BioProcess Blog

Biosimilar Competition is Only One of Several Threats Facing Biopharma Blockbuster Drugs

Julia Adam — Tue, 08 May 2012 13:30:00 +0000

By Patti Seymour (pseymourbptccom)

Biopharmaceutical products will dominate the list of top ten best selling drugs in 2012. Abbott Laboratories’ arthritis drug Humira^® (adalimumab) is forecasted to become the world’s top selling drug in 2012, followed closely by Johnson & Johnson’s Remicade^® (infliximab) and Amgen’s Enbrel^® (etanercept). Roche is also a member of this exclusive group, with three anti-cancer drugs, Rituxan^® (rituximab), Avastin^® (bevacizumab) and Herceptin^® (trastuzumab) ranked in the top ten. As described in a recent BPTC report, seven biopharmaceutical blockbusters had sales in excess of $5 billion per year in 2010, with total biopharmaceutical sales exceeding $100 billion. According to the IMS Institute for Healthcare Informatics, global biopharmaceutical spending is forecasted to grow to $200 billion by 2015. This market growth is being fueled by the approval of new products and expansion of therapeutic indications from existing products – Humira just received approval for its seventh indication and Remicade has 16 approved indications! However, the blockbuster status of these drugs is being threatened on numerous fronts.

Several of these top selling products will lose patent protection in the next few years, and biosimilar developers have been ramping up to take advantage of these huge market opportunities. By the middle of this decade, spending on biosimilars is expected to grow to $2 billion from $311 million in 2010. Biopharm companies aren’t ready to cede market share to potential biosimilar competitors, though. Roche recently announced plans to cut the price of Herceptin and MabThera (rituximab) in India and rename them in an effort to gain market share and avoid competition from biosimilars in that country. Roche hopes that the lower prices will increase usage rates in India "at least several-fold higher" than current levels, according to Tuygan Goeker, head of Middle East and Asian markets at Roche. The new product names should create an obstacle to companies seeking to divert the Indian products and resell them at a significant profit in other markets, but this is no guarantee that the drugs won’t be diverted to other markets, as Roche knows all too well.

Roche is dealing with the fall-out from counterfeit Avastin from Turkey making its way into the United States supply chain. According to World Health Organization, less than 1 percent of medicines available in the developed world are likely to be counterfeit. While the threat of counterfeit medicines entering the supply chain in the United States is lower than elsewhere, the temptation for doctors to seek cheaper versions of high cost drugs is increasing, especially for biopharmaceuticals, leading to potentially more counterfeited high value drugs finding their way into the US pharmaceutical supply chain. Doctors may unknowingly purchase inferior or unsafe drugs, as was the case in the most recent Avastin counterfeit incident involving “product” that contained no active ingredient.

Another threat facing these blockbuster products is the potential issuance of compulsory licenses to generic manufacturers as evidenced by the Natco Pharma case. In March, Indian drug company, Natco Pharma, was authorized by the Indian government to make and sell a generic version of Bayer’s patented cancer drug, Nexavar. Roche’s plan to rebrand Herceptin and MabThera in India is considered by many a preemptive move to avoid being compelled under Indian law to allow generic drug makers to produce less-expensive versions of these drugs, a fate that Bayer wasn’t able to avoid. In response to India’s issuance of a compulsory license to Natco Pharma for Nexavar, PhRMA President and CEO John Castellani said, “If countries begin to routinely use compulsory licenses, we could see a ‘race to the bottom’ in which governments in the developing world walk away from their responsibility to support research and innovation in public health. In the absence of the investment made by our members, and the resulting research and development, there would be no generic medicines for the world’s patients.”

While companies are taking proactive measures to protect top selling biopharmaceuticals from biosimilar competition, effective annulment of patent protection through compulsory licensing initiatives coupled with the increased counterfeiting of high value products in emerging markets could pose more insidious threats to biopharmaceutical product companies than the emergence of biosimilars.

15th Annual American Society of Cell and Gene Therapy Meeting

Julia Adam — Mon, 07 May 2012 11:55:24 +0000

David Broad (dbroadbptccom) , Senior Consultant, will be representing BPTC at the ASCGT 15th Annual Meeting to be held in Philadelphia, PA from May 15-19, 2012. To schedule a meeting with David at this year’s event, please click here (dbroadbptccom) .

