THE NEW BIOLOGICS IN THE RHEUMATIC DISEASES. Benjamin Wang, M.D., FRCPC Division of Rheumatology Mayo Clinic Jacksonville, FL

Transcription

1 THE NEW BIOLOGICS IN THE RHEUMATIC DISEASES Benjamin Wang, M.D., FRCPC Division of Rheumatology Mayo Clinic Jacksonville, FL

2 Disclosures None

3 Topics The Biologics Era Mechanisms of Action Biologics and the Diseases Treated Use and Precautions Biosimilars: A New Era?

4 The Biologics Era A new period of molecular medicine : the therapeutic use of directed macromolecules The first commercial biologic: human insulin (1982, Eli Lilly and Genentech) Other early drugs: tissue plasminogen activator (1987, Genentech), erythropoietin (1983, Amgen) First biologics in arthritis: Remicade (infliximab) [Centocor, Aug. 24, 1998] Enbrel (etanercept) [Immunex, Nov. 2, 1998] Humira (adalimumab) [Abbot, Dec. 31, 2002]

5 The result of understanding molecular targets Choy, E.H. NEJM 2001; 344(12):

6 The result of advances in manufacturing

7 Advanced Biotechnology

8 Advanced Biotechnology

9 Available Anti-TNF Biologic Drugs I. Solovic et al. Eurr Resp J :

10 The Origin of Species (of mabs)

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12 The simple days are over ciprofloxcin Cipro ixekizumab Ick (??) Taltz

13 Mechanisms of Action: 1)Bind the ligand (e.g. cytokine molecule) Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) Certolizumab (Cimzia) Golimumab (Simponi) Ustekinumab (Stelara) Secukinumab (Cosentyx) Pedersen J. World J Gastroenterol. Jan 7, 2014; 20(1): 64-77

14 Mechanisms of Action: 2)Block the receptor (e.g. cytokine receptor) Tocilizumab (Actemra) Anakinra (Kineret)

15 Mechanisms of Action: 3)Inhibit cell-cell signaling and activation (e.g. T cell activation) Abatacept (Orencia)

16 Mechanisms of Action: 4)Cellular lysis Rituximab (Rituxan) Samantha M. Jaglowski et al. Blood 2010;116:

17 Mechanisms of Action: 5) Block growth and differentiation factors Belimumab (Benlysta) Stohl & Hilbert.Nature Biotechnology 30:69 77 (2012).

18 Mechanisms of Action: 6)Block intracellular signaling (e.g. JAK-STAT) Pedersen J. World J Gastroenterol. Jan 7, 2014; 20(1): Tofacitinib (Xeljanz)

19 Biologics in Rheumatic Diseases -- Reference Abbreviations: mab-monoclonal antibody; TCZ-tocilizumab; RA-rheumatoid arthritis;psa-psoriatic arthritis; JAK-Janus kinase Indicates FDA approved and commercially available as of March 2018 Venuturupalli S. Immunol Allergy Clin N Am 37 (2017)

20 Biologics in Rheumatic Diseases -- Reference Abbreviations: mab-monoclonal antibody; TCZ-tocilizumab; RA-rheumatoid arthritis;psa-psoriatic arthritis; JAK-Janus kinase Venuturupalli S. Immunol Allergy Clin N Am 37 (2017)

21 Biologics in Rheumatic Diseases -- Reference Abatacept (T cell signaling inhibitor) RA, PSA Anakinra (IL-1 receptor antagonist) RA Ustekinumab (IL-12/23 receptor antagonist) Psoriasis, PSA Belimumab (B cell proliferation inhibitor) SLE Guselkumab (IL-23 receptor antogonist) Psoriasis, PSA Apremilast (Phosphodiesterase 4 inhibitor) Psoriasis, PSA Abbreviations: mab-monoclonal antibody; TCZ-tocilizumab; RA-rheumatoid arthritis;psa-psoriatic arthritis; JAK-Janus kinase Venuturupalli S. Immunol Allergy Clin N Am 37 (2017)

