Dr Bryan Betty General Practitioner Porirua Union and Community Health Service East Porirua

Dr Bryan Betty
                           General Practitioner
                           Porirua Union and Community Health Service
                           East Porirua

14:00 - 14:55 WS #138: Biologics and Biosimilars: Why should GP’s be interested?
15:05 - 16:00 WS #150: Biologics and Biosimilars: Why should GP’s be interested? (Repeated)

Biologics and Biosimilars: why GP’s should be interested
Dr Bryan Betty, Deputy Medical Director, PHARMAC
G.P. East Porirua

Overview

 •   Global National Context
 •   What are Biologics and Biosimilars?
 •   GP’s: Specific Issues
 •   Summary

The funding environment

Bang for the buck

Health care wants will always exceed resources available…

                       Demand

                        Ability
                        to pay

                      … so choices need to be made

PHARMAC’s role
          “To secure for eligible people in need of pharmaceuticals, the best
          health outcomes that can reasonably be achieved, and from within
                            the amount of funding provided.”
      Note: ‘pharmaceuticals’ = medicine, therapeutic medical device, related product or related thing

      Our principles:
      •   The budget is capped: approx. $800 million
      •   There is an opportunity cost to every decision
      •   Nationally consistent and equitable access

Working to a Fixed Budget

PHARMAC’s management model
                            New Medicines

                  Savings                    Competition

          re-investment in the sector       e.g. Generics

PHARMAC’s long-term impact

              22.7m          41.8m

Biologics Challenge

The promise of biologics……

 •   Biologics have had a profound effect health through
     treatment of many diseases
       •   Primarily rheumatology, inflammatory conditions and oncology
            • Filgrastim, pegfilgrastim, erythropoetin, somatropin, insulins
            • Adalimumab, etanercept, rituximab, trastuzumab (‘mAbs’)

       •   Potential for wide application across a range of diseases

       •   Anti-TNF inhibitors for inflammatory conditions :
               Rh.A, psoriasis, IBD

Controlling Rheumatoid Arthritis

         Thermal imaging of hand and                        ..and after Mab therapy
         elbow joints before……

       http://users.ox.ac.uk/~path0116/tig/new1/thefg.gif

Challenges of biologics

International Expenditure                                                  NZ Expenditure Growth
    Major growth area in
     healthcare
          •     Global spend on all medicines
                grew 24% from 2007-2012
          •     Biologics spend grew 367%
                over the same time period
•   Global biologics sales forecast to
    grow to US$220 billion by 2017
      •       Source The Global Use of Medicines: Outlook through 2017.

              Report by the IMS Institute for Healthcare Informatics   .

Growth in biologics in NZ is unsustainable…..

Top 20 CPB funded meds by cost
                                 •   2500 Meds
                                     funded

                                 •   These 20 meds
                                     1/3 total budget

The Challenge…
     Biologics are the fastest growing category of medicines in NZ
       48% increase over the last five years

     Monoclonal antibodies (mAbs) largest and fastest growing segment
       Approx. 10% of total NZ medicines expenditure

Competition for biologics is needed

                                                   +
                    =            =
      More              Lower         Increasing
      competition       Prices        value

The good news is many biologic patents have expired or are nearing
expiration…
                                                               2013 global
            Brand name           Active                           sales        Patent expiry
                                               Treatment
             (Supplier)        ingredient                         (US$            EU/US
                                                                 billion)

         MabThera (Roche)      rituximab      Arthritis, NHL       8.6       Nov 2013/Dec 2018

         Herceptin (Roche)    trastuzumab     Breast cancer        6.8       Jul 2014/Jun 2019

                                 insulin
           Lantus (Sanofi)                      Diabetes           7.8          2014/2014
                                glargine

         Remicade (Janssen)    infliximab       Arthritis          8.9       Aug 2014/Sep 2018

           Enbrel (Pfizer)     etanercept       Arthritis          8.3       Feb 2015/Nov 2028

          Neulasta (Roche)    pegfilgrastim   Neutropenia          4.4       Aug 2017/Oct 2015

          Humira (Abbvie)     adalimumab        Arthritis         10.7       Apr 2018/Dec 2016

          Avastin (Roche)     bevacizumab        Cancer             7        Jan 2022/Jul 2019

                                  ….opportunities for competition and lower prices

What are Biologics and Biosimilars?

Biopharmaceuticals aka “Biologics”

         Produced by, or extracted from, living organisms(as opposed to
         synthesized chemical process)
         Many made using recombinant DNA technology in bacteria,
         yeast or mammalian cells
          •   hormones : insulin, growth hormone
          •   monoclonal antibodies: autoimmune diseases (Rh.A, Psoriasis, IBD)
              and cancers
          •   blood products: haemophilia
          •   immunomodulators :multiple sclerosis
          •   vaccines

Biologics are inherently variable

Variability is natural in biologic systems
        genetics + environment
Variation in itself is not necessarily an issue:
        The key is determining the clinical consequences, if any, of known (and
        unknown) variation

                                              •   Potential consequences of
                                                  variation
                                                   •   None
                                                   •   Loss of efficacy
                                                   •   Enhancement of efficacy
                                                   •   Safety
                                                   •   Immunogenicity

Generics versus Biologics/Biosimilars
 •   Innovator small molecules vs. generics
     •   Chemically synthesized to identical molecular structure
 •   Innovator biologics vs. Biosimilars
     •   Both made in living systems therefore have inherent variability
 •   Micro- heterogeneity: small differences between batches.
     •   Applies to both biologics and biosimilars
 •   Regulatory process: Different pathway, extensive evidence
     required biosimilars

What is a Biosimilar?

