Economic Analysis of Availability of Follow-on Protein Products. Most Likely Candidates for FoPPs and Rationale for their Selection

07/27/2009

1. Evaluation of Biologic Categories

As described in Section III: Methodology, each of the top 10 biologic categories according to 2006 annual sales was evaluated using a set of criteria (e.g., regulatory route, market factors) to determine which categories are most likely to include candidates for FoPPs over the next decade. Information gathered during this review is presented by biologic category in Appendix B and summarized in Table 1.

Based on the factors listed for each category, in addition to feedback from expert stakeholders, two categories (i.e., recombinant coagulation factors and enzyme replacement biologics) were eliminated from consideration. Also, this analysis focuses on biologics currently under the PHS Act that would be eligible for a new abbreviated pathway with the passage of proposed legislation; therefore, the regulatory route for the biologic category was a key consideration. Given that hGH and insulin were approved under the FDCA rather than via the BLA pathway under the PHS Act, these two categories were also eliminated from further consideration.

2. Evaluation of Specific Biologics within the Selected Biologic Categories

Starting with the six remaining categories (i.e., EPO, MAb, anti-TNF, interferon beta, G-CSF, and interferon alpha), we examined individual biologics within these categories that ranked in the top 20 biologics according to 2006 sales. Criteria for this review are described in Section III: Methodology. Detailed information gathered during this review is presented in Appendix C and summarized by biologic category following Table 1.

Table 1: Findings from Analysis of Biologic Categories [72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82]
Biologic Category  Factors Increasing the Attractiveness of Developing FoPPs  Factors Decreasing the Attractiveness of Developing FoPPs
Erythropoietin (EPO)
  • Highest annual sales of all biologic categories
  • Large affected population
  • EU-approved FoPP
  • FoPPs for EPO are estimated to have the largest influence on the market of all biologic categories (tied with hGH)
  • Relatively low growth rate in annual sales
  • Recent research findings regarding adverse cardiovascular and oncological effects
Cancer monoclonal antibodies (MAb) 
  • Second-highest annual sales of all biologic categories
  • Largest growth rate in annual sales
  • FoPPs for MAbs are estimated to have the fourth largest influence on the market of all biologic categories
  • Patent protection for recombinant MAbs is projected to last until as late as 2018
Anti-tumor necrosis factor (anti-TNF) agents
  • Third highest annual sales of all biologics categories
  • High growth rate in annual sales
  • Non-biologic treatments available, which could lessen demand for biologic treatments
  • Anti-TNFs that use MAb technology may have patent protection until 2018
Insulin and insulin analogs 
  • Fourth-largest annual sales of all biologics categories
  • Largest reported affected population
  • High growth rate in annual sales
  • FoPPs for insulin are estimated to have the second-largest influence on the market of all biologic categories
  • Second-generation and analog products have eroded the market
  • Monopoly held by very few, large companies
Recombinant coagulation factors
  • Fifth-largest annual sales of all biologics categories
  • Moderate growth rate in annual sales
  • Clinical trials required for the approval of every product, therefore every product is technically a new biologic and would not likely be considered a FoPP
  • Small affected patient populations
  • FoPPs for recombinant coagulation factors are estimated to have the fifth-largest influence on the market of all biologic categories
Interferon beta
  • Large affected population
  • Moderate growth rate in annual sales
  • FoPPs for interferon are estimated to have the third-largest influence on the market of all biologic categories
  • Sixth-largest annual sales of all biologics categories
  • Non-biologic treatments available
Granulocyte-colony stimulating factor (G-CSF)
  • Moderate growth rate in annual sales
  • Seventh-largest annual sales of all biologics categories
  • Market erosion by second generation pegylated G-CSF
Human growth hormone (hGH)
  • FoPP Omnitrope already approved for use in the US
  • No second-generation products to erode the market
  • FoPPs for hGH are estimated to have the largest influence on the market of all biologic categories (tied with EPO)
  • Eighth-largest annual sales of all biologics categories
  • Small affected population
  • Low growth rate in annual sales
Interferon alpha
  • FoPPs for interferon are estimated to have the third-largest influence on the market of all biologic categories
  • Pegylated interferon alpha products offer a significant clinical advantage over non-pegylated products
  • Ninth-largest sales of all biologics categories
  • Small affected population
  • Shrinking growth rate in annual sales
  • Second-generation pegylated products have eroded the market
Enzyme replacement
  • High growth rate in annual sales
  • Smallest annual sales of top 10 biologics categories
  • Comprised of several smaller treatment indications
  • Small affected population
  • FoPPs for enzyme replacement biologics are estimated to have the sixth-largest influence on the market of all biologic categories

Erythropoietin (EPO)

The three biologics considered within this category were Aranesp® (darbepoetin alfa), Procrit® (epoetin alfa), and EPOGEN® (epoetin alfa). While Aranesp® has the highest sales and market share of all EPO biologics, its patent is not expected to expire until 2016.[83],[84] During preliminary research, we noted that patents for Procrit® and EPOGEN® were reported to expire in 2004, although there was discussion of some uncertainty about applicability of some patents. A recent federal court ruling on an Amgen patent (commonly known as the "422 patent") appears to postpone patent expiration for Procrit® and EPOGEN® to 2013.[85] Notwithstanding this court ruling, the size of the market for these products suggests that they are likely to remain among the more attractive candidates for FoPPs.

