2. Multiple anti-TNFα drugs motives and implications Presented by: Ofer Katzir, Yonatan moshkovits and Asher Moshe June 2015

3. Multiple drugs targeting the same illness Multiple drugs targeting the same illness

4. Advantages Encouraging competition between the companies More employee are needed to the pharmatheutical industry

5. Advantages Greater market supply Constant desire to improve the drug

6. Advantages Reduce cost of the drug Different side effects to each drug Different reaction to the drug

7. Advantages Higher population coverage

8. Disadvantages Mix and confuse between the different drugs Inappropriate consumption

9. Disadvantages Drugs interactions Low fidelity product

10. Polypharmacy In Israel: 8 and above drugs taken per person ROW: 5 and above Negative connotation: health damage, financial cost, lack of professionalism. Controlled, justified and based by the doctors

11. Polypharmacy – etiology Polypharmacy – etiology Increase in life expectancy Increased chronic diseases Proliferation diseases in one person Drug development accelerated Aggressive marketing Workload and minimal time to listen to the patient Multiple experts- multiple medications Low adherence to treatment Communication problems- a mismatch between the doctor's instructions and the actual use of drugs by patients Financial situation

12. The risks in polypharmacy The risks in polypharmacy Side effects Drugs interactionsFalls in the elderly community

13. Recommendations for reducing polypharmacy New drug- treatment’s goals and estimated time needed Follow the patient’s reaction and adjust dose (start low) Documented continuous monitoring of the need and benefits, side effects, questioning regarding other medications, dietary supplements and OTC medications. Verify compliance The “brown bag visit” Priority to short-term medications

14. Recommendations for reducing polypharmacy Stop taking the medication at the right time Go to a geriatrician (specialize in medical care for the elderly) Follow the doctor’s instructions Monitor and inform about the side effects Routine medical checks

15. TNF - α blockers that are in use today (FDA approved)

16. HUMIRA Generic Name: adalimumab Brand Name: Humira Manufacturer :AbbVie and Zydus Cadila Activity: Adalimumab is an injectable antibody that binds TNF-α and prevent its binding to TNFα receptors and therefore blocks the inflammatory effects of TNF alpha. Adalimumab was the first fully human monoclonal antibody drug approved by the FDA. It was derived from phage display. Uses : Adalimumab is used for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease of the intestine.

17. HUMIRA Side effects : rare fast-growing type of lymphoma, Serious and sometimes fatal infections, hypersensitivity reactions (including anaphylaxis) and reduced levels in the blood of platelets and red cells. Cost: approximately $3,100 per month. Administration: injection under the skin Sales: In 2012, Humira had $4.3 billion of sales in the US and $9.3 billion worldwide.

18. CIMZIA Generic Name: certolizumab pegol Brand Name: CIMZIA Manufacturer : UCB Activity : CIMZIA is a recombinant, humanized antibody Fab fragment, with specificity for human TNFα, conjugated to an approximately 40kDa polyethylene glycol.The Fab fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG, to generate certolizumab pegol. CIMZIA is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use glass syringe for subcutaneous injection. Uses: it is use for the treatment of Crohn’s disease and rheumatoid arthritis.

19. CIMZIA Side effects : diarrhea, flu symptoms, swelling of your ankles or feet ; fast or slow heart rate ; pain or burning when you urinate ; confusion, neck stiffness, seizure (convulsions);severe blistering, peeling, and red skin rash ; vision problems, dizziness, numbness or tingly feeling, muscle weakness in your arms or legs; Administration: injection under the skin Cost: $3237.7 for a month. Sales : In 2011, had €312 million of sales.

20. simponi Generic Name: Golimumab Brand Name: simponi Manufacturer : Centocor (Johnson & Johnson) Activity: SIMPONI (golimumab) is a human IgG1κ monoclonal antibody specific for human TNFα that exhibits multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. SIMPONI was created using genetically engineered mice immunized with human TNF. SIMPONI is produced by a recombinant cell line cultured by continuous perfusion. The SIMPONI drug product is a sterile solution of the golimumab antibody supplied as either a single dose prefilled syringe or a single dose prefilled autoinjector. Uses: it is use for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

21. simponi Side effects : fever, night sweats, weight loss, tiredness, feeling full after eating only a small amount, pain in upper stomach that may spread to the shoulder, easy bruising or bleeding, pale skin, feeling light-headed. Administration: injection under the skin Cost : $5 for each SIMPONI injection $10,000 annual. Sales : In 2012, had $607 million of sales.

