be appended to a HCPCS code on an individual claim. The modifiers are posted on a dedicated CMS webpage. For example, the modifier for Zarxio is “ZA.” In addition, under an FDA draft guidance, for pharmacovigilance and other purposes, the nonproprietary names of biological products would include a unique four letter suffix that is devoid of meaning (e.g., “filgrastim-bflm” instead of the current “filgrastim-sndz” for Zarxio). Inflectra was assigned the nonproprietary name “infliximab-dyyb” upon its licensure.

3. The payment for biosimilars under Medicare Part B is generally based on the products’ average sales price (ASP) of all national drug codes (NDCs) assigned to the biosimilar biological products included within the same HCPCS code. An additional amount of 6 percent of the ASP of the reference product would be added. The total payment limit for biosimilars therefore is 100 percent of the weighted ASP of all the biosimilar products sharing the same HCPCS code plus 6 percent of the ASP of the reference product. On March 8, 2016, CMS announced a proposal to test new Part B payment models for prescription drugs, including biosimilars. Spurred by the rising expenditures for Part B drugs (from $11 billion in 2007 to an estimated $22 billion in 2015), CMS promulgated a proposed rule that would proceed in two phases. In Phase I, CMS would test moving from the current ASP plus 6 percent add-on formula to an ASP plus 2.5 percent add-on, along with a flat fee of $16.80. In Phase II, CMS would use a value-based purchasing strategy, which may include discounting or eliminating patient cost sharing; feedback on prescribing patterns and online decision support tools; indications-based pricing; reference pricing; or risk-sharing agreements based on outcomes.

4. Under Medicare Part D, biosimilars may be added to a plan formulary at any time as a formulary enhancement, but are not considered interchangeable with the reference product. Biosimilars are not subject to the coverage gap discount and, because they are not generics, biosimilars are subject to higher maximum copayments for individuals eligible for low income subsidies or who have entered catastrophic coverage.

5 On Feb. 2, 2016, CMS restated its March 2015 guidance on the classification of biosimilars under the Medicaid program, confirming that biosimilars are “single source drugs” and subject to higher rebates under the Medicaid Drug Rebate Program.

6. CMS has repeatedly stated in its rules and guidance that the reimbursement policies are developing and that the agency would consider refinements in future policies and guidance. In addition, the FDA has not yet released draft guidance on what is needed to obtain approval of an “interchangeable” biosimilar product nor approved any biosimilars as interchangeable with their reference products. Stakeholders should therefore monitor for developments in light of the recent approval of Inflectra, pending biosimilar applications for FDA review and the possibility of future approvals of interchangeable products.

US Biosimilar Reimbursement: Medicare and Medicaid

The biosimilar erythropoiesis-stimulating agent (ESA) epoetin was well-tolerated and efficacious in the treatment of geriatric patients with chemotherapy-induced anemia (CIA), a recent study found.

CIA is a common complication among cancer patients, particularly older individuals. Biosimilar ESAs can lower the costs of supportive cancer treatments for this patient population. In a subanalysis published in Dove Press, investigators compared the efficacy and tolerability of an epoetin biosimilar for the treatment of CIA in patients <70 years versus patients ≥70 years.

Patients with CIA (hemoglobin [Hb] <11 g/dL) in association with chemotherapy for solid tumors, lymphoma, or myeloma, were enrolled in the ORHEO observational trial. Participants were administered an epoetin biosimilar, and were evaluated at 3 and 6 months for a response.

A response was defined in the study as achieving target Hb without blood transfusions during the 3 weeks preceding measurement, Hb ≥10 g/dL, or Hb increase ≥1 g/dL since study enrollment.

The secondary endpoints were changes in Hb level, transfusion rates, treatment interruptions, and adverse events (AEs), according to the study.

All statistical analyses were conducted on the per protocol population, which excluded patients with missing baseline Hb values, patients for whom age was not recorded, patients who had not initiated chemotherapy at baseline, patients who were not receiving an epoetin biosimilar at baseline, and patients who switched to another epoetin treatment between baseline and 6 months.

ORHEO is a large, observational, non-interventional, longitudinal, national, multi-center study that included 2333 patients from 235 centers.