First Monoclonal Antibody Submitted to EMA for Biosimilar Approval

Julia Adam — Wed, 02 May 2012 18:19:00 +0000

By Patti Seymour (pseymourbptccom)

Not surprisingly, a biosimilar version of Remicade^® (infliximab) is the first regulatory application for a biosimilar monoclonal antibody (mAb) submitted to the EMA this month. Remicade^®, marketed in the EU by Janssen Biotech (a subsidiary of Johnson and Johnson), is a mAb against tumor necrosis factor (TNF) alpha and is approved for a whopping 16 indications. While the name of the company submitting the application wasn’t disclosed by the EMA, it is widely acknowledged to be Celltrion’s submission.

Celltrion’s infliximab clinical trials were conducted with a total of 874 rheumatoid arthritis patients at 100 sites in 19 different countries throughout 2010 and 2011. It is unknown at this point if Celltrion is requesting approval for other indications in addition to rheumatoid arthritis as EMA Guidance allows for extrapolation of clinical efficacy and safety data to other indications for which the reference mAb has been approved. It is not necessary that these indications be specifically studied during the clinical development of the biosimilar as long as there is evidence of overall biosimilarity provided by the comparability exercise with adequate justification.

Approval from the EMA to extrapolate to multiple indications will be important for Celltrion to capture a meaningful portion of the $21 billion TNF-a antagonist market. While Remicade is forecasted to be one of the top three selling drugs in 2012, it was also one of the earliest mAbs to receive regulatory approval, and as a chimeric mAb (containing both human and murine sequences), it has some safety limitations associated with immunogenicity. Over the past decade, these older products are being supplanted with newer, humanized or fully human mAb versions such as Humira^®. While biosimilar competition remains a concern, the verdict is still out as to whether Remicade’s $8 billion market is more likely to be cannibalized by biosimilars or by biobetter and next generation products, such as Janssen’s own Simponi product.

Now it is a waiting game for Celltrion as the earliest patents for Remicade do not expire until 2014 in the EU. However, Celltrion isn’t taking a ‘sit and wait’ approach – the company is preparing to file for Korean Food and Drug Administration approval this year. After that, the company plans to register their biosimilar infliximab product in emerging markets in Asia and Central/South America, where Remicade does not have patent protection.

While Celltrion was the first to file for approval of a biosimilar mAb, there are sure to be many more companies submitting biosimilar mAb applications in the near future. The first-mover advantage could be short-lived for Celltrion as more companies seek biosimilar market authorization, and branded products continue their strong market performance. This is further compounded by the fact that overall adoption of the early biosimilar products in Europe has not been as strong as anticipated or hoped even with price discounts up to 40% for some products from the branded product’s price. Samsung, clearly positioning itself to be a dominant player in the biosimilar market, predicts it will be a stronger overall competitor by selling its biosimilar portfolio at up to 50% off the innovator drug price. We believe that such price drops are achievable and will lead to significant gains in market share by Samsung and other biosimilar companies able to actually deliver on this promise. However, before steep price discounts can become a reality, products must be approved. So the questions remain – What hurdles will Celltrion face in the approval process? How easily will they be able to access other indications after approval? And of course, what kind of market penetration will Celltrion’s infliximab really achieve?

8th Annual PEGS

Julia Adam — Tue, 24 Apr 2012 13:27:24 +0000

Join Tom Ranshohoff (transohoffbptccom) , Sheila Magil (smagilbptccom) , Susan Dana Jones (sjonesbptccom) , Howard Levine (hlevinebptccom) , Patti Seymour (pseymourbptccom) and Julie Adam (jadambptccom) in celebrating BPTC’s inaugural conference exhibition at CHI’s 8th Annual PEGS to be held in Boston, MA from April 30 – May 4, 2012. BPTC is pleased to be a sponsor of this event that brings together so many innovators and thought leaders in the biopharmaceutical industry. Next week’s conference promises to be an exciting event covering the latest developments in protein engineering. We invite you to stop by our booth (#58) to learn how BPTC can help advance your program from clone to commercial. If you are interested in scheduling a meeting during the conference, please click here (jadambptccom) .

The Future of Vaccine Manufacturing and Supply

Julia Adam — Thu, 29 Mar 2012 14:49:00 +0000

By Patricia Seymour

The results from BPTC’s bioPULSE survey on vaccine manufacturing highlight industry predictions for new technologies and risks involved in vaccine manufacturing.

