Biologics and Biosimilars Bits and Bytes – December 10, 2015

Amgen files for first European Approval of a Biosimilar to Humira®

On December 4, 2015, Amgen Inc. (Amgen) announced the filing of a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for ABP 501, a biosimilar version of AbbVie Inc.’s (AbbVie) Humira® (adalimumab). According to Amgen, its MAA submission included analytical, clinical and pharmacokinetic data. Amgen conducted Phase 3 comparative efficacy and safety studies in both moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis patients. Amgen indicated that its Phase 3 studies met their primary endpoints showing clinical equivalence to Humira®. The safety and immunogenicity of ABP 501 was also comparable to Humira®. Additionally, data to support the transition of Humira® patients to ABP 501 was also included in the filing.

This MAA filing follows Amgen’s November 25, 2015 filing of a 351(k) application with the U.S. Food and Drug Administration (FDA) for ABP 501.

Coherus Files Two New IPR Petitions against AbbVie’s Patents Covering Humira®

On December 7, 2015, Coherus Biosciences Inc. (Coherus) filed two new IPR petitions, IPR2016-00188 and IPR2016-00189, against AbbVie’s U.S. Patent Nos. 9,017,680 and 9,073,987 covering Humira®. These filings come almost a month after the November 9th filing by Coherus of IPR petition, IPR2016-00172, against another AbbVie patent covering Humira®, U.S. Patent No. 8,889,135. Coherus’ three IPR petitions can be found here: 1. IPR201600188 2. IPR201600189 3. IPR201600172. This brings the total number of IPR petitions filed against AbbVie patents covering Humira® to five. Earlier this year, on June 26, 2015 Amgen filed IPR petitions, IPR2015-01514 and IPR2015-01517 against two other AbbVie patents, U.S. Patent Nos. 8,916,157 and 8,916,158.

Infliximab Biosimilar Approved in Korea

On December 4, 2015, Samsung Bioepis Co., Ltd., (Samsung Bioepis) announced that Korea’s Ministry of Food and Drug Safety (MFDS) approved Renflexis®, a biosimilar version of Remicade® (infliximab), also known as SB2. Renflexis® was approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis, psoriatic arthritis and plaque psoriasis. This is the second biosimilar approved in Korea for Samsung Bioepsis, a joint venture between Biogen and Samsung Biologics. The first approval was in September 2015 for Brenzys®, a biosimilar version of Enbrel® (etanercept), also known as SB4.

In February 2013, Samsung Bioepis and Merck & Co. (Merck) announced a development and commercialization agreement under which Merck would commercialize multiple pre-specified and undisclosed biosimilar products in certain partnered territories. Under terms of the agreement, Samsung Bioepis was responsible for preclinical and clinical development, process development and manufacturing, clinical trials and regulatory registration. Merck was responsible for commercialization. As a result, Merck will commercialize Renflexis® in South Korea and plans to launch in the first half of 2016.

This post was written by Lisa Mueller.


5 Lessons From FDA’s First Biosimilar Review

Lisa Mueller, partner in Michael Best’s Intellectual Property and Chair of the Life Sciences and Chemical Practice Groups and Laura Opperman, Ph.D., a Patent Scientist in the Intellectual Property Practice group, gave input for a Law360 article titled, “5 Lessons From FDA’s First Biosimilar Review – Law360,” on January 8, 2015. To view the full article, click here.

2014 Year in Review of U.S. Biosimilar Activity

Lisa Mueller, partner and Chair of the Life Sciences and Chemical Practice Groups, and Laura Opperman, Patent Scientist and member of the Intellectual Property Practice group at Michael Best & Friedrich LLP, published an article on Law360 highlighting activity taking place in respect to biosimilars in 2014.

Here is a short excerpt: “This year witnessed significant activity in the U.S. with respect to biosimilars. Highlights include issuance by the U.S. Food and Drug Administration of two new guidances, further debate over the naming of biosimilars, acceptance by the FDA of the first biosimilar application, publication of the “Purple Book” and continued legal wrangling over the so-called patent dance patent resolution provisions added to the Public Health Service Act by the Biologics Price Competition and Innovation Act of 2009…” Click here to read more of Lisa and Laura’s article.