Biosimilar Shows Promise Treating Chemotherapy-Induced Anemia in Elderly Patients

In April 2016, the Food and Drug Adminstration FDA approved Inflectra, a biosimilar to infliximab (Remicade), which was the first monoclonal antibody biosimilar---and here 

 reviews subsequent developments regarding biosimilars for rheumatic diseases.

Since April, two other biosimilars have received approval: Erelzi, a biosimilar to etanercept (Enbrel), and Amjevita, a biosimilar to adalimumab (Humira).

The American College of Rheumatology (ACR) has stated, "The FDA considers a product to be 'biosimilar' to a reference product if it is shown to have no clinically meaningful differences with respect to safety, potency, and purity."

 of the ACR's Committee on Rheumatologic Care told 

, "The ACR is hopeful that biosimilars will help reduce the cost of biologics and thus improve patient access to these complex and lifesaving drugs."

Eight months later, he said, "We remain cautiously optimistic about biosimilars including Inflectra. The most important development since April, in my opinion, is the release of the results of NOR-SWITCH. This trial provided real-world data on maintenance of efficacy as well as adverse events after nonmedical (that is, no medical indication to change drugs) switching from reference to biosimilar infliximab in 481 patients with a diagnosis of rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, Crohn's disease, ulcerative colitis, or psoriasis."

, presented in a late-breaker session at the ACR meeting, followed patients for 52 weeks after either being switched from reference infliximab to the biosimilar CT-P13 or continuing on infliximab, and found disease worsening in 26.2% and 29.6%, which was within the non-inferiority margin.

"Unfortunately, I've not seen any reason to believe that the availability of biosimilars in the U.S. will reduce the out-of-pocket expenses to patients who rely on biologic therapies," White said. "Nor have I seen any evidence that the availability of biosimilars will reduce costs to these patients by reducing their insurance premiums. Indeed, early pricing information that I've seen indicates that discounts will be modest at best. Hopefully that will change as more biosimilars enter the market and competition increases."

"In addition to ongoing court battles between manufacturers, unresolved issues surrounding biosimilars include the FDA's final decisions regarding interchangeability and the state laws and regulations that will govern switching and notification. We continue to keep a close eye on those developments," White concluded.

 noted, "Across the country, legislation governing the use and especially substitution of biosimilars has been moving through state legislatures. These bills and laws vary to some extent but are fairly uniform in that they will allow for the substitution by a pharmacist with a lower cost biosimilar that the FDA has designated as interchangeable. Without interchangeable status, a new prescription must be obtained in order to switch."

The three rheumatology biosimilars presently approved do not have interchangeable status.

, of McDonnell Boehnen Hulbert & Berghoff, told 

 on October 17 that it would begin shipping the Inflectra biosimilar in late November. "This press release indicated that it would be introduced at a 15% discount to the current wholesaler acquisition cost of Remicade," said Williams, who specializes in patent litigation in pharmaceuticals and biotechnology.

At the time of approval, Janssen, the owner of Remicade, had asserted that Inflectra infringes on a patent that doesn't expire until September 2018 and vowed to defend their intellectual property rights. However, in September 2016, the District Court found that U.S. patent no. 

 ("Anti-TNF Antibodies and Assays Employing Anti-TNFa Antibodies") was invalid, based on "

," Williams explained. Janssen had also held patent 

, ("Anti-TNF Antibodies and Peptides of Human Necrosis Factor"), which expired in July 2011.

"In briefing for extending a deadline in the Federal Circuit, Janssen stated that U.S. sales began on November 28, 2016. Celltrion, et al. also indicated on December 6, 2016 in a different brief that they had recently launched," Williams said.

Developments in Biosimilars for Rheumatic Diseases

Did you know that biosimilars account for less than 0.5% of the value of the mature markets biologic spend---but in pharmerging markets, non-original biologics are over 10% of all biologics spend?  

According to a report by the IMS Institute for Healthcare: 

The Global Use of Medicines: Outlook through 2017

and are expected to represent 19-20% of the total market value in 2017. Other insights in the market:

• Biologics growth is driven by Monoclonal Antibodies (MABs) and human insulin, with four out of the top five biologics in 2012 being MABs.

