INTEC PHARMA The Accordion Pill - World Drug Delivery & Formulation Berlin, February 2014

INTEC PHARMA
       The Accordion Pill™
    World Drug Delivery & Formulation
          Berlin, February 2014

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Disclaimer

    The information presented in this presentation was prepared by Intec Pharma Ltd. and is
    being furnished solely for use in connection with this presentation. We make no
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Presentation Outline

    1.   Intec Pharma, the Corporate
    2.   The Accordion Pill™, AP technology
    3.   Gastric Retention, the Need
    4.   Examples for APs efficacy:
         a. For Narrow Absorption Window drugs
         b. For BCS Class 2 and 4 drugs.
    5. Accordion-Pill™ Manufacturing
    6. Short and Cost – Effective Development Program and
       human POC For Partnering

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Intec Pharma –Profile

     Intec applies its innovative proprietary gastro-retentive technology, the
       Accordion Pill™, in order to develop better medications for various indications
     Initiated operations: 2003
     45 employees, located in Jerusalem, Israel
     A public company , traded in TASE (INTP, Tel-Aviv Stock Exchange)
     Fully equipped cGMP facilities, R&D and Quality Control Labs
     Strong IP portfolio
     Faster regulatory process - 505(b)(2)
     Collaborations with multinational pharmaceutical companies

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Business Strategy

                                          Joint development
                                          with pharmaceutical
    In house development
                                          companies

           In house
        development
          of existing                                PLCM
         drugs up to
         late clinical                  Drugs in
            stages                    Development

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Product Pipeline

         The drug          Indication   Phase I   Phase II

        Accordion-        Parkinson’s
    Carbidopa/Levodopa      disease

    Accordion-Zaleplon     Insomnia

                            Various
    Accordion-Baclofen
                          indications

         Early stage
          programs
                          Undisclosed
    (in-house and under
       collaborations)

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The Accordion PillTM, AP
     Multi-layer, planar structure, composed of biodegradable films folded in an
       accordion shape into a standard size capsule
     All excipients are listed in the inactive ingredients list of the FDA (IIG)

                                     General Structure

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The Accordion PillTM, AP

     When the AP reaches the stomach, the standard gelatin capsule dissolves.
       The Accordion pill unfolds and releases the drug in a pre-defined manner.

     The Accordion pill is retained in the stomach for 8-12 hours.

     Gastric retention is obtained under regular calorie diets.

     The drug release mechanism is independent of the Accordion pill retention
       mechanism

     Once the Accordion pill is expelled from the stomach, it is fully degraded within
       3 to 4 hours in the intestine.

     The Accordion pill can combine immediate and controlled-release profiles and
       can contain more than one API.

     High drug loading: 350mg -550mg.

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Accordion Pill™ Animation
    See at: www.intecpharma.com

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The Accordion PillTM - Safety

  The AP’s safety was successfully tested in more than 30 clinical studies,
     with more than 2,000 administrations
  Gastric retention was demonstrated in various MRI studies
  Safety was also demonstrated in a multiple-dosing endoscopy trial
  No interaction was found with gastric emptying of food (g-scintigraphy)
  Full biodegradability was proven in human with Magnetic marker
     Monitoring (MMM)
  Safety was also demonstrated in multiple dosing oral toxicity study in
     pigs

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Gastric Retention Performance
     Various MRI clinical studies demonstrated that:
      8 hours gastric retention is obtained in more than 80% of the subjects (healthy
       volunteers and patients)
      Gastric retention is achieved under regular calorie diets

     MRI study IN 09 009 (N=11)
                                        % of subjects with AP gastric retention
                       100
                        90
                        80
                        70
                        60
                   %

                        50
                        40
                        30
                        20
                        10
                         0
                             1    2        3   4   5      6      7   8    9   10     11    24   48
                                                              Hour

                   Breakfast (-0.45 min)               Lunch (+4 hours)            Dinner (+10 hours)

                        552 kcal                        862 kcal
                                                                                   Not standardized
                    265 kcal, fat 48%              229 kcal, fat 26.5%
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A Solution for Key Unmet Needs

     The Accordion pill is an effective delivery solution for drugs that are characterized
        by one of the following:
      Narrow absorption window (poor colonic absorption)
         •   PK correlates with limited efficacy, poor safety profile and frequent daily
             dosing.
          AP formulation provides a continuous absorption of the drug, resulting in
             improved PK parameters such as lower Cmax, reduced peak to trough ratio
             and/or higher AUC.
      Poor solubility, BCS (Biopharmaceutics Classification System) class II or IV
         •   Low bioavailability, nonlinear pharmacokinetics and high variability.
          AP formulation can enhance the drug’s absorption by increasing the
             apparent solubility in the stomach and GI tract, resulting in a consistent
             increase of the available drug amount at the site of absorption.
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A Solution for Key Unmet Needs

      Act locally, in the stomach or in the upper part of the GI tract
         • Rapid transit time results in poor exposure.
          AP formulation can release the drug in vicinity to the drug’s action site
            resulting in a continues and effective exposure.
      Adverse effects correlates with the drug reaching to the distal parts of the
        GI tract
          AP formulation can prevent the drug reaching to the distal parts of the GI
            tract.