A Report from the “Biosimilars and Biotech: MENA Conference” in Istanbul, Turkey: Part 1

This is part 1 in a series reporting on the conference entitled, “Biosimilars and Biotech:  MENA Conference” sponsored by Informa in Istanbul, Turkey on November 18-19th. As mentioned in my post of November 17th, not only did I attend the conference but presented as well. I found the conference to contain a number of really exciting, interesting and useful presentations. In the next few posts, I will provide a summary of some of the presentations that I believe readers of the BRIC Wall Blog will find insightful, and hopefully useful. 

Biosimilar Development in the Middle East – A Report

A very interesting presentation was given by Dr. Claudia Palmer (Partner and Managing Director of 55east FZ LLC) on the development of biosimilars in the Middle East. Dr. Palmer started her presentation by discussing the exchange she frequently has when asking various stakeholders in the Middle East for their view on the biosimilar marketplace. The response she typically receives is: “Biosimilars? Do you have them?” Ms. Palmer stated that currently, because there are so few companies in the area dealing in biopharmaceuticals, very few biosimilars are actually available. 

Despite the limited number of biosimilars presently available, Ms. Palmer stated that the region holds substantial potential for the growth of these products. Specifically, she noted: (1) the population in the Middle East is more than 200 million and is among the fastest growing in the world; (2) there is now political and fiscal stability in the region; (3) the economies of many countries in the area are booming; (4) there is a growing middle class; (5) life styles are changing and life expectancy is increasing; (6) the incidences of serious disease is increasing; and (7) the quality healthcare is improving and the sophistication of treatment increasing. 

With respect to biologics, Ms. Palmer stated that the price tag that typically accompanies biologics (such as seen in the U.S.) simply is not viable for many of the smaller Middle Eastern countries. In fact, in her view, as the incidences of cancer grow in this area, biosimilars will be the only affordable treatments for these diseases in many of these countries. Interestingly, Ms. Palmer commented that no one is really sure the exact amount that can be saved by treating a patient with a biosimilar instead of with an innovator biologic. 

In Ms. Palmer’s view, there is an opportunity for early entry of three biosimilar products in the region. These products would be erythropoietin (EPO), somatotropin and filgrastim. Ms. Palmer believes that the market opportunity for these three drugs in the Middle East, Turkey and Africa (META) region would be around $160-$190 million dollars, about 3% of the total biosimilar market. She indicated that this number was small because the path to market for any biosimilars in the region was going to be challenging.   First, she noted that it generally takes about two to three years once a biologic is approved in the U.S. or Europe for that biologic to become accessible in the Middle East. Once the biologic becomes available in the region, adoption tends to be slower than in the rest of the world due to a lack of infrastructure and the lack of insurance coverage for these products. Additionally, further complicating matters is that a number of countries in the Middle East have not yet established biosimilar frameworks. As Ms. Palmer noted, a biosimilar is only a biosimilar if it has gone through a biosimilar pathway. 

Ms. Palmer also stated there will likely be issues with pricing and reimbursement for biosimilars in these countries. Specifically, she noted that tenders comprise a majority of the market (likely over 80%) and the systems are not always transparent. Moreover, in many instances, preference for tenders is given to local biopharmaceutical companies. 

With respect to potential customers, Ms. Palmer stated that the typical buying entities for speciality drugs in this region will likely include: Ministries of Health, central pharmacies, army/military, hospitals, non-governmental organizations (NGOs) and dialysis centers. Ms. Palmer noted that biologics treatment is normally provided in the region by hospitals and dialysis centers. For nationals receiving these treatments, the treatment is generally paid for by the national healthcare system or by insurance. 

Ms. Palmer noted that so far, competition for biosimilars in the region has been limited. Multinational generic companies such as Hospira and Sandoz seem to have the best regional footprint so far. She also noted that currently there are really no local manufacturers in the area to speak of. The lack of such local manufacturers presents a number of positives and negatives. In terms of positives, no local manufacturers means that there will be a longer lead time for local companies to enter the market. Moreover, the lack of local manufacturing might make it hard for authorities to insist on a preference for a local product (particularly if there is none). Finally, the lack local manufacturers might facilitate the slowing of price erosion. With respect to the negatives, the lack of competition will likely mean that there will be few to no companies to partner with for the purposes of contract manufacturing. This lack of manufacturers might cause a cojoining of manufacturers and distributors which might result in a skills gap that could create challenges in distribution. Additionally, the lack of local manufacturers might also impact the ultimate acceptance of these biosimilar products and might instead increase tolerance for products imported from India or China. 