22 Approved Biologic Therapies Drug Target Dose Prescreen Other Rheumatoid Arthritis Remicade (infliximab) TNF 3-10 mg/kg IV q4-8 wk TB, HBV, HCV with MTX Enbrel (etanercept) TNF 50 mg SQ qwk TB, HBV, HCV Humira (adalimumab) TNF 40 mg SQ q2wk TB, HBV, HCV Also Uveitis Cimzia (certolizumab) TNF 200 mg SQ q2wk OR 400 mg SQ q4wk TB, HBV, HCV Simponi (golimumab) TNF 50 mg SQ q4wk TB, HBV, HCV Orencia (abatacept) T cell mg IV q4wk OR 125 mg SQ qwk Rituxan (rituxumab) B cell 1000 mg IV q2wk x 2 HBV Actemra (tocilizumab) IL mg/kg IV q4wk OR mg SQ q1-2wk Kineret (anakinra) IL mg SQ qd CBC Xeljanz (tofacitinib) JAK 1,2 5 mg PO BID OR 11 mg PO qd TB TB, HCV, HBV, lipids TB, HBV, HCV, lymphocyte count (>500 cells/mm3) or abs neutrophil count (>1000 cells/mm3), hemoglobin level greater than 9 g/dl Load 400 mg SQ at week 0, 2, 4

23 Approved Biologic Therapies Drug Target Dose Prescreen Other Psoriatic Arthritis: see also Enbrel, Remicade, Humira, Cimzia, Simponi, Orencia Stelara (ustekinumab) IL-12/ mg SQ q12wk TB Cosentyx (secukinumab) IL-17A SQ q4wk TB Taltz (ixekizumab) IL mg SQ q4wk TB Tremfya (guselkumab) IL mg SQ q8wk TB Otezla (apremilast) PDE4 30 mg PO BID TB, HBV Ankylosing Spondylitis: see Enbrel, Remicade, Humira, Cimzia, Simponi, Cosentyx Systemic Lupus Erythematosus Benlysta (belimumab) 10 mg/kg IV q4wk None Vasculitis Rituxan (rituximab) B cell 375 mg/m2 IV qwk x 4 ANCA vasculitis Actemra (tocilizumab) IL mg SQ qwk GCA

24 Side Effects Actemra (tocilizumab): infections, increased liver function tests, neutropenia, thrombocytopenia, increase of lipid levels, and gastrointestinal perforation (rare) Benlysta (belimumab): infection, hypersensitivity reactions, depression. progressive multifocal leukoencephalopathy (rare) Orencia (abatacept): Side effects: infections, increased frequency of chronic obstructive pulmonary disease exacerbations, injection site reactions, hypersensitivity reaction Otezla (apremilast): nausea, vlimiting, diarrhea, URTI Rituxan (rituximab): infection, infusion reactions, cytopenias, hepatitis B reactivation. Rarely progressive multifocal leukoencephalopathy, cardiac arrhythmias, angina Stelara : infections, tuberculosis and other mycobacterial conditions, anaphylaxis, reversible posterior leukoencephalopathy syndrome Taltz (ixekizumab): Infections, tuberculosis reactivation, hypersensitivity, Inflammatory Bowel Disease exacerbation TNF Inhibitors: infections, including fungal infections and tuberculosis reactivation, hepatitis B reactivation, cytopenias, heart failure, lupus-like syndrome, non-melanoma skin cancer, demyelinating disease (rare) Tremfya (guselkumab): upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections Xeljanz (tofacitinib): infections, monitor labs (lymphocytes, neutrophils, hemoglobin, liver enzymes, lipids). Rarely GI perforation Adapted from Wolfe and Ang. Immunol Allergy Clin N Am 37 (2017)

25 Biosimilars in Rheumatology Biopharmaceuticals that replicate originator molecules using similar, but not identical biomanufacturing processes Biosimilar must demonstrate no significant difference from its reference product Robust analytical, toxicologic, PK/PD, and immunogenicity studies in comparison to reference product Smaller comparative effectiveness clinical trial(s), which must be conducted in pts with a disease for which the reference product is licensed No need to demonstrate efficacy in all indications No differences in safety or efficacy are expected between an approved biosimilar and its reference product In Europe, the advent of biosimilars to infliximab, etanercept and rituximab has introduced more treatment choice and led to cost reduction

26 Why Biosimilars Are NOT Generic Biologics Parameter Biosimilar Products Generic Drugs Synthesis Structure vs reference product Structural complexity Immunogenic potential Interchangeability with reference product Automatic substitution Nomenclature In living systems, generally with recombinant DNA technology Similar Many layers of structure, including posttranslational modification Possible; requires testing and pharmacovigilance monitoring Only when higher standard of interchangeable has been met Guidance pending FDA proposes unique INN (eg, reference product with a distinguishing 4-letter suffix that is devoid of meaning) Chemical synthesis Almost completely identical Typically simple molecular structure Less likely; allergic reactions can occur Allowed by legislation if standards of purity and bioequivalence have been met Generally allowed; depends on state law and physician preference INN generally same as reference product Rak Tkaczuk KH, et al. Semin Oncol. 2014;41:S3-S12. Olech E. Semin Arthritis Rheum. 2016;45:S1-S10. Slide credit: clinicaloptions.com