The two most prevalent technological advances expected to have the greatest impact on vaccine manufacturing in the next 5 years are flexible manufacturing and novel delivery systems. Respondents indicated that microbial fermentation, followed closely by mammalian cell culture, are the two technologies best suited to develop new or pandemic vaccines. Compared with mammalian cell culture, microbial fermentation has the advantage of relatively short production cycles and low cost. However, several new, highly effective vaccines are being developed using mammalian cell culture to overcome limitations of traditional egg-based production systems. Application of Quality by Design (QbD) and Process Analytical Technologies (PAT) are also rapidly gaining acceptance in all aspects of biomanufacturing, according to a majority (73%) of respondents. Formulation development (44%) and downstream purification (44%) would benefit far greater than upstream processes (12%) from application of QbD according to respondents. (Share your thoughts on QbD in our current bioPULSE survey!)

Nearly half think access to manufacturing capacity is the greatest risk factor in meeting global demand for vaccines. As the patients in emerging markets are able to access these lifesaving medicines more routinely, vaccine use is expected to increase significantly in the coming years. Recognizing the growing need for new vaccines, two-thirds of the survey respondents indicated that they are either currently developing or plan to develop vaccines. The overall vaccine market has seen growth rates of up to 10% in the past few years fueled by wider use of current vaccines and introduction of new vaccine therapies. Compared to the 5% growth for the overall pharmaceutical industry, the vaccine market should continue to be a bright spot.

One third of respondents are planning to increase the use of disposable technologies in order to allow manufacturing facilities to be rapidly and cost effectively established locally in emerging markets. Only small percentages (4%) of companies are out-licensing vaccine products to companies in emerging markets. This low percentage is most likely due to concerns about protection of intellectual property and manufacturing know-how.

To ensure that new vaccines can reach the patients who need them, it is important for global regulatory agencies not to set divergent requirements for the approval of vaccines in their territories, which ultimately could increase the cost and time to commercialize vaccines, or worse, disincentivize manufacturers from marketing their vaccines in certain territories. It is not surprising that the majority, 64%, of survey respondents indicated that governments should fund the research and development of pandemic vaccines. This may be controversial in some circles, but without government support, most not-for-profits could not provide the funding needed to bring a vaccine completely through its development cycle, and for-profit companies have little or no incentive to develop pandemic vaccines if there is not a guaranteed market (i.e., governments).

The objective of all bioPULSE^TM surveys is to obtain relevant and focused feedback on topics of interest to the biologics manufacturing community. The web-based surveys are quick, short, and rewarding (everyone who participates will be emailed a summary and analysis of the aggregate results), so we hope you will join the growing bioPULSE community and contribute your insight.

MassBio Annual Meeting 2012

Julia Adam — Mon, 19 Mar 2012 13:50:15 +0000

Connect with Julie Adam (jadambptccom) , Manager of Sales and Marketing, at MassBio’s 2012 Annual Meeting where local biotech industry professionals will gather to discuss the latest science and business innovation challenges, promote collaboration, and build new relationships. To pre-arrange a meeting with Julie to learn more about BPTC’s breadth of consulting services and how we can help you meet your development milestones faster with less expense and risk, click here (jadambptccom) .

Biosimilars and Biobetters

Julia Adam — Mon, 12 Mar 2012 14:24:24 +0000

Patti Seymour (pseymourbptccom) , Senior Consultant, will be presenting a talk entitled, “Biomanufacturing Capacity for Biosimilars: Is there enough?” at CHI’s inaugural Biosimilars and Biobetters conference to be co-located with the third annual Biotherapeutics Analytical Summit in Baltimore, Maryland from March 19-20, 2012. To pre-arrange a meeting with Patti to learn how BPTC can help develop your company’s biosimilar or biobetter strategy from clone to commercial, click here. (pseymourbptccom)

10th Biosimilars Americas

Julia Adam — Mon, 05 Mar 2012 20:50:26 +0000

Join Patti Seymour, Senior Consultant, at the10th Biosimilars Americas conference, to be held March 13-15, 2012 in Boston, MA to learn more about manufacturing strategies for biologics, biosimilars and novel therapies. To pre-arrange a meeting with Ms. Seymour at the conference, please click here (pseymourbptccom) .