• Development and production of biologics, both branded and generic, is increasingly competitive with a broad range of players, from small to large pharma companies now attracted to the market.

• In many countries with less rigorous IP protection laws, there has been a recent surge of non-original biologics (NOBs).

• The price premium typically associated with biologics has turned them into an obvious target for government savings in some markets. Connsequently, biosimilar pathways have been defined in Europe, US, and increasingly in pharmerging markets in an effort to encourage lower cost competition.

• In pharmerging markets, both governments and patients struggle to pay for biologics and hence NOBs, encouraged by market demand and government policy, have grown very quickly.

Biologic Agents Continue to Outpace Overall Pharma Spending Growth 

US Payers do not expect the biosimilars market to be like the generics market and they also do not expect the US biosimilars market to be like that in Europe, according to a report published by biotech giant Amgen.

While small molecule drugs are ideal for generics replication, biological drugs are not so simple. Biological drugs are usually large, complex molecular structures derived from or produced through a living organism, making them very difficult to replicate.

The Amgen survey of 40 different payers found that payer perceptions of biosimilars include:

• Payers anticipate biosimilars will be a strategy to reduce specialty drug prices and most (88%) believe the category represents a compelling business opportunity

• Most (80%) do not expect biosimilars to emulate the generics market; instead, payers expect to consider them as lower-cost branded options

• While there are analogues from the European commercial experience, at this time, few US payers are relying on Europe’s experience for US forecasting

The survey also showed that although US payers are eager for biosimilars to reduce specialty drug prices, Europe’s experience shows the level of savings may vary. European experience suggests that the most important conditions for market uptake of biosimilars are driven by factors such as physician perception, patient acceptance, local pricing and reimbursement regulations and procurement policies and terms. Amgen’s research also indicates that the US path may share few characteristics with the global experience to date.

The main difference between the US and Europe when it comes to biosimilars are interchangeability and substitution at the pharmacy level.

In Europe, the European Medicines Agency does not make any evaluation of interchangeability and individual Member States decide whether a biosimilar may be substituted at the pharmacy or not. In the US, the Food and Drug Administration (FDA) has the authority to make a decision on interchangeability. In addition, the Biologics Price Competition and Innovation (BPCI) Act gives FDA the authority to designate a biosimilar as interchangeable with its reference product. This means that the biosimilar may be substituted for the originator product by the pharmacist without reference to the prescribing physician.

US payers do not expect the biosimilars market to be like the generics market.

How Do US Payers View Biosimilars From a Cost Perspective?

 today announced that the results of the HERITAGE study have been published in the J

ournal of the American Medical Association

Study results confirm the efficacy, safety and immunogenicity of MYL-14010, the proposed biosimilar trastuzumab co-developed by Mylan and Biocon, in comparison to branded trastuzumab. The results of the trial were first presented at this year's American Society of Clinical Oncology (ASCO) Annual Meeting and the European Society for Medical Oncology (ESMO) Congress.

Branded trastuzumab is indicated to treat certain HER2-positive breast and gastric cancers.

"The development of biosimilars requires a systematic scientific approach from design of the process to development. Biocon and Mylan have a scientifically rigorous, ethically compliant and structured development strategy to establish comparative safety and efficacy of our products. The global clinical progress of our various biosimilars programs demonstrates the strength of our R&D capabilities in this area. We are pleased that JAMA has published the clinical study results of trastuzumab after its very rigorous peer review process," said Dr. Narendra Chirmule, Sr. Vice President & Head R&D, Biocon.

Dr. Hope S. Rugo, professor of medicine at the University of California, San Francisco, commented: "We are encouraged by the confirmatory efficacy and safety results of the HERITAGE study recently published in JAMA. This study was the last major step of a multiple-phased program to demonstrate that proposed biosimilar trastuzumab meets the criteria for equivalence in comparison to branded trastuzumab. Published study results showed an overall response rate of 69.6% for MYL-14010 compared to 64% for branded trastuzumab. Tumor progression, progression-free survival and overall survival was not statistically different between proposed biosimilar trastuzumab and branded trastuzumab at week 48."