Near the end of her presentation, Ms. Palmer stated that companies interested in entering the biosimilar market in the Middle East will need to enhance their capabilities across their organizations and value chains. Ms. Palmer stated that any such companies will want to first make sure they have obtained either a U.S. or European registration for their biosimilars. Next, companies will want to invest in stakeholder management. Specifically, companies will want to: (1) build a network of regional stakeholders; (2) create awareness among these stakeholders; and (3) educate and train these stakeholders. Moreover, when dealing with local regulatory organizations, companies will want to drive rapid marketing authorizations. Businesses will also need to adapt their value chain by: (1) building a tender infrastructure; (2) enhancing supply chain capability; (3) enabling distributors; and (4) engaging with local players. Finally, businesses will want to align the commercial organization by: (1) establishing a speciality marketing approach; (2) developing key account skills; (3) clarifying conflicts of interest; (4) customizing medical education; and (5) leveraging existing footprints. 

At the end of her presentation, Ms. Palmer concluded with the following: 

  1. In general, the Middle East and Africa are the final frontier in pharma: In Ms. Palmer’s view, this is the last sizable area of untapped growth having limited competition. 
  2. Biosimilars hold a big promise for the Middle East: Biosimilars will provide modern treatments for large populations with limited purchasing power. 
  3. The biosimilars market will have to be built: Companies will need to work heard to create awareness, education and a safe supply of drugs. 
  4. This will be a marathon, not a sprint: As discussed previously, the current META commercial opportunity is around $160-$190 million for EPO, filgrastim and somatotropin.
  5. Regulatory capability, market access and process management will drive success: The complexity of the challenge will be an opportunity for the right company. 
  6. The government will become your partner: According to Ms. Palmer, with tenders comprising 80% and more of the biosimilars market, stakeholder management and key account skills will be essential. 
  7. Build a biosimilars ecosystem:  Ms. Palmer noted that like a highly developed machine, biosimilar treatment can only thrive in a sophisticated, supportive environment. 

This post was written by Lisa Mueller.

Biosimilars and Biotech: MENA Conference – Istanbul, Turkey – November 18-19th

Informa Life Sciences will be hosting a conference entitled, “Biosimilars and Biotech:  MENA Conference” in Istanbul, Turkey on November 18th-19th.  I will be presenting during this conference on the topic of global biosimilar development as well as providing an update on biosimilars in the U.S. 

The conference will examine a number of topics that may be of interest to BRIC Wall Blog readers, including biosimilar development in Turkey and the Middle East, as well as an interesting session on understanding and accessing biosimilars in Iran.

I will be providing updates to BRIC Wall readers on topics from the conference beginning tomorrow.

If any of our readers are attending the conference, please stop by and say hello.

This post was written by Lisa Mueller.

A Review of the Status of Biosimilars in the U.S.

The Biologics Price Competition and Innovation (BPCI) Act of 2009 was enacted as part of the Patient Protection and Affordable Care Act to establish an abbreviated pathway for the licensure by Food and Drug Administration (FDA) of biological products demonstrated to be biosimilar to or interchangeable with a FDA-licensed reference product. We at the BRIC Wall Blog decided to review the current status of biosimilars in the U.S.

FDA Guidances

Since the BPCI Act was signed into law on March 23, 2010, the FDA has issued six guidances relating to biosimilars or reference biological products. These guidances are:

1.  Guidance for Industry on Biosimilars: Q & A’s Regarding Implementation of the BPCI Act of 2009 – issued February 9, 2012.

2.  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product – issued February 9, 2012.

3.  Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product – issued February 9, 2012.

4.  Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants – issued March 29, 2013.

5.  Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Clinical Pharmacology Guidance) – issued May 13, 2014.

6.  Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Exclusivity Guidance) – issued August 4, 2014.

A detailed examination of the Clinical Pharmacology Guidance and Exclusivity Guidance, the two guidances released in 2014, is provided below.

Clinical Pharmacology Guidance

Clinical pharmacology studies are a critical part of demonstrating biosimilarity and are used to support a demonstration that there are no clinically meaningful differences (in terms of safety, purity and potency) between a proposed biosimilar product and a reference product. The Clinical Pharmacology Guidance provides information for proposed biosimilar products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required as part of the stepwise approach in developing the data and information necessary to support a demonstration of biosimilarity. Specifically, this guidance discusses concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database and the utility of modeling and simulation for designing clinical trials.