22. ENBREL Generic Name: Etanercept Brand Name: Enbrel Manufacturer : Amgen Activity: Etanercept is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein that blocks the binding of TNF alpha to its receptors. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Uses: It is use for the treatment of Moderate to Severe RA,Moderate to Severe Polyarticular juvenile RA, psoriatic arthritis, Ankylosing Spondylitis and Moderate to Severe plaque Psoriasis.

23. ENBREL Side effects : fever, night sweats, weight loss, tiredness, feeling full after eating only a small amount, pain in upper stomach that may spread to the shoulder, easy bruising or bleeding, pale skin, feeling light-headed. Administration: injection under the skin Cost : approximately $20,000 a year Sales: Sales were $3.3 billion in 2010.

24. REMICADE Generic Name: Infliximab Brand Name: REMICADE Manufacturer : Centocor (Janssen Pharmaceutica) Activity: Infliximab is an artificial antibody. It was originally developed in mice as a mouse antibody, the mouse common domains were replaced with similar human antibody domains to produce a chimeric monoclonal antibody. Infliximab works by binding to TNF-α. In rheumatoid arthritis, infliximab seems to work by preventing TNF-α from binding to its receptor in the cell. Uses :It is used for the for the treatment of psoriasis, psoriatic arthritis, Ankylosing Spondylitis, rheumatoid arthritis Crohn’s disease and ulcerative colitis.

25. REMICADE Side effects : rarely cause serious (possibly fatal) liver disease. Headache, stomach pain, or nausea pain/swelling at injection site, joint/muscle pain, swelling ankles/feet, easy bruising/bleeding, visionchanges, seizures, confusion, muscle weakness, numbness/tingling of arms/legs Administration: by vein, the infusions are administered at a doctor’s office or at an infusion center. These treatments could take up to 3 hours. Cost : A single dose of Remicade can cost from $1,300 to $2,500. Sales: Sales were $5.2 billion in 2013.

26. So why so many? Implications of multiple drugs

27. Differences in drug approaches Strategies used to neutralize TNF-α: Monoclonal IgG antibody Soluble TNF-α receptor Activity: Binding trimeric (active) form of TNFα only Binding both monomeric (inactive) and trimeric (active) form TNFα Ability to bind also TNF-β (Etanercept) Ability to lyse cells that express TNF-α on their surface S. Mpofu et al. 2004

28. Differences in drug approaches Treatment effect: In Crohn’s disease and Behçet's disease there is a clear clinical benefit with infliximab but not etanercept. infliximab aggravated the condition of severe heart failure, whilst etanercept did not. S. Mpofu et al. 2004

29. Dosing and Methotrexate DrugDosing Methotrexat e? Infliximab (Remicade ®) Initially: Given at the clinic or at an infusion center as an intravenous infusion (IV) at a dose of 3-5 mg/kg (according to body weight) at weeks 0, 2, and 6. Maintenance: IV infusions every 4-8 weeks. Dose may be increased to 5- 10 mg/kg. Yes Etanercept (Enbrel ®) Initially: 50 mg once a week or 25 mg twice a week as a self-administered subcutaneous injection. Maintenance: Same No Adalimumab (Humira ®) Initially: 40 mg every other week as a self-administered subcutaneous injection. Maintenance: Same Suggested, not required Certolizumab (Cimzia ®) Initially: 400 mg on week 0, 2 and 4 as a self-administered subcutaneous injection. Maintenance: 200 mg every other week. Note: Each 400 mg dose should be administered as 2 injections of 200 mg each. No Golimumab (Simponi ®) Initially: 50 mg once per month as a self-administered subcutaneous injection. Maintenance: Same Yes American College of Rheumatology

30. Methotrexate Originally developed and continues to be used for chemotherapy. In low doses methotrexate is a generally safe and well tolerated drug in the treatment of certain autoimmune diseases. Weekly doses is beneficial for 12 to 52 weeks duration therapy although discontinuation rates are as high as 16% due to adverse effects Can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal). Oral doses are taken weekly, not daily, to limit toxicity.

31. summery Can target a larger patient population (since the different drugs act differently) More options, gives ability to better fit the drug to the patient needs. May reduce price due to competition (not very effective in our case)

32. Questions?