          Herd 1                          Herd 2

                        A Glass of Milk

                          ‘Biosimilar’

Biologics and Biosimilars
  “Biosimilars” must be highly similar to an originator reference
  product.
    •   Not better, or worse to the originator product

  Biosimilars must demonstrate comparable quality, safety and
  efficacy to an approved reference biologic
    •   No clinically meaningful differences

  Natural variability means exact copies can’t be made
    •   Even original biologics being used today are different form their first
        batch

Variability of Innovator Biologics

Changes include:
   Change in supplier of cell culture media
   New purification methods
   New manufacturing sites

Changes for innovator molecules                                                                   37 changes
approved by comparability exercise –                                                             for infliximab

rarely require clinical trials

 “ the medicine that a clinician administers to a patient today is not ‘identical’ (but
comparable) to the medicine authorised years ago”
“no batch of any reference product is ‘identical’ to the previous one - ‘non-
identicality’ is a normal feature of biotechnology”
                                              From Schneider C K Ann Rheum Dis 2013;72:315-318

Variability of biologics and biosimilars

                                                                      Acceptable for biologic

Not Acceptable

                                                                        Acceptable for biosimilar

    Biosimilars fall within the ‘goal posts’ of the original biologics’
                             quality variation
                                  McCamish, M and Woollett, G. mAbs (March/April 2011) 3:2, 209-217

Biologics and Biosimilars
 •   Unlike the original biologics Phase III studies the aim of biosimilar clinical trials is not
     to prove benefit of treatment per se to patients.

 •   It is to prove biosimilarity to the original biologic

 •   Intended to be clinically equivalent.

Biosimilar development Pathway
   Comprehensive and thorough
      •   More extensive and complex than for generic medicines
   Head-to-head studies with the original biologic medicine
   Pre clinical data:
           comparable analytics and manufacturing

   Clinical data :
      •   Phase I
            •   Comparable PK & PD
      •   Phase III
            •   Comparable quality, efficacy and safety
      •   Phase IV
            •   Post approval risk-management plan

G.P Issues

Immunogenicity
 All biologics and biosimilars, confer a risk of immunogenicity

 Neutralizing antibodies (anti-drug antibodies)
    •   Loss of efficacy e.g. infliximab 17-60%, often methotrexate co-
        prescribed
    •   Anaphylaxis (rare) , Red Cell Aplastic Anaemia(1990’s) erythropoietin

 Regulators require extensive data for biologics and biosimilars to assess
 risk of immunogenicity

 Ongoing real world pharmacovigilance undertaken for biologics and
 biosimilars to assess any potential rare reactions

Specific GP clinical issues with biologics/biosimilars

   1.       Issues with biosimilars same as for original biologic
            (Variability)

   2.       Majority of mAb biologics in GP practice are
            immunomodulatory (Inflammatory disease)
              Anti-TNFs adalimumab (Humira) , etanercept (Enbrel)
              Rheumatoid arthritis, Psoriasis, Crohn’s Disease, Ulcerative Colitis

   3.   Initial specialist Rx, follow-up scripts GP’s.

Specific GP clinical issues with biologics/biosimilars
  1.       Contraindicated in patients with :
            severe active infections including sepsis, active tuberculosis,
             opportunistic infections

  2.       Caution in patients with:
            active infections: including chronic or localised infections until infections
             are controlled.
            patients who have been exposed to tuberculosis,
            Hepatitis B virus (HBV) infection, (reactivation can been fatal)
            moderate to severe alcoholic hepatitis
            moderate to severe heart failure (NYHA class III/IV).
            Malignancy within 5 years

Specific GP clinical issues monitoring
  1.   Develop serious infection: Prompt action contact specialist
  2.   Heart failure developing or worsening with mild CCF
  3.   Interstitial lung disease - dry cough, increase SOB
  4.   Periodic skin exam for non - melanoma skin cancers

  5.   Vaccination prior to commencing, avoid live vaccines during
       treatment (MMR, varicella, BCG)
  6.   Not proven in pregnancy: Contraception
  7.   Surgery with-held
  8.   Bloods may Include: FBC (cytopenias), CRP, LFT
  9.   Long term: Lymphoma risk (2-2.5* risk)

PHARMAC and Biologics

PHARMAC’s Work on Biosimilars

Drugs                                    Change in Cost and Access
        •   Filgrastim / Pegfilgrastim
        •   Somatropin
                                            Total Drug Cost
        •   Erythropoietin
        •   Infliximab
        •   Insulin Glargine
        •   Adalimumab/Etanercept           Number of Patients

Creating competition: filgrastim

        “The introduction of lower cost biosimilar filgrastim and the subsequent price reduction on
          pegfilgrastim means we use fewer hospital resources and deliver optimal chemotherapy
          more safely to more women with breast cancer.”
                                            Dr Richard Isaacs, Medical Oncologist, Palmerston North

Summary

G.P’s: Biologics and Biosimilars
 •   Increasingly important in General Practice

 •   G.P’s will have patients on biologics, and biosimilars into the future. :
      •   Increasingly see patients on these medications and expected to review:
          (Esp: Rh.A., Psoriasis, IBD)

 •   Biosimilar not generic versions of biological medicines.
      •   Biologics/Biosimilar using living systems : inherently variable
      •   Biosimilars comparable safety and efficacy to biologics

G.P’s: Biologics and Biosimilars

 •   Trials need to demonstrate: Comparable, Quality, Efficacy, Safety.

 •   Immunogenicity and micro-heterogenicity important concepts.
         •   Neutralizing anti-bodies
         •   Adverse Events: reported to CARM

 •   Monitoring: Serious infection developing, CCF, interstitial lung, non-
     melanoma skin ca, vaccinations. (Fluvax), pregnancy, surgery.

Questions

More Information

www.pharmac.govt.nz            www.bpac.org.nz