Our mission is... to deliver a method for intradermal drug delivery, which is patient-friendly, precise, and reliable.

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2 Our mission is... to deliver a method for intradermal drug delivery, which is patient-friendly, precise, and reliable. 19/04/2016 2

3 Intended use of DermalDose microneedle system Easy for self injections at home No pain from injection No needles visible Dose sparing with vaccine delivery 19/04/2016 3

4 The DermalDose system Handheld unit: comfortable injection Disposable container: Can dose 10 up to 100 µl medication/vaccine Unique hollow, hidden, microneedles 19/04/2016 4

5 Intradermal drug delivery Mantoux test for tuberculosis Immune system strong activation for e.g. vaccination Rich in blood and lymphatic capillaries [1] fast uptake 19/04/2016 5

6 Intradermal drug delivery Immune system strong activation for e.g. vaccination Rich in blood and lymphatic capillaries [1] fast uptake 19/04/2016 6

7 Intradermal drug delivery with the DermalDose system 19/04/2016 7

8 Pharmacokinetics Pharmacokinetic profiles in swine [11] A.J. Harvey, S.A. Kaestner, et.al. Microneedle-based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs, /04/2016 8

9 Methotrexate in rheumatoid arthritis MTX is the first choice for rheumatoid arthritis treatment 90% cleared quickly (half-life of 7-10 hrs) [3][4] 10% MTX moves into mostly red blood cells MTX in red blood cells is stable over 9 days [5] MTX levels in red blood cells reaches a steady state after 7 weeks (1 injection/week) [5] 19/04/2016 9

10 Side effects Frequency of adverse reactions are dose dependent [10] In practice > 20 mg/week is a common regime [10] Yamanaka, Hisashi, et al. Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients, /04/

11 Side effects? Frequency of adverse reactions are dose dependent [10] In practice > 20 mg/week is a common regime [10] Yamanaka, Hisashi, et al. Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients, /04/

12 Compliance Only 64% of patients achieved 80% adherence followed for 1 year (Harley, 2003) 40% of MTX users under dose injections, estimated by a treating rheumatologist 30% of participants withdrew within two years from a MTX study (Hoekstra, 2003) [19] Harley CR, Frytak JR, Tandon N. Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate, /04/

13 Conclusion I DermalDose System Easy for self injections at home No pain from injection No needles visible Includes communication technology for monitoring compliance 19/04/

14 Research of interest Is MTX intradermally effective? Can intradermal administration of MTX reduce the dose required? Can the dose be lowered even more when administrating more frequently? 19/04/

15 Research of interest Will this lead to reduction of side effects and better compliance? 19/04/

16 Conclusion II DermalDose System Easy for self injections at home No pain from injection No needles visible Includes communication technology for monitoring compliance Potential reduction of side effects as nausea? Potential improvement of compliance? Earlier remission due to improved compliance? Health care improvement? 19/04/

17 1. Zehrung D, Kristensen D. Intradermal Delivery of vaccines, A review of the literature and the potential for development for use in low- and middle income countries. Program for Appropriate Technology in Health (PATH), World Health Organization Birchall JC, Clemo R, Anstey A, John DN. Microneedles in clinical practice--an exploratory study into the opinions of healthcare professionals and the public. Pharm Res. 2011;28(1): Świerkot J, Szechiñski J. Methotrexate in rheumatoid arthritis. Pharmacological Reports. 2006;58(473): Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate deficiency and formation of polyglutamates. Arthritis & Rheumatism. 1986;29(7): Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology (Oxford). 2010;49(12): Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub R. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Annals of the rheumatic diseases. 2001;60(8): Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis. The Journal of rheumatology. 2006;33(3): Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Annals of the rheumatic diseases. 1999;58(4): Hoekstra M, Van Ede A, Haagsma C, Van De Laar M, Huizinga T, Kruijsen M, et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2003;62(5): Yamanaka H, Inoue E, Tanaka E, Nakajima A, Taniguchi A, Terai C, et al. Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients: evidence based on the variety of prescribing approaches among practicing Japanese rheumatologists in a single institute-based large observational cohort (IORRA). Mod Rheumatol. 2007;17(2): References 11. Harvey AJ, Kaestner SA, Sutter DE, Harvey NG, Mikszta JA, Pettis RJ. Microneedle-based intradermal delivery enables rapid lymphatic uptake and distribution of protein drugs. Pharm Res. 2011;28(1): K. J. Hansen, L. Chu, S. Schaefer, S. A. Burton, Hollow Microneedle Delivery of a therapeutic dose of Methotrexate and Humira advantages of intradermal delivery over conventional routes, Shah UU, Roberts M, Orlu Gul M, Tuleu C, Beresford MW, Group NMARUPRCS. Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs). Int J Pharm. 2011;416(1): Schnabel A, Reinhold-Keller E, Willmann V, Dihlmann W, Gross W. Side effects and efficiency of 15 mg and 25 mg methotrexate per week in chronic polyarthritis. Zeitschrift fur Rheumatologie. 1993;53(3): Muller RB, von Kempis J, Haile SR, Schiff MH. Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort. Semin Arthritis Rheum. 2015;45(1): Linde L, Hetland ML, Ostergaard M. Drug survival and reasons for discontinuation of intramuscular methotrexate: a study of 212 consecutive patients switching from oral methotrexate. Scand J Rheumatol. 2006;35(2): Haq MI, Smith E, John DN, Kalavala M, Edwards C, Anstey A, et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed Microdevices. 2009;11(1): Harley CR, Frytak JR, Tandon N. Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate. American Journal of Managed Care. 2003;9(6; SUPP/2):S136-S Norman JJ, Choi SO, Tong NT, Aiyar AR, Patel SR, Prausnitz MR, et al. Hollow microneedles for intradermal injection fabricated by sacrificial micromolding and selective electrodeposition. Biomed Microdevices. 2013;15(2): /04/

18 We are inviting experts to take part in this research on intradermal methotrexate delivery