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Example 1:
     The Accordion PillTM for Drugs with
        Narrow Absorption Window:
         AP- Carbidopa/Levodopa
                    for
         Parkinson's disease (PD)

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Unmet Needs in Levodopa Treatment
      Levodopa - the most widely used therapy for Parkinson’s disease (PD)

      However, Levodopa (LD) treatment is associated with motor complications,
       mainly wearing “OFF” periods and LD-induced dyskinesia.

      PD patients experience wearing off between LD doses, due to the Short Term
       Duration of effect from each dose of LD. This phenomenon occurs roughly in
       parallel with the drug’s peripheral PK profile1.

      Therefore, improving consistency in LD’s plasma levels becomes the major
       factor for improving anti-Parkinsonian control1.

      Current controlled-release formulations of LD provide only limited efficacy
       because LD’s absorption is confined to the upper part of the GI tract (narrow
       absorption window)

      The AP-CD/LD is a gastric-retentive dosage form containing Carbidopa and
       Levodopa in both immediate and controlled-release ways.
     1.   PK/PD Crossover Comparison of Two LD Extension Strategies, Peter LeWitt et all, Movement Disorders, Vol 24, No.9, 2009
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Accordion Pill CD/LD Significantly Improves
                                                 LD’s PK Profile
           Mean Levodopa Plasma Concentrations (N=8, part of a phase II study)

                                               AVE 4X18.7/187.5 mg CD/LD IR                           AVE BID AP CD/LD 50/375
                                  4000

                                  3500
            Concentration ng/ml

                                  3000

                                  2500

                                  2000

                                  1500

                                  1000

                                   500

                                     0
                                         0.0    1.0   2.0   3.0   4.0   5.0   6.0   7.0   8.0   9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0

                                                                               Time (h)

      LD plasma levels in advanced PD patients following BID administration (8 hours apart) of AP-CD/LD 50/375
       vs. QID administration (4 hours apart) of a commercial CD/LD formulation (equivalent daily dose).
      PK was performed on day 7, following 6 days of drug administration at home. No LD medication was allowed
       for 10 hours before the first administration at day 7.
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Accordion Pill CD/LD -PK Results, Summary

      The PK of AP-CD/LD demonstrated an efficient controlled-release
       profile, with significantly more stable LD levels. LD's absorption phase
       was increased by more than 6-fold.
      BID administration of AP-CD/LD provided daily coverage of therapeutic
       LD plasma levels.
      Peak to trough ratio was significantly decreased by the AP-CD/LD
      The LD morning plasma levels (pre-first dose) were significantly higher
       with the AP-CD/LD. No LD medication was allowed for 10 hours before
       the first, morning dose administration of the PK day.

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Phase II, Groups 4&6: Design
                                                  AP CDLD Arm or Current Treatment Arm
                                                        Adjustment     Test period
                       Randomization
                                                             2W           1W
                                       2W         1W
         Screening
                                Adjustment    Test period
                             AP CDLD Arm or Current Treatment Arm

      Days 1-20, self-administered at home : AP-CD/LD (50/375 in group 4 and 50/500
       in group 6, N=34) was dosed at 0 and 8 h on each day, plus add-on immediate-
       release tablets, if needed.
      The reference products were the commercially available CD/LD formulations,
       dosed according to each patient’s optimal current treatment
      Patient diaries (during 24 hours) were filled at days 18-20 of each study arm
       (Total OFF Time, Total On with Troublesome Dyskinesia etc.)
      The only food requirement related to the AP was to take the pill with food.
18     Patients diets at home were not supervised.

Phase II Results - Mean Total OFF Time
                        in 24h

                AP CD/LD     Optimized Current Treatment

                                                      5.1
                       4.3
                                   45% Reduction
     44% Reduction
                                             2.8
              2.4

        Group 4, N=16, P< 0.0001       Group 6, N=18, P< 0.0001
        AP CD/LD 50/375 mg             AP CD/LD 50/500 mg

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Phase II Results –TS Dyskinesia (h)

                                 Total ON with TS. Dys.
                         AP CD/LD     Optimized Current Treatment
                                                           1.2

                                    0.7            0.7
                           0.6

                                                                 TS. Dys = Troublesome Dyskinesia

                          Group 4,N =16      Group 6, N=18, P= 0.002
                      AP CD/LD 50/375 mg      AP CD/LD 50/500 mg
      Products for enhancing Levodopa, currently on the market, are frequently
       associated with increasing dyskinesia.
      Furthermore, according to relevant publications, other products that are
       currently in development for enhancing Levodopa have not demonstrated
       reduction of both Total OFF Time and dyskinesia.
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Phase II: Safety

        No serious adverse events were reported.

