Biosimilars

Biosimilars

1. BIOSIMILARS Dr. Chandini Moderator: Dr. Chandralekha

2. Overview Introduction Definition Differences b/w biosimilars & generics Regulatory approval Examples Potential concerns Conclusion

3. Introduction Biological drugs – essential part of modern pharmacotherapy 1 st developed in 1980s – Recombinant technology Complex proteins ( eg . monoclonal Abs) (DNA manipulation in bacteria, yeast or mammalian cells)  

4. Other eg – cytokines, hormones, interleukins, human insulins , clotting factors, enzymes, vaccines, cell & tissue based therapies. Up to 50% share in global pharmaceutical market in the next few years.

5. What is a Biological agent? aka Biopharmaceutical. “ any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention , treatment, or cure of disease or injuries of man”

6. What are Biosimilars ? A biologic medical product which is almost an identical copy of an original product that is manufactured by a different company. Biosimilars (Europe) = Follow-on biologics (USA) Officially approved versions of original "innovator" products. M anufactured when the original product's patent expires.

7. 1 st biosimilars approved by EMEA (2006) - Omnitrope : biosimilar to Genotropin Valtropin : “ “ Humatrope US-FDA: Zarxio ( filgrastim-sndz ) – 2015 Recomb forms of Somatostatin

8. India : 1 st ‘similar biologic’ – 2000 (for Hep B vaccine), according to GaBI One of the leading contributors. (50 biopharmaceutical brands approved) Affordability & easy accessibility  good reputation among healthcare professionals.

9. Why biosimilars are not generic drugs? Generic drugs Biosimilars Chemical & therapeutic equivalents of chemical drugs. Structure: smaller, less complex, 1D Molecular weight: low Copies of existing biological medicinal products or protein drugs Large & complicated (100-1000x), 3D High

10. Generic drugs Biosimilars More stable Route: Oral Manufacturing process: less complex Registration procedure: simple (ANDA) Sensitive to changes in physical conditions Injected/Inhaled complex, lengthy & expensive (require different cell lines) Complicated (EMEA/FDA)

11. Regulatory approval Stringent criteria – quality, safety & efficacy. Feb’06: EMEA – guidelines on clinical, nonclinical & quality expectations. Approved biosimilars of - S omatropin ( omnitrope , valtropin ) - E poietin ( abseamed , binacrit etc ) & - G-CSF( ratiograstim , biograstim , tevagrastim )

12. EMEA guidelines

13. Feb’12: FDA – 3 draft guidance documents - Scientific Considerations - Quality Considerations - Questions and Answers (regarding Implementation of the Biologics Price Competition and Innovation Act of 2009) India: lacks specific guidelines  unrestrained flooding of biosimilars

14. Nonclinical testing Extensive in vitro & in vivo investigations. Eg . 1 st monoclonal Ab biosimilar approved CT-P13 (Infliximab) - molecular structure - product stability & quality - binding affinities for TNF- α - PK & toxicity profile (10 & 50mg/kg in rats)

15. Clinical evaluation Aims - to resolve slight differences arising in previous steps of the development process. - to confirm comparable clinical performance between the biosimilar & reference products (immunogenicity , PK equivalence , & therapeutic equivalence) Eg . HX575 - bioequivalent (PK & PD) to epoetin based on a study in 80 healthy subjects.

16. Biosimilar product Reference product INN Indication Approval date Omnitrope Genotropin Somatotropin (GH) GH deficiency Hypothalamic disease April 2006 Valtropin Humatrope Abseamed Epogen / Procrit Epoetin alpha Chemotherapy-induced anemia August 2007 Epoetin alpha Hexal Anemia associated with CKD Binocrit  blood transfusion

17. Biosimilar product Reference product INN Indication Approval date Biogastrim Neupogen Filgrastim Cancer Sep 2008 Ratiogastrim Hematopoietic stem-cell transplantation Sep 2009 Nufil Grafeel India Inflectra Remicade Infliximab Ankylosing spondylitis Sep 2013 Remsima Crohn’s , Ulcerative colitis, psoriasis, RA July 2012

18. Biosimilar product Reference product INN Indication Approval date Reditux Rituxan / Mabthera Rituximab NHL, CLL, RA India Cresp Aranesp Darbepoetin alpha ESA for anemia d/t CKD , In chemotherapy 2010 (India) Silapo Dec 2007 Other eg – biosimilars for Enbrel ( etanercept ), Herceptin ( trastuzumab ), Humira ( Adalimumab ), Neulasta ( pegfilgrastim ) etc.

19. Potential concerns 4 major concerns – Safety Substitution Naming Labeliing

20. Safety Biosimilars – only ‘similar’, not identical Safety profile of biosimilar not identical to that of reference product. Eg . Valtropin ( biosimilar GH) has different precautions & warnings than Humatrope (ref product) - d/t different cell lines used to produce both drugs ( Valtropin – yeast, Humatrope – E.Coli )

21. Immunogenicity - unique safety issue Rarely Ab -related reactions – serious & life-threatening. Various potential consequences of immunogenicity – - loss or enhancement of efficacy - neutralization of a native protein - general immune effects ( allergy, anaphylaxis, serum sickness)

22. Eg . the complication of epoetin therapy - Pure red cell aplasia. assoc with specific formulation of epoetin α ( Eprex ) production of neutralizing antibodies against endogenous epoetin ( Eprex – human albumin stabilizer replaced by polysorbate 80 & glycine  immunogenicity) Recomb IFNs  neutralizing Abs  its own production  

23. Recent EMEA guidelines – Preclinical data insufficient to demonstrate immunologic safety of some biosimilars . Pharmacovigilance is mandatory - type of A/E - data about drug (proprietary name, international non-proprietary name & dosage given)

24. Substitution Principle behind substitution of traditional chemical drugs - original drug & its generic are identical & have the same therapeutic effect.   Chemical generics - automatic substitution is appropriate & can produce cost savings

25. Same rules cannot be applied to biotechnological medicines - not identical - safety of therapy/ cause therapeutic failure. Uncontrolled substitution  confound accurate pharmacovigilance . (A/E ascribed to wrong product) Awareness among prescribers & pharmacists necessary  

26. Naming INN - technical name for the medical products Chemical generics assigned the same name B iosimilars require unique INNs - facilitate prescribing & dispensing of biosimilars & also aid in precise pharmacovigilance .

27. Labelling Labels of originator & biosimilar products must be different . Product characteristics Reference products Data for approval Unique safety data Substitution advice

28. Conclusion Biotechnological medicines - important part of future healthcare Biosimilars - availability - alternative Rx options - direct costs of therapies  

29. Biosimilars never identical to reference products - Substitution rules must be different for generics & biosimilars Biosimilars differ from reference products - efficacy - safety - immunogenicity

30. References Khraishi , M., Stead, D., Lukas, M., Scotte , F., & Schmid , H. (2016). Biosimilars : A multidisciplinary perspective.  Clinical Therapeutics, 38 (5), 1238-1249. Misra , M. (2012). Biosimilars : Current perspectives and future implications.  Indian Journal of Pharmacology, 44 (1), 12-14 . Nowicki M. Basic facts about biosimilars : Review. Kidney Blood Press Res 2007;30:267–272 Ventola CL. Biosimilars : Part 1: Proposed Regulatory Criteria for FDA Approval.  Pharmacy and Therapeutics . 2013;38(5):270-287.