Initially, Procrit® and EPOGEN® were evaluated as separate candidates, given that their sales and market share data are listed separately in the LaMerie Top 20 Biologics report (as well as on the Amgen website).[86],[87] In a 1985 agreement between Amgen and Johnson & Johnson, Amgen licensed to Johnson & Johnson the exclusive right to promote and sell Procrit® for non-dialysis use in the US, while Amgen retained the right to promote and sell EPOGEN® for dialysis use.[88] In considering the potential economic impact of a FoPP, these two products could be modeled as separate entities, i.e., as per the licensing distinction. However, as the two products are labeled with identical dosing and indications, and may be prescribed as such, they can be modeled as the same drug, with combined annual sales and market share figures higher than those of Aranesp®.[89],[90]

Discussions with expert stakeholders yielded information regarding clinical differences between Procrit®/EPOGEN® and Aranesp® that may influence the willingness of physicians and patients to switch to a FoPP in the future. Aranesp® is a longer-acting form of EPO that must be administered less frequently than Procrit®/EPOGEN®. One stakeholder noted that Aranesp® offers only a marginal clinical improvement over Procrit®/EPOGEN® and, therefore, may not be viewed as a cost-effective alternative.[91] Such a marginal improvement by Aranesp® may work to the advantage of a FoPP for Procrit®/EPOGEN®, as physicians may be more willing to choose the FoPP if they perceive only a marginal clinical difference.

With regard to currently approved FoPPs or FoPPs under development, in June 2007, EMEA approved three FoPPs for epoetin alfa: Binocrit® (Sandoz GmbH), Epoetin alfa Hexal® (Hexal Biotech Forschungs GmbH), and Abseamed® (Medice Arzneimittel Pütter GMBH & Co.).[92] According to available sources, no FoPP is currently approved or in development for Aranesp®.

Based largely on 2006 sales, market share, patent expiration, and availability of an EMEA-approved FoPP, Procrit®/EPOGEN® was selected as a likely biologic candidate for FoPPs. Aranesp® was not considered as likely a candidate given its later patent expiration, marginal improvement over Procrit®/EPOGEN®, and the lack of approved FoPPs or FoPPs under development.

  • EPO biologics selected: Procrit®/EPOGEN®
  • EPO biologics not selected: Aranesp®

Major Cancer Monoclonal Antibodies (MAbs)

Three MAb biologics were reviewed, including Rituxan®, Herceptin®, and Avastin®. Erbitux®, Vectibix®, Lucentis® and other newer MAbs were not reviewed, given that they did not rank in the top 20 biologics according to 2006 annual sales. Since these newer MAbs were approved more recently than the three MAbs reviewed here, it is likely that their patent protections will extend further, making them less likely candidates for FoPPs in the near term.

Patent considerations are particularly complex for the MAb biologics. Genentech received a patent in 2001 for Cabilly II, a combination of Cabilly and Boss technologies, and, as a result, holds the technology that nearly all companies planning to manufacture recombinant MAbs must license. The patent for Cabilly II originally was not set to expire until 2018, but, after a patent challenge, the US government revoked the patent. Genentech has appealed this decision and the patent remains valid and enforceable throughout the appeals process; however, not all MAbs are recombinant and other sources indicate different patent expiration dates.[93],[94],[95],[96] Due to the ambiguity of patent information and the large market for MAbs, patent expiration was deemed of secondary importance relative to other factors, such as 2006 sales, market share, and presence or development of a FoPP in other foreign markets.

MAbs are used for the treatment of various forms of cancer (e.g., metastatic colorectal cancer, non-Hodgkin's lymphoma, certain forms of breast cancer) and have a very large market due to the broad affected population.[97],[98] Rituxan® and Herceptin® had very high 2006 sales, market share, and FoPPs in development in India . Avastin® has relatively lower sales within the MAb category, and this review returned no evidence of FoPPs in development in any foreign markets. However, the market for MAbs is large and Avastin® has different indications than those of Rituxan® and Herceptin®. Therefore, the market for Avastin® is unlikely to be

affected by a FoPP for either Rituxan® or Herceptin®. Given these factors, all three MAbs were selected as likely candidates for FoPPs.