Mylan President Rajiv Malik added, "We are proud that JAMA has recognized the results of the HERITAGE study and are encouraged that the proposed biosimilar trastuzumab, MYL-14010, could provide an effective treatment option for metastatic breast cancer patients. Phase 3 study results show that a biosimilar can deliver similar efficacy in comparison to a branded product. Once approved, we believe our proposed biosimilar trastuzumab will provide a lower cost treatment option for breast cancer patients. Welook forward to continuing our industry-leading role with Biocon toexpand patient access across the globe to this critically important medicine as well as Mylan's broad portfolio of 15 additional biologics and insulin analogs currently in development."

The HERITAGE data was submitted by Mylan to the U.S. Food and Drug Administration (FDA).

Branded Trastuzumab HERITAGE Study Published in JAMA

The Knowledge Group/The Knowledge Congress Live Webcast Series, the leading producer of regulatory focused webcasts, announced today that it has scheduled a live webcast entitled: The BPCIA Patent Dance — What Biosimilar Companies Need To Know.

On or about seven years now, the Biologics Price Competition and Innovation Act (“BPCIA”) of 2009 has continually facilitated entry of biosimilar products into the market. By allowing submission of an abbreviated Biologics License Application (“aBLA”) to an already approved and licensed FDA product, BPCIA aids in making the pioneer and the applicant meet halfway. However, meeting halfway is not as easy as it sounds. There are matters to deal with: agreements and disclosures to be settled down before the commercial marketing of a biosimilar product begins. Patent disputes are among the most debated, and often controversial issues that biosimilar companies are faced with.

In its second part, BPCIA addresses certain patent resolution issues. Commonly called as the “patent dance”, 42 U.S.C. § 262(l) provides the steps and schedule when a reference sponsor product and a biosimilar applicant exchange “confidential information” about the aBLA. Typically, the confidential information disclosed by the applicant is its application and manufacturing trade secrets.

Indeed, the music hasn’t stopped for biosimilar companies, and “patent dance” is still obviously becoming a dance craze for them. Questions remain as to whether or not companies facing the “dance” will minimize the potential for litigation under the BPCIA, and to what extent will this craze bring the industry.

The Knowledge Group has assembled a panel of key thought leaders to provide the audience with an in-depth analysis of the BPCIA “Patent Dance” and its recent developments. In this two-hour LIVE Webcast, a panel of distinguished professionals and thought leaders will help biosimilar companies understand the important aspects of this significant topic. Speakers will also offer best practices in helping the audience better understand the steps and legal issues brought by the latest litigations.

This 2-hour webcast will discuss the following key provisions:

-Nature of the abbreviated Biologics License Application (“aBLA”)

-The 180-day Notice of Commercial Marketing

For an updated list of the faculty panel, please visit:

https://theknowledgegroup.org/event-homepage/?event_id=2114

Live webcast on what biosimilar companies need to know.

The BPCIA Patent Dance – What Biosimilar Companies Need To Know

UK-based Mundipharma has made steps towards its goals of becoming a leader in the biosimilars field, it has announced this week. It announced on Tuesday that it had secured a distribution licence from South Korea’s Celltrion for Truxima, a biosimilar of Roche's (ROG: SIX) blockbuster drug MabThera (rituximab). This biosimilar received a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use last week for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. These are all of the indications of the reference biologic.

If approved, Truxima would be the first rituximab biosimilar approved by the European Commission. Mundipharma and its network of independent associated companies will have exclusive rights to market and distribute Truxima in the UK, Germany, Italy, Ireland, Belgium, Luxembourg and the Netherlands.

It will be the second biosimilar monoclonal antibody to be marketed and distributed by the Mundipharma network.

The company’s managing director Antony Mattessich said: “Mundipharma is establishing itself as a leader in biosimilars with our deep understanding of European markets and track record in delivering marketing excellence in a complex area.

“Biosimilar rituximab has an enormous potential to deliver patient benefits while freeing up resources for novel cancer treatment options. That’s why biosimilars are becoming a key part of our business in Europe and we look forward to building on our partnership with Celltrion and continuing to identify further partnerships in this area.”