Follow-on Proteins and Biosimilars

Michael Siem

March 28, 2008

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions

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Hatch-Waxman AimsCongress wanted branded manufacturers to have incentives to innovate.Congress also wanted to ensure that there was incentive for generics to enter market immediately upon patent expiration.

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Hatch-Waxman GenerallyAutomatic 30-Month StayStreamlined process for approval of generic –Abbreviated New Drug Application (ANDA)First filer of ANDA receives 180-day generic drug exclusivity provision

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Standard of Review for Generic DrugsA generic drug contains the same active ingredient as an innovator or brand name drug and has the same dosage form, strength, route of administration, labeling, and conditions of use.

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Legal Background: 1984 Hatch-Waxman Act

Before Hatch-Waxman

Generics 19% of pharmaceutical market (prescriptions filled)(1984)

After Hatch-Waxman

Generics 63% percent of pharmaceutical market (prescriptions filled)(2006)

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions

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Biological Product or Biosimilar?“Biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product …applicable to the prevention, treatment, or cure of a disease or condition of human beings. (PHSA, 42 U.S.C. § 262)Biosimilars (or Follow-on proteins) refer to new versions of proteins or peptides intended to be sufficiently similar to innovator biological products

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Variation in product complexity

AspirinMW 158

Monoclonal AntibodyMW 150,000

InsulinMW 5800

Diazepam (valium)MW 284

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Difficult to define and quantify; Viral/bacteria/fungal/TSEDefined Standards/SpecsImpurities

Variable potential for antibody formationExtremely RareImmunogenicity

Difficult to quantifyDefined ActivityBioactivity

Complex/Heterogeneous LimitationsSimple Definitive Detail/StandardsCharacterization

Living Systems - Inherent heterogeneity affected by minor changes

Chemical Synthesis -predictable & well definedManufacturing

Large (>5000)Small (<5000)Size

BiologicsChemical DrugParameter

Chemical Drugs versus Biologics

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Inherent biologics product variabilityCarbamylationCarboxylationFormylationO-linked GlycosylationN-linked GlycosylationMethylationOxidationPhosphorylationSulphation

Amino Acid SubstitutionTruncationMismatched S-S bondsN- and C-terminal differenceAggregationMultimer DissociationDenaturationAcetylationAcylationAddition of lipidAmidation/Deamidation

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Immunogenicity concernsMany biologics cause an immune reactionUsually the immune reaction is benignPotential risks

Inactivation of the biologic productInactivation of the body’s naturally occurring proteins

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent US Regulatory Framework United States Legislative ProposalsEuropean ApproachConclusionQuestions

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FDA Registration PathwaysPHSA

Biologics License Application (BLA)» Covers vaccines, blood and blood products, some but not all therapeutic

proteins, and cell/gene therapyFDCA

New Drug Application (NDA): 505(b)(1)» Must show safety, efficacy, and quality based on ‘full reports’

New Drug Application (NDA) 505 (b)(2)» References previously approved innovator product» May rely on third party data to show safety and efficacy» Differences must be justified by additional studies on safety and

efficacyAbbreviated New Drug Application (ANDA): 505 (j)

» Must be therapeutically equivalent predicate product — innovator approved under 505(b)(1)

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Scientific principles for 505(j)“Therapeutic Equivalence” requires:

Bioequivalence» same “rate and extent” of absorbance & availability at site

PLUS

Pharmaceutical Equivalence» same active ingredients, dosage form, route of administration,

strength, GMPs

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Scientific principles for 505(b)(2)Suitable Applications (1999 FDA Guidance)

Changes in dosage form, dosing regimen, strength, formulation, or route of administrationA new combination product, including substitution of an active ingredientNew indicationsRx/OTC Switch

Not generally suitable for PHSA-licensed biologics products

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FDA Assessment of Follow-on ProteinsFactors that influence data required for FOP approval:

robustness of the manufacturing processdegree to which structural similarity can be assessedextent to which mechanism of action was understoodexistence of valid, mechanistically related pharmacodynamic assayscomparative pharmacokineticscomparative immunogenicityamount of clinical data available andextent of experience with the original product, or products

» Nature Reviews Drug Discovery 6, 437-442 (June 2007)