  • MAb biologics selected: Rituxan®, Herceptin®, Avastin®
  • MAb biologics not selected: None

Anti-Tumor Necrosis Factor (Anti-TNF) Agents

The three biologics considered within the anti-TNF category were Enbrel®, Remicade®, and Humira®. These anti-TNFs are used for the treatment of rheumatoid arthritis, psoriasis, and other conditions (e.g., Crohn's disease, ulcerative colitis)[99],[100] Enbrel® was selected as a potential candidate for a FoPP, as it had the highest sales of all biologics in 2006, its patent is expected to expire in 2012, and there is already a FoPP available in China.[101],[102],[103],[104] Remicade® was also selected as a potential candidate for a FoPP, as it had the fourth-highest sales of all biologics in 2006, and its patent is due to expire in 2014.[105],[106] While there is no FoPP approved or under development for this biologic, the high sales and forthcoming patent expiration make it a strong candidate. Humira® was not selected as a candidate for a FoPP, despite its large sales in 2006, due to its patent expiration date of 2016 and because there is no FoPP approved or under development in any country, according to published reports.[107],[108]

  • Anti-TNF biologics selected: Enbrel®, Remicade®
  • Anti-TNF biologics not selected: Humira®

Interferon Beta

Within the interferon beta category, Avonex®, Rebif®, and Betaseron® were reviewed. All three of these biologics have relatively large sales and patents that either already expired or are soon to expire. Interferon beta is prescribed for the treatment of multiple sclerosis, a disease that affects approximately 340,000 individuals in America . Although these biologics appear to be good candidates for FoPPs, published reports provide no indication of FoPPs in development in other countries. [109],[110],[111] While all three drugs have similar strengths and weaknesses as candidates for FoPPs, because the market for interferon beta is smaller than that of other biologic categories, only two drugs from this category were included in the final list of candidate biologics. Of the interferon betas, Betaseron® had the lowest sales and market share in 2006 was, therefore, not included as a candidate for FoPPs.[112]

  • Interferon beta biologics selected: Avonex®, Rebif®
  • Interferon beta biologics not selected: Betaseron®

Granulocyte-Colony Stimulating Factor (G-CSF)

The two biologics considered within the G-CSF category were Neupogen® and Neulasta®. Neupogen®, the older and shorter-acting of the two, had high sales in 2006; a significant portion of the global market share; several FoPPs approved or in development in foreign markets including the EU, China, and India; and anticipated patent expiration in 2013.[113],[114],[115],[116] These factors make it a good candidate for FoPPs in the US; however, market erosion has occurred due to the second generation pegylated G-CSF product, Neulasta®, which can be administered less frequently than Neupogen®. Neulasta® had higher 2006 sales and double the global market share of Neupogen®; however, the Neulasta® patent is not expected to expire until 2015.[117],[118],[119],[120] In addition, there is debate over how large of a clinical improvement pegylation adds to G-CSF biologics. As a biologic indicated for the treatment of congenital and acquired neutropenia (i.e., from cancer radiation therapy),[121] less frequent dosing would appear to be a major improvement in the pegylated biologic. However, while less frequent dosing generally tends to improve compliance with any drug therapy, the relative clinical benefit of the long-lasting G-CSF is only considered marginal, and some anticipate that a FoPP for Neupogen® may compete directly with Neulasta®.[122] Given these considerations and the later patent expiration of Neulasta®, it was not selected as a candidate for FoPPs in this analysis.

  • G-CSF biologics selected: Neupogen®
  • G-CSF biologics not selected: Neulasta®

Interferon Alpha

Pegasys®, a second generation pegylated interferon alpha, was the only interferon alpha with 2006 annual sales in the top 20 for biologics. Its annual sales were the lowest of the top 20 biologics and the next highest selling interferon alpha, Peg-Intron®, was not listed among the top 20 with sales of only $837 million in 2006. Sales of Pegasys® comprised more than half of the 2006 sales of interferon alpha, while the first generation product, Intron A®, accounted for only 10% of the total sales for the category. [123] Due largely to the relative novelty of pegylation technologies, Pegasys® has patent protection extending to 2017.[124] A key consideration in this category is the significance of clinical benefit of pegylation. Given the harsh side effects of interferon alpha drugs used for the treatment of such serious conditions as hepatitis B and C, renal cell carcinoma, malignant melanoma, myeloma, and certain leukemias,[125] decreased dosing of pegylated products not only increases the likelihood of compliance to the prescribed therapy but confers a clinical benefit to the patient.[126] While interferon alpha has a smaller market than the other biologic categories, the addition of this class of biologics increases the scope of this analysis, and, due to the market dominance of Pegasys®, a FoPP for this drug may have a large economic impact.

  • Interferon alpha biologics selected: Pegasys®
  • Interferon alpha biologics not selected: None

3. Most Likely Candidates for FoPPs

Given the aforementioned considerations, the most likely candidates for FoPPs include:

    1. Procrit®/EPOGEN® (EPO)
    2. Rituxan® (MAb)
    3. Herceptin® (MAb)
    4. Avastin® (MAb)
    5. Enbrel® (anti-TNF)
    6. Remicade® (anti-TNF)
    7. Avonex® (interferon beta)
    8. Rebif® (interferon beta)
    9. Neupogen® (G-CSF)
    10. Pegasys® (interferon alpha)

Projected cost savings associated with establishing a regulatory pathway for FoPPs are based on modeling the anticipated experience with FoPPs for these 10 products, as described in the following sections.

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