According to the guidance, in the step-wise assessment of biosimilarity, extensive and comparative structural and functional studies (such as, bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar. The guidance describes four possible assessments of biosimilarity. These are:

1.  Highly similar with fingerprint-like similarity: Under this assessment, the proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The result of the analysis permits a high level of confidence in the analytical similarity of the proposed biosimilar and the reference product. Thereupon, under this assessment, it is appropriate for the sponsor to use a more targeted and selective approach to conduct animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity. This is the gold standard.

2.  Highly similar:   Under this assessment, the proposed biosimilar product meets the statutory standard for analytical similarity. Specifically, the results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it is appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

3.  Similar: Under this assessment, information is needed to determine if the proposed biosimilar product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if the observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. The example provided in the guidance is glycosylation. Glycosylation plays an important role in the PK of certain protein products and manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product would be helpful in resolving whether some of the differences in glycosylation identified in the analytical studies are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

4.  Not similar: Under this assessment, differences in the results of the analytical characterization may lead to an assessment of “not similar” for the proposed biosimilar product. In this instance, further development under the 351(k) regulatory pathway (namely, the regulatory pathway for biosimilars) is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that are likely to lead to a highly similar biological product.

According to the guidance, the outcome of the comparative analytical characterization provides information to the sponsor regarding the next steps needed to demonstrate biosimilarity.

Exclusivity Guidance

The Exclusivity Guidance describes how the FDA will determine the date of first licensure of a reference product and the types of information reference product sponsors should provide to facilitate FDA’s determination of the date of first licensure for their products. The guidance states that in most instances, the date of first licensure will be the initial date the particular product at issue was licensed in the U.S. However, the 12-year exclusivity period does not apply if the licensure is for:

1.  A supplement for the biological product that is the reference product; or

2.  A subsequent application filed by the same sponsor or manufacturer of the biological product (or a licensor, predecessor in interest, or other related entity) for:

a.  A change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

b.  A modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Moreover, according to the guidance, the burden is on the sponsor to demonstrate that a new licensure meets the standards for exclusivity.

For biological products that may or may not be entitled to reference product exclusivity, the FDA suggests a four-step process for sponsors to provide certain relevant information.  Specifically, the FDA suggests that sponsors provide the following:

1.  A list of all the licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application (namely, a biologics license application (BLA)) being considered.  This includes products that share the same molecular target or have some of the same principal molecular features.  Where molecular targets have not been defined, the list should include products that share the narrowest target that can be characterized (this may be a pathway, celltype, tissue or organ system).  If a sponsor determines there are no licensed products that fall into these categories, it must provide an “adequate justification” to support this assertion.

2.  Of the licensed products from item 1, a list of those which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.  The term “licensors” is defined broadly to include “any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive”. This definition includes entities that continue to retain rights to develop, manufacture, or market the biological product, and/or rights to intellectual property that covers the biological product. The term “predecessors in interest” has been interpreted by FDA to mean an entity (such as a corporation) that the sponsor has taken over, merged with, or purchased, or from which the sponsor has purchased all rights to the drug (namely, the reference product). Additionally, the FDA has construed the term “predecessor in interest” to include an entity which has granted to the sponsor exclusive rights to a new drug application or the data upon which exclusivity is based, which may include licensors, assignors, and joint venture partners, depending on the circumstances of a case. Moreover, the FDA will consider any entity that the sponsor has taken over, merged with, or purchased or that has granted the sponsor exclusive rights to market the biological product under a BLA application, or had exclusive rights to the data underlying the application to be a predecessor in interest. 

The BPCI Act does not define the term “other related entity”. Nonetheless, the FDA generally considers a sponsor to be a “related entity” if: (i) either entity owns, controls or has the power to own or control the other entity (either directly or thorough one or more other entities) or (ii) the entities are under common ownership or control. According to the guidance, the FDA expects to consider not only ownership and control of the investigational new drug application (IND) and BLA, but also the level of collaboration between the entities during the development of the program as a whole.

3.  A description of the structural differences between the proposed biological product and any products identified in item 2.  For protein products, sponsors are asked to discuss “differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events, infidelity of translation or transcription, differences in glycosylation patterns or tertiary structure, and differences in biological activities.”. 