27 Critical Attributes for Biosimilarity High-Quality Biosimilar Not a Biosimilar Higher order structure Primary structure Biological function Higher order structure Primary structure Biological function Similar Acceptable differences Difference with critical or unknown impact Product purity Product purity General properties and excipients Stability Particles and aggregates General properties and excipients Stability Particles and aggregates Processrelated impurities 95 attributes similar 2 acceptable differences 0 critical differences Processrelated impurities 87 attributes similar 7 acceptable differences 3 critical differences Lot-to-lot variability of critical quality attributes must be assessed and controlled to ensure consistent product quality FDA. Overview of biosimilar products Slide credit: clinicaloptions.com

28 Immunology Biosimilars in the United States Biosimilar Approval Date Reference Product Rheumatologic Indications Infliximab-dyyb Infliximab-abda Infliximab Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis Adalimumab-atto 2016 Adalimumab Etanercept-szzs 2016 Etanercept 1. Infliximab-dyyb [package insert] Infliximab-abda [package insert] Adalimumab-atto [package insert] Etanercept-szzs [package insert] Rheumatoid arthritis Juvenile idiopathic arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Juvenile idiopathic arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis Slide credit: clinicaloptions.com

29 Pts With Endpoint at Wk 52 (%) NOR-SWITCH: Switch to Infliximab-dyyb for Multiple Indications Treatment Difference: -4.4% (95% CI: -12.7% to +3.9%) Treatment Difference: 0.6% (95% CI: -7.5% to +8.8%) wk randomized, double-blind phase 4 trial in pts with RA, SpA, CD, Ps, PsA, or UC on stable infliximab for 6 mos Primary endpoint: disease worsening during 52-wk follow-up Prespecified non-inferiority margin: 15% Result: Switching from infliximab to infliximab-dyyb noninferior to continued treatment with infliximab n/n = 0 53/202 61/ / /206 Disease Worsening* Remission Infliximab (n = 202) *Primary endpoint. Infliximab-dyyb (n = 206) Jørgensen KK, et al. Lancet. 2017;[Epub ahead of print]. Slide credit: clinicaloptions.com

30 VOLTAIRE-RA phase III randomised equivalence study of adalimumab biosimilar BI and Humira reference product Cohen SB et al. Ann Rheum Dis 2018 epub ahead of print.. doi: /annrheumdis

31 Biosimilars Currently in the Pipeline for Rheumatologic Conditions Reference Biologic Rituximab [1-3] Drug Class CD20 inhibitor ~ Patent Biosimilars With Phase III Exp. Indication Clinical Trials Date 2016 Lymphoma; RA BCD-020 equivalent PK/PD, efficacy, safety in inhl CT-P10 equivalent PK/PD, efficacy, safety, immunogenicity in RA RTXM83 equivalent PK, safety in DLBCL Adalimumab [2-4] TNF-α inhibitor 2022* Autoimmune diseases BI accepted for FDA review Multiple others registered/under way Infliximab [2-4] TNF-α inhibitor 2018* Autoimmune diseases Multiple registered/under way *Ongoing patent litigation. 1. Rugo HS, et al. Cancer Treat Rev. 2016;46: Stevenson JG, et al. Ann Pharmacother. 2017;[Epub ahead of print]. 3. Panesar K. US Pharm. 2016;41: Goel N, et al. Rheumatology. 2017;56: Slide credit: clinicaloptions.com

32 Potential Scenarios: Incorporation of Biosimilars Into Clinical Practice Gradual introduction of biosimilars only in patients newly starting a biologic Instant switching to biosimilars for patients currently receiving a biologic Switching due to loss of response or adverse events with a biologic Switching between the biosimilar and the reference drug on an alternating basis, depending on pharmacy supply and drug product availability In the United States, the complexity of drug pricing and distribution through Pharmacy Benefit Managers does not guarantee easier access or significantly lower cost (Fleischmann, Arthritis Rheum 2018) Slide credit: clinicaloptions.com

33 Summary Biologics are now a well-established form of drug therapy using a variety of targeting molecules based on the knowledge of the mechanisms of disease As molecular pathways become clearer, more directed treatments will emerge Biologics for diseases of immunity and inflammation are highly efficacious and share similar side effects Biosimilars are molecules manufactured in the same principle of their parent originator drugs they hold the promise of providing greater access, equal efficacy and safety, and lower cost

34 Thank you