Biosimilars Congregation 2012

Julia Adam — Fri, 24 Feb 2012 22:01:25 +0000

With the global market for biosimilars forecast to exceed $4 billion by 2015, there is intense focus on the development and commercialization of these products as a means of bringing cost-effective biologic theapeutics to patients worldwide. Join Dr. Howard L. Levine (hlevinebptccom) , Principal Consultant, and Dr. Susan Dana Jones (sjonesbptccom) , Senior Consultant, at the Biosimilars Congregation 2012 on February 24, 2012 at the Thistle Marble Arch, London, UK. This exciting conference will unite industry leaders to analyze commercial developments and identify successful management strategies for biosimilars worldwide. Drs. Levine and Jones look forward to seeing you in London. To schedule time with either of them to discuss your CMC needs, click here (sjonesbptccom) .

FDA Takes Big Step Forward in Biosimilar Regulatory Pathway

Julia Adam — Wed, 15 Feb 2012 15:29:00 +0000

By Patti Seymour (pseymourbptccom) and Howard Levine (hlevinebptccom)

Nearly two years after the Biologics Price Competition and Innovation (BPCI) Act was passed, FDA has finally taken the big step towards defining a regulatory pathway for biosimilars in the US. On February 9, 2012 FDA issued three draft guidance documents, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, along with a Q&A summary of these documents, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, describing the Agency’s interpretation of the Act’s requirements for biosimilar product licensure.

These guidances reflect the broad framework that FDA officials have spent months outlining and are consistent with their August 2011 New England Journal of Medicine article, stating that FDA will take a “totality of evidence” approach to biosimilar approval and require extensive characterization of the biosimilar product using state of the art analytical techniques. Even with this detailed characterization, animal and human clinical studies will still be mandated for the foreseeable future. Consistent with EMA’s approach to biosimilar approval, the detailed and extensive analytical characterization will allow a reduction in the scope and extent of animal and/or human studies required.

While the guidances cover many issues important to the overall development of biosimilars, we are encouraged by several points that are especially relevant for the CMC development of biosimilars. The current draft guidances do allow for differences in the formulation of a biosimilar product compared to its reference product. For example, FDA indicates that it may be possible for a biosimilar product formulated without human serum albumin to be considered similar to a reference product formulated with human serum albumin. We applaud this rationale and sensible position of allowing biosimilar developers to move away from potentially dangerous raw materials used in the innovator products and implement technical advances in formulation development without losing the biosimilar status of the product. We also support allowing biosimilar products to use different delivery devices or container closure systems from that used in the reference product making it possible, for example, for a biosimilar product to be approved in a pre-filled syringe or auto-injector device while the reference product may be in a conventional vial presentation.

As you may recall from our previous post on this topic, we are in favor of allowing data generated using a non-US licensed reference products in support of a biosimilar application in the US. FDA agrees with this approach and will consider the use of a non-US licensed reference product in certain studies to support biosimilarity. Since most biologic products today are sourced from a single manufacturing location, but sold globally, FDA will require the relationship between the license holder for the non-US licensed product and BLA holder for the US licensed reference product to be disclosed, including whether the non-US licensed product is manufactured in the same facility(ies) as the US-licensed reference product and whether the facility(ies) are licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA. Even if non-US licensed reference product data can be used, analytical characterization and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study must directly compare the biosimilar product with the US licensed reference product.

To help companies with the design of acceptable biosimilar development plans, FDA is encouraging them to meet with the Agency to discuss their detailed plans and share manufacturing information and preliminary comparative analytical data so that the Agency and the Sponsor can agree on the type and amount of animal and clinical data needed to support eventual licensure of the biosimilar product. According to Theresa Mullin, director of FDA’s Office of Planning and Informatics, FDA has received 31 requests for such meetings and had held 21 of these meetings as of December 2011.

These guidances are an important and meaningful first step toward full implementation of the BPCI Act. Overall, the guidances do not contain any surprises although we are pleased to find them more open to permissible deviations from the reference product than expected. The Agency is accepting public comment on the draft guidances for the next 60 days and will, hopefully issue its final guidances shortly thereafter. Now that these general guidances for biosimilar development have been published we hope FDA will turn its attention to product specific guidances as has already been done in Europe to ensure a clear and meaningful roadmap for the development and approval of biosimilar products in the US.