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions

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Current Proposals GenerallyHR 1038 – Access to Life Saving Medicine Act

Sponsored by Henry Waxman (D-CA)Generic LeaningBIO Strongly Opposes this bill

HR 1956 – Patent Protection and Innovative Biologic Medicines ActSponsored by Jay Inslee (D-WA)Brand LeaningBIO Strongly Supports this bill

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Current Proposals GenerallyHR 5629 – Pathway for Biosimilars Bill

Sponsored by Anna G. Eshoo (D-CA) Joe Barton (R-TX) Bipartisan SupportBIO Strongly Supports this BillGPhA Strongly Opposes this Bill

S 1695 – Biologic Price Competition Innovation ActSponsored by Edward Kennedy (D-MA)Bipartisan SupportBIO Appears to Support this bill

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Current Congressional Proposals

No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product

N/A

Requires biosimilarity and limits FDA discretion

HR 1038Access to Life-Saving

Medicine Act

No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product

No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product

No stay, but the innovator may seek a preliminary injunction to prohibit generic from manufacturing the product

30-month stay of generic approval if patent litigation suit is filed

12-year innovator exclusivity

12 year innovator exclusivity plus additional two years for medically significant indication.

14-year innovator exclusivity

5-year new chemical entity exclusivity for innovator

Requires biosimilarity and gives FDA discretion

Requires biosimilarity plus analytical studies, animal studies and clinical studies.

Requires biosimilarity and creates committee to set standards

Requires bioequivalence

S 1695 Biologic Price

Competition Innovation Act

HR 5629Pathway for Biosimilars

Act

HR 1956Patient Protection and

Innovative Biologic Medicines Act

Hatch-Waxman

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Current Congressional Proposals

N/A

N/A

HR 1956Patient Protection and

Innovative Biologic Medicines Act

Reference applicant must provide a list of patents for which an infringement claim could be made within 60 days of receiving generic application.

Reference applicant must provide a list of patents for which an infringement claim could be made within 60 days of receiving generic application.

Generic may request list of patents, and the holder of the approved reference must provide the information within 60 days, but may demand up to $100 to cover costs.

Patents must be listed in the Orange Book.

At least one year of generic exclusivity for interchangeable products.

At least two years of generic exclusivity for interchangeable products.

At least 180 days of generic exclusivity for interchangeable products.

180-day generic exclusivity for generic approval under Paragraph IV.

S 1695 Biologic Price Competition

Innovation Act

HR 5629Pathway for

Biosimilars Act

HR 1038Access to Life-Saving

Medicine Act

Hatch-Waxman

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions

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European ApproachBiosimilars approvals beginning in 2006Marketing Authorization Application

“Similar biological medicinal product”» Not suitable for generic products

Comparable to “Reference Product”» Requirements set forth in 2004/27/EC» Comparability in terms of quality, safety and efficacy

Data Exclusivity“8+2+1” for Reference Product

» Period of data protection as incentive for innovation

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EU Legal Framework for BiosimilarsComparability

Safety, quality and efficacyComparability data requirement to determine the risk/benefit balance

Biosimilar Guidelines General guidelines

» EMEA/CHMP/437/04Specific topic guidelines

» EMEA/CHMP/49348/05 (quality)» EMEA/CHMP/42832/05 (non-clinical, clinical)

Specific product class guidelines

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EC Biosimilar Approvals

28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Abseamed (Medice)

28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Epoetin alfa Hexal (Hexal)

28 August 2007Eprex/Erypo (Janssen-Cilag) Epoetin alfa Binocrit (Sandoz)

24 April 2006Humatrope (Eli Lilly) Somatropin Valtropin (Biopartners)

12 April 2006Genotropin (Pfizer) Somatropin Omnitrope (Sandoz)

Approval dateReference product INN Biosimilar

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TopicsGeneric Rules for Small MoleculesBiologics OverviewCurrent Regulatory FrameworkUnited States Legislative ProposalsEuropean ApproachConclusionQuestions

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ConclusionUS Legislation is going to happenDrawbacks and benefits for incumbentsBetter to prepare for the worstPotential impact on licensing and deals

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Questions

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www.fr.com

Follow-on Proteins and Biosimilars