4.  Evidence of the change in safety, purity, and/or potency between the proposed biological product and any products identified in item 2. Such evidence should include a description of how the structural differences identified in item 3 relate to changes in safety, purity and/or potency.

The FDA encourages sponsors to provide this information at the time of 351(a) application is submitted (as correspondence to the application) or as an amendment to an application.

What is in a (biosimiliar) name?

There have been several reports that the FDA has completed a draft guidance document on the naming of biosimilar products. However, the reason the draft guidance has not yet been released is a delay by the Department of Health and Human Services in completing its review of the document. In fact, in August 2014, two of the Senate’s high ranking legislators on healthcare, Lamar Alexander (R-TN) and Orrin Hatch (R-UT), called for the release of FDA’s biosimilar naming guidance. Unfortunately, despite the Senators urging, the guidance has still not yet been released and the time table for release is unknown.

The Purple Book

In September 2014, the FDA began publishing the “Purple Book”, the biologic counterpart to the Orange Book for “small molecule” drugs. The book is split into two parts, one for products approved by the Center for Drug Evaluation and Research (CDER) and the other for products approved by the Center for Biologics Evaluation and Research (CBER). Information included in the Purple Book includes:

1.  BLA number;

2.  Product (Proper) Name;

3.  Proprietary Name;

4.  Date of Licensure;

5.  Date of First Licensure;

6.  Reference product Exclusivity Expiry Date;

7.  Interchangeable or biosimilar; and

8.  Withdrawn.

Unfortunately, the published information presently contained in the Purple Book is not very complete. Specifically, the date of first licensure and the date of expiration of product exclusivity is provided for only a very small number of products. Also, unlike the Orange Book, the Purple Book does not list any patent information.

Awaiting Approval

As readers may recall, in July 2014, Sandoz announced that it had filed a 351(k) application for a biosimilar version of filgrastim. Sandoz’ biosimilar of filgrastim is marketed in more than 40 countries under the brand name ZARZIO®. Approximately one month later, Celltrion announced the filing of its 351(k) application for a biosimilar of infliximab (Remicade®). The industry is anxiously awaiting news regarding the approval of these products.

This post was written by Lisa Mueller of Michael Best & Friedrich.

BRIC-a-BRAC: March 14, 2014

1.  As a follow-up to our post on Patent Trolls: A View from Europe, on February 28, 2014, Apple Inc. (Apple) won dismissal of the US $2 billion patent infringement lawsuit brought by IPCom GmBH (IPCom) in the District Court of Mannheim, Germany. Specifically, the Court held that Apple did not infringe the two patents asserted by IPCom (although the reason for the decision was not given). IPCom is appealing the decision. Visit Bloomberg’s article to learn more about this decision.

2.  Is the road to riches for pharmaceutical companies not paved with biosimilars and the BRIC markets? This is the question examined in an article at According to the article, it is becoming clear that only a handful of companies may make substantial profits with biosimilars. In fact, some suggest that biosimilars represent “fool’s gold” for many companies. With respect to the BRIC markets, the article notes that the sales in the BRIC countries, which were expected to spearhead pharma’s emerging markets strategy, are not meeting expectations. The reasons include price controls in China, India and Brazil as well as slowing growth in China and the use of compulsory licensing in India. Russia is struggling to keep investors due to the falling ruble and the Russia-Ukraine faceoff.

3.  Will there be a Global Regulatory Supergroup? According to Regulatory Focus (RF), U.S. and international regulators are working to create a new global regulatory organization whose focus would be on leveraging and sharing resources and information among various regulatory authorities. The announcement of the existence of this organization was made on March 6, 2014 by Margaret Hamburg, the Commissioner of the U.S. Food and Drug Administration (FDA), speaking at the Medicines and Healthcare Products Regulatory Agency’s (MHRA) Annual Lecture in London. According to Commissioner Hamburg, “Regulators around the world have begun to collaborate around the formation of an International Coalition of Medical Regulatory Authorities (ICMRA).” While the details of the ICMRA are still in the early stages, Commissioner Hamburg envisions that the organization will be a “high-level, strategic advocacy and leadership entity.” A full transcript of Commissioner Hamburg’s speech can be found here. Please watch the BRIC Wall Blog for further updates on the ICMRA.