Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	Sandoz announced on Sept. 3, 2015 that despite the barriers erected by competitor Amgen, Sandoz officially launched Zarxio (filgrastim-sndz), its biologic version of Amgen’s neutropenia medication Neupogen (filgrastim). To complement the drug launch, Sandoz is also launching Sandoz One Source, a patient services center providing support for and information on the medication.

follows the release of FDA draft guidance

 on the naming of biosimilars, which proposed that each biologic have a core name plus a suffix to create a proper name. In the case of Zarxio, trial data demonstrated enough similarity between the biosimilar and the reference product to warrant extrapolation of the use of Zarxio to five indications associated with the reference product. FDA said in the draft guidance that the naming convention for related biological products that do not share all of the same indications as their reference products may differ from that of the proposed naming conventions for biosimilars that have all of the same indications as an innovator product.
	
	Zarxio will be offered at a 15% discount from the the price of Amgen's Neupogen in the United States, although in Europe, the discount ranges from 20-30%, 

Articles

After many legal proceedings surrounding the first FDA-approved biosimilar, Zarxio officially launched commercially on Sept. 3, 2015.

Sandoz Officially Launches Zarxio

	Valeant announced on Sept. 1, 2015 that it has entered into an agreement to develop and commercialize brodalumab. The company will license the novel, investigational product from AstraZeneca for an upfront payment of $100 million, and will also pay AstraZeneca pre-launch milestone payments of up to $170 million and post-launch fees of up to $175 million. According to Evercore ISI analyst Umer Raffat, the deal marks Valeant’s “first foray into biologics.”

	Although J. Michael Pearson, chairman and CEO of Valeant, said in a press release that the monoclonal antibody (mAb) is “potentially the most efficacious therapy yet for moderate-to-severe plaque psoriasis,” Amgen-who was a co-developer of the drug with AstraZeneca-essentially abandoned the project earlier in the year because of reports of suicidal ideation and behavior in the program. Amgen thought the risks would likely “necessitate restrictive labeling,” and would effectively limit the patient population that could receive the drug, according to an Amgen 

	Valeant will hold exclusive rights to brodalumab, except in Japan and certain other Asian countries, where rights are held by Kyowa Hakko Kirin under a prior arrangement with Amgen. Other potential competitors in the interleukin-17 (IL-17) space include Lilly’s ixekizumab and Novartis’ Cosentyx (secukinumab), but as Raffat points out, brodalumab is an antibody to the IL-17 receptor, while ixekizumab and secukinumab work by targeting the IL-17 ligand.

	Despite the apparent risks involved with the novel mAb, brodulumab did 

 in a head-to-head clinical trial that it was more successful in clearing skin plaques than Johnson & Johnson's Stelara (ustekinumab).

The investigational monoclonal antibody targets interleukin-17 and is in clinical trials for the treatment of plaque psoriasis.

Valeant Licenses Brodalumab Candidate from AstraZeneca

	FDA announced on Aug. 27, 2015 that it approved Repatha (evolocumab), Amgen’s PCSK9 inhibitor for the treatment of heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), and clinical atherosclerotic cardiovascular disease. PCSK9 inhibitors represent a brand new class of drugs.

	The approval comes just one month after the approval of the first PCSK9 inhibitor in the US-Sanofi and Regeneron’s Praluent (alirocumab).  Compared with placebo, Repatha reduced low-density lipoprotein (LDL) by approximately 60%, while trial participants taking Praluent had an average reduction in LDL cholesterol ranging from 36–59%. Unlike Praluent, Repatha was approved for HoFH, an additional indication. Both drugs were not approved for their ability to lower low-density lipoprotein (LDL) alone in patients (i.e., primary prevention in statin-intolerant patients). In the EU, however, Repatha was approved for a more broad indication; the European Commission accepted the lowering of LDL as a surrogate endpoint in those trials.

 to have a slightly lower price than Praluent ($14,100 per year vs. $14,600, respectively). Regeneron 

 that the pricing of Praluent is consistent with the pricing of most other monoclonal antibody (mAb)-based drugs currently on the market. Praluent dosing is 75 mg or 150 mg (depending on patient response) once every two weeks, while Repatha is administered as a 140-mg injection every other week or a 420-mg injection once a month.

	Both drugs are antibodies that facilitate the removal of low-density lipoprotein from the blood by blocking the protein PCSK9. PCSK9 normally reduces the number of receptors available to remove LDL from the blood, so blocking PCSK9’s function allows more receptors to work within the liver to remove cholesterol. The drugs will compete with Genzyme's Kynamro (mipomersen) for the treatment of HeFH and HoFH and Aegerion's Juxtapid (lomitapide) for HoFH.

The drug was the first PCSK9 inhibitor approved in Europe and the second approved in the US.

