Biologics: Specific Drug Safety Challenges. Violetta B. Kyburz

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1 Biologics: Specific Drug Safety Challenges Violetta B. Kyburz

2 Biologics: Specific Drug Safety Challenges Topics for discussion Particular issues in the preclinical development of biologics Challenges for biologics in clinical development Are there differences between small molecules and biologics post marketing? Biosimilars: implications for pharmacovigilance

3 Biologics: Increasing Role in the Treatment of Cancer and Autoimmune Diseases Biologics: Recombinant human proteins (enzymes, cytokines, growth factors, hormones), monoclonal antibodies (mabs), fusion proteins Large, highly complex molecules with a very high target affinity and a much higher species specificity than small molecules First biomolecular drug launched in 1982: Humulin (human insulin), first mab launched 1986: OKT 3 For many years one of the fastest growing drug classes

4 Differences Between Small Molecules and Proteins Molecular weight Complex secondary, tertiary, and quaternary structures Biologics: targeted therapy to interact or modulate human cellular targets Source: Amouzadeh and Vargas, 2013

5 Significant Rise of Biologics/Orphan Drugs are Changing Drug Development and Drug Safety Landscape Source: FDA, Office of Orphan Products Development, Mathew T. Thomas

6 Significant Rise of Biologics/Orphan Drugs are Changing Drug Development and Drug Safety Landscape Source: Jim Kling, Nature Biotechnology; Vol. 32; , 2014

7 Number of Patients Studied Prior to Approval Orphan Source: Duijnhoven et al. PLoS March 2013

8 Top Selling Drugs in 2013: 7 of the Top 10 were Biologics Product INN Company Global Sales 2013 (in bio $) Biosimilars 1. Humira adalimumab AbbVie/Eisai 11.0 Phase III 2. Enbrel etenercept Amgen/Pfizer/ Takeda 3. Remicade infliximab J&J/ Merck & Co 8.8 Phase III 8.4 EU approved, Advair fluticasone GSK 8.25 NA 5. Lantus Insuline glargine Sanofi 7.6 EU approved, Rituxan/ MabThera rituximab Roche/BiogenIdec 7.5 Phase III 7. Avastin bevacizumab Roche 6.8 Phase III 8. Herceptin trastuzumab Roche 6.6 Phase III 9. Crestor Rosuvastatin AstraZeneca 6.0 NA 10 Abilify Aripiprazole BMS/Otsuka 5.5 NA Source: First Word and Fierce Pharma, March 2014

9 Specifics of Biologics in Preclinical Development Selection of relevant animal model is often a challenge For mabs: usually immunogenic in animals Prolonged half-life and lag time for pharmacodynamic effect MoA for new targets often not entirely clear ADRs for biologics are typically «on-target» effect but off-target toxicities cannot be excluded Toxicology profile for a biologic can be unrevealing: Predictability of adverse drugs reactions based on animal trials is low Additional in-vitro, in-vivo and ex-vivo tests necessary

10 Developing and Manufacturing Biologics vs Small Molecules Biologics Manufactured in a living system such as a microorganism, plant or animal cells Complex to manufacture Higher GMP requirements Difficult to characterize Small Molecules Manufacturing process is chemical synthesis, combining specific chemical ingredients in an ordered process Well-defined chemical structures Finished drug can usually be analyzed to determine all its various components

11 Developing and Manufacturing Biologics vs Small Molecules Biologics Manufactured in a living system such as a microorganism, plant- or animal cells Complex to manufacture Higher GMP requirements Difficult to characterize Small Molecules Manufacturing process is chemical synthesis, combining specific chemical ingredients in an ordered process Well-defined chemical structures, Finished drug can usually be analyzed to determine all its various components Picture from

12 Developing and Manufacturing Biologics The Process is the Product Even minor alterations in the manufacturing process or in the formulation may produce functional changes (cell behaviour, differences in structure, stability or other quality aspects) Batch-to-batch variability regarding purity and aggregation is the norm Any of these alterations may affect the safety and efficacy of the biologic and can increase the risk of immunogenicity and ADRs

13 Challenges in Clinical Development of Biologics Pre-clinical trials are often not predictive for acute and long-term toxicity of biologics ADRs of biologics are often related to immune function, may be more complex and rare; late onset is possible Number of patients treated in pivotal clinical trials often smaller (biologics often developed for orphan/rare diseases or as third-line therapy) and longer-term usage even less, i.e. too small to detect more rare ADRs