        The most commonly observed adverse events nausea and vomiting
         and general disorders such as fatigue and somnolence. The severity
         was mild and did not differ in consistency or major ways from the
         current treatment formulations.

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Example 2:
     The Accordion Pill® for
     BCS Class II& IV Drugs

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BCS Class II& IV Drugs – The Need
 Around 25- 40% of drugs on the market are poorly soluble1,2.
 Around 90% of drugs in development are either BCS (Biopharmaceuticals
  Classification System) Class II (low solubility, high permeability) or Class
  IV (low solubility, low permeability) drugs3.
 In a study conducted on Catalent's behalf by McKinsey and Co., top
  managers at development-stage pharmaceutical companies listed
  bioavailability enhancement as the most significant challenge in their drug
  delivery and formulation efforts3.
 Various methods4 including physical and chemical modifications that are
  commonly used to increase the solubility or the dissolution rate of such
  drugs do not provide an optimal solution.

1.   WHO.
2.   Prediction of Solubility and Permeability Class Membership, Provisional BCS Classification of the world’s Top Oral Drugs,
     Dahan, Amidon et al, The AAPS Journal, Vol 1, No 4, December 2009
3.   Drug Development and Delivery, October 2012, Dr. Hans Maier, Catalent
4.   Techniques for solubility enhancement of poorly soluble drugs: an overview, Sikarra et al, Journal of Medical
     Pharmaceutical and Allied Sciences (2012) 01; 1-22

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GR Rationale for BCS Class II & IV Drugs
                          Biopharmaceutics Classification System (BCS)

      A gastro-retentive formulation can enhance the absorption of poorly soluble drugs
       by increasing the apparent solubility in the gastrointestinal (GI) tract.
      By retaining the dosage form in the stomach and releasing the drug gradually
       towards the upper part of the GI tract, the available drug at the site of absorption
       can be consistently increased due to:
             1. Enhanced exposure of the drug to bile salts.
             2. Effective exposure of the drug to a relative larger volume of GI media.
             3. Solubility increase of drugs with pH-dependent solubility.
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Bioavailability Enhancement of
                  an Undisclosed, BCS Class IV drug, by AP

      AP formulation containing a BCS class IV drug was developed. The
       drug’s solubility strongly decreases with increasing pH, and it is practically
        insoluble at pH 4 and higher.
      The PK of the drug's current marketed formulation shows:
         •   Extent of absorption about 30%
         •   Nonlinear exposure with increasing dose
         •   Significant food effect
         •   Inter-individual variability
      The formulation was tested in a single-dose, three-way, crossover,
       comparative pharmacokinetic study in twelve healthy subjects.
      The purpose was to compare the PK profile of the drug following a
       single oral administration of two doses of AP formulation (one AP and
       two APs taken together) with the commercial formulation of the drug.

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Bioavailability Enhancement of
                  an Undisclosed, BCS Class IV drug, by AP
                                                   AP Xmg   2 AP Xmg      Commercial formulation Xmg

                    Drug concentration ng/ml

                                               0     12     24         36        48        60          72
                                                                       Hour

      The AP formulation significantly extended the absorption phase of the drug.
      The drug exposure was significantly increased by the AP formulation. The
       bioavailability of the drug was doubled.
      The AUC and Cmax achieved with one AP and two APs were found proportional,
       whereas the commercial formulation does not show dose proportionality in these
       ranges.
      Significantly reduced peak-to-trough ratio in steady state.
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Accordion Pill® - Manufacturing

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Film Coating

     Coating Machine

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Automated Web Converting (assembly) Line

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Short and Cost – Effective
     Development Program and human POC
                 For Partnering

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Partnering
     Fast human proof-of-concept (POC), to demonstrate the superiority of Accordion
     Pill formulation with the partner’s proprietary drug under LCM

                Formulation      Scale-up &                                              Overall
      Stage                                       Batch Release      Human POC
                Development      Production                                             Duration

                                  Scale up &                          PK human study:
              Development of                     batch release and
                                 production for                        Accordion Pill
               Accordion Pill                       preliminary
     Activity                   human POC, at                           drug vs. the
                  with the                          accelerated
                              Intec’s cGMP pilot                          existing,
               partner’s drug                    conditions stability
                                production site                        marketed drug

                   In vitro
                                 Bio batch for   COA and Stability Pharmacokinetic
     Outcome     dissolution
                                 human POC           report            profiles
                    profile
                                                                       3 months
     Typical                                                                             9-10
                 3-4 months       2 months           1 months          including
     Duration                                                                           months
                                                                      bioanalysis

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Thank You

     See you at booth No. 8

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