FDA Approves Amgen’s PCSK9 Inhibitor Repatha

	The long-awaited draft guidance on biosimilar naming has been posted by FDA, and within the document, the agency suggests naming follow-on biologics by a common nonproprietary name, followed by a suffix that will identify the manufacturer of the particular biosimilar. The naming scheme is consistent with the way the agency labeled Zarxio (filgrastim-sndz), the first biosimilar product to be approved by FDA. The naming convention will be used for all future biosimilar products and will also be applied retroactively, meaning the naming convention will apply to biologic products (submitted for approval through the 351[k] or 351[a] pathways) that are already on the market.

	The renaming of all biologic medications has a dual purpose, says FDA: to facilitate the “routine” use of suffixes for biologics, and to “avoid inaccurate perceptions of the safety and efficacy of biological products based on their licensure pathway.” In other words, FDA does not want healthcare providers to judge a drug’s quality based on its name. As such, FDA will use the same nonproprietary name for biosimilars (i.e., the generic or “core name”) plus a manufacturer-specific suffix; taken together, the core name and suffix will produce a “proper name”.

	Although FDA did not provide a full rollout plan for how all the existing biologics will be renamed, it did say that it intends to “assign distinguishing suffixes to a limited group of these products.” The originator biologics that will get new designations first are those reference products that will be susceptible to biosimilar competition in the near future, and FDA is considering a rulemaking action to implement the retrospective naming of biologics. For future products, manufacturers will propose suffixes for their products themselves in application documents. It is still unclear if these suffixes will be required to directly reference the manufacturer, as in the case of Sandoz’s filgrastim-sndz, or if the suffix will be chosen based on other parameters, but FDA said the suffix should be unique, “devoid of meaning”, and should not be promotional. For example, proposing adalimumab-best as a proper name for Humira would likely be blocked by the agency. The suffix also cannot be a commonly used abbreviation in clinical practice, contain reference to a drug core name, or be confusingly similar to the originator product’s suffix (once assigned) or to a similar product’s suffix.

	Some biological products will be exempt from the renaming initiative, says FDA; these include products “for which a proper name is provided in the regulations” and those medications that already have robust pharmacovigilance programs in place. FDA attests that current originator products will benefit from a suffix title, as it will help with pharmacovigilance efforts. It’s unclear how many originator biologics will actually be renamed, as the directives in the FDA guidance are meant as suggestions, not requirements, and it may be difficult to assess which drugs already have “proper names” by FDA standards and which ones do not.

	Though FDA said the naming protocol is meant to prevent inadvertent substitution among biologic products that have not been determined to be interchangeable, the agency did not say how it will label interchangeable biologics and how these are to be differentiated among the other products in the same class. All the agency said was that it was “considering whether the suffix should be unique or should be the same as the reference product.” If an interchangeable product shared the same suffix as the originator, however, the tracking of a drug’s safety by its suffix would not be feasible, and pharmacovigilance problems could persist. Determination of interchangeability and the naming of interchangeable products will be covered in a future guidance, and FDA requested feedback on how to name interchangeable products.


	FDA categorized products not just as originator or biosimilar, but as originator, related biological product, or biosimilar. A related biological product was defined by the agency as a biosimilar that may be licensed for fewer indications than the originator (i.e., in cases where indications are not extrapolated), is licensed for fewer routes of administration than its innovator counterpart, or has a different packaging/drug-delivery system than the originator. FDA explicates that related biologic products are “not required to include any comparative data to any other biological product in support of licensure,” unlike the applications for true biosimilars. The “related biological product” category likely includes products submitted through a biologics license application (BLA); these products are treated more like competing brands in the same class and are not traditionally called biosimilars. An example of this type of product is Teva’s Granix (tbo-filgrastim) injection, which was approved in the US prior to Zarxio and could be considered by some as the true “first biosimilar”, even though it is not designated as a biosimilar because it was not submitted through the biosimilar pathway. Teva’s product was released before FDA released any significant guidance on biosimilars. In the case of tbo-filgrastim and another product, ado-trastuzumab emtansine, FDA justified the use of unique proper names (with prefixes), saying the prefixes were necessary to reduce medication errors. FDA said it may continue to use prefixes “where appropriate” when a suffix does not suffice.


	While FDA says that the proposed naming program will help facilitate use of The Purple Book to help prescribers make decisions for their patients, AbbVie has pointed out that because The Purple Book does not identify indications or routes of administration for which a product has been found biosimilar to its reference product, it is not an adequate resource to help providers make informed decisions; only product-specific disclosures on a biosimilar’s label will be adequate for this purpose. As mentioned previously, for related biological products that do not share all of the same indications/routes of administration, FDA may consider the continued use of prefixes.

Healthcare computerized systems/databases


	FDA says that national drug code numbers (NDCs) and proprietary names are not sufficient to track adverse events in electronic and billing records, and that NDC numbers are not routinely recorded in settings where a physician is administering a biologic. Sharing the same core name, said FDA, will allow similar products to be grouped together in electronic databases. Prefixes may cause related biological products to not be grouped with their counterparts with the same proper names, however, an issue that the National Council for Prescription Drug Programs (NCPDP) has presented to FDA in previous communications. NCPDP says that giving biosimilars the same nonproprietary names would mean that products with shared ingredients would not necessarily be alphabetically adjacent, and the effort to map therapeutic alternatives would require significant time and resources. These arguments may be especially relevant if prefixes continue to be used; a unique naming system for interchangeable products also has the potential to cause sorting issues.