14 Lack of Preclinical Toxicity Finding does not Preclude that Things Can Go Terribly Wrong: TGN 1412 (TeGenero) In Phase I trial, 6/8 patients developed serious adverse events: organ failure, respiratory distress, DIC Transferred to ICU (part of same facility) Initial signs appeared min after dosing Produced by Cytokine Release Storm

15 Adverse Drug Reactions Specific to Biologics Immunotoxicity: immune-response mediated reactions such as immunogenicity, hypersensitivity, and acute phase reactions Usually ADRs are «on-target» and thus often affect the immune system. However there are differences between biologics for the same biologic in different indications ADRs of biologics typically include: infections reactivation of viruses and bacteria malignancies

16 Immune Related Safety Warnings of Top Biologics Biologic Type Indications Immune Related Safety Warning Adalimumab Human mab RA, CD, AS Serious infections, malignancies, HSTCL, immunogenicity Etanercept Fusion protein RA, AS, psoriasis Serious infections (TB, fungal), malignancy PML, neutropenia, infections Infliximab Chimeric mab RA, CD, AS, UC Serious infections, malignancy, PML, HSTCL, immunogenicity CRS/SIRS, immunogenicity, Rituximab Chimeric mab NHL, CLL, RA, Wegener s granulomatosis Acute infusion reactions, CRS, TLS, severe mucocutaneous reactions PML Source: Satish et al, Nature Reviews, April 2013, Vol 12;

17 Approval Process for Small Molecule Generics, New Biologic Agents, and Biosimilars Quality Small Molecule Generic Individual quality assessment Comparison with reference product New Biological Agent Individual quality assessment Preclinical No data required Full pre-clinical program Clinical Bioequivalence study Phase I Phase II Phase III in all indications Risk Management Plan Biosimilar Individual quality assessment Comprehensive comparison with reference product Abbreviated pre-clinical program (tolerance, PK/PD) Phase I PK/PD study Phase III study in one sensitive, representative indication Risk Management Plan Source: Mellstedt, Clinical considerations for biosimilar antibodies, EJC, Vol.11 (3); 1 11, Dec 2013

18 Biosimilars and Implications for Pharmacovigilance Since 2005/2007, relatively simple biosimilars such as growth hormones, erythropoietin and GCSF available With the upcoming patent expiry of several mab biologics, biosimilar mabs are close to market entry Pre-clinical/clinical path already established by reference biologic BUT Although similar to the reference biologic, the biosimilar may be different with respect to molecular structure, glycosylation etc. This may affect both efficacy and safety.

19 Biosimilars and Implications for Pharmacovigilance Even fewer patients studied during clinical development of biosimilars Unlikely to detect rare ADRs risk minimization strategies of safety and monitoring of efficacy (especially in indications where the biosimilar drug has not been studied) will be important All currently approved biosimilars in the EU have additional requirements regarding surveillance (patient questionnaires, registries, post-marketing surveillance)

20 Remsima: First Biosimilar mab Approved in 2013 (RA, Crohn s Disease, UC, Ankylosing Arthritis, Psoriasis) A total of 440 patients treated with Remsima for at least 30 weeks: Several PAES studies and registries for Crohn s disease and IB requested by EMA to further clarify long-term safety profile of patients Source: Assessment Report Remsima EMA, June 27, 2013

21 Conclusions Biologics currently represent 30% of licensed products and are among the world s best-selling pharmaceuticals Due to high affinity for targets, biologics usually have fewer unwanted effects compared to small molecules ADRs fall into two groups: «on-target» ADRs triggered by exaggerated pharmacology and «off-target» ADRs Developing biologics is complex and requires a thorough understanding of disease, immune system, target of immunomodulation and of the biologic itself Preclinical studies, particularly animal studies (due to the species specificity) can be unrevealing Patient numbers studied prior to approval are smaller for biologics compared to small molecules and even smaller for biosimilars Pharmacovigilance of biologics needs (even more) expertise and thorough understanding of biologics and diseases

22 Thank you Violetta Kyburz, Commercial Director Fishawack Archimed Tel: LinkedIn: Fishawack Group of Companies