	"Adverse events and product recalls for small-molecule and biologic drugs already are successfully identified using the national drug code (NDC code), and lot number and company name, and there is no compelling evidence that biosimilars should be handled differently," said Bertrand C. Liang, chairman of the Biosimilars Council, in an emailed statement. He argues there is already a successful system for shared international nonproprietary names in practice overseas. "Adding a random collection of letters to the product’s nonproprietary name confers no additional safety benefit, and in fact, would require the healthcare professional to be armed at all times with a code-breaking reference." In summary, the Biosimilars Council believes the additional suffix proposed would needlessly complicate the current prescribing system.

In a new draft guidance, FDA proposes the use of a nonproprietary name plus a four-letter suffix to identify all biologic products, both new and old.

FDA Releases Guidance on Biosimilar Nomenclature, Requests Comments on Interchangeable Product Naming

	Shire announced on Aug. 25, 2015 that it has entered into an agreement with its manufacturing partner for Cinryze (C1 esterase inhibitor [human]), Sanquin Blood Supply, to allow Shire to use other manufacturers in addition to Sanquin to produce enough drug to meet increasing demand. Cinryze is indicated for hereditary angioedema (HAE), a rare genetic disease characterized by recurrent sudden attacks of swelling of the skin or the mucous membranes.

	“We wanted the freedom to operate and expand in a way that makes strategic sense for our business,” said Flemming Ornskov, MD, CEO of Shire, in a press release. “When Shire acquired ViroPharma in January 2014, we inherited an arrangement under which Sanquin was the exclusive manufacturer for Cinryze. We’re pleased that Sanquin was open to expanding our partnership and agreeing to support us as we increase production options for this important therapy.”

	Under the terms of the agreement, Sanquin will receive royalty payments if certain milestones are met, including the successful technical transfer to a second-source manufacturer.

Shire requests a technical transfer from Sanquin to widen its manufacturer base for the production of Cinryze.

Shire to Add Manufacturing Capacity for Cinryze

	AbbVie is not thrilled with FDA’s stance on biosimilar naming. The company sent an addendum on Aug. 10, 2015 to its original June 2, 2015 Citizen Petition to FDA on the subject, citing various offenses related to FDA statements on interchangeability and the agency’s stance on the inclusion of reference biologic studies in place of biosimilar study information in a biosimilar’s product label.

	AbbVie is concerned with an explanation FDA gave the Senate Committee on Heath, Education, Labor, and Pensions (HELP Committee) about interchangeability information on biosimilar labels. In an April 30, 2015 letter to FDA, the HELP committee said that while FDA’s draft guidance acknowledges that knowing a drug’s interchangeability is crucial to making prescribing decisions, the final version of the 2012 document omitted key information about what exactly a biosimilar’s label should say about its interchangeability status. With this guidance deletion, the HELP Committee argued that, “FDA has made its policy on the issue more uncertain.”

	AbbVie took particular issue with the fact that FDA told the HELP Committee that all information on interchangeability could be found in The Purple Book and, therefore, did not need to be included on a biosimilar product label. AbbVie countered that this argument goes against the “foundational principles” of FDA law, and wrote that, “The proposition that The Purple Book could cure a material omission in the labeling for a biosimilar is indefensible.” AbbVie added that because The Purple Book does not identify indications or routes of administration for which a product has been found biosimilar to its reference product, it is not an adequate resource to help providers make informed decisions. Only product-specific disclosures on a biosimilar’s label can fully inform healthcare providers, AbbVie argued.

AbbVie to FDA:
	Use a biosimilar’s own clinical data in its label


	It is also misleading to include study information on another drug in a label for a biosimilar without acknowledging that the studies were not performed on the biosimilar itself, AbbVie wrote. They said that including study information on filgrastim, rather than on the specific biosimilar Zarxio, is a “shortcoming to FDA’s current approach to biosimilar labeling.” Studies comparing the biosimilar and the reference biologic should be part of a biosimilar’s label, AbbVie argued, and should identify whether a biosimilar is interchangeable with its reference product.

	Lastly, AbbVie said that multiple new organizations have pointed out issues with the current labeling practices for biosimilars since the company filed its original petition, including the American Pharmacists Association, the American Society of Health-System Pharmacists, the Alliance for Patient Access, Patients for Biologics Safety and Access, the Global Healthy Living Foundation, the Coalition of State Rheumatology Organizations, and the Biosimilars Forum, an organization run by the Generic Pharmaceutical Organization.

The company adds a few new arguments-as well as new stakeholder support-to its Citizen Petition on biosimilar naming.