Abbreviated Drug Monograph: Interferon beta lb(Extavia®)
`
`Interferon Beta lb (Extavia®)
`Abbreviated National Drug Monograph
`September 2010
`VA Pharmacy Benefits Management Services,
`Medical Advisory Panel and VISN Pharmacist Executives
`The PBMprepares abbreviated reviews to compile information relevant to makingformulary decisions. The manufacturer '5
`labeling should be consultedfor detailed information when prescribing interferon beta-Ib VA clinical experts may provide input
`on the content. Widerfield review is not sought. Documents no longer current will be placed in the Archive section.
`
`Executive Summagy
`
`Biologic drugs do not have generic equivalents
`There are no head to head trials of Extavia® vs. Betaseron® available.
`
`0
`
`0
`
`The FDA did not grant Extavia® therapeutic interchangeability with Betaseron®, but approved
`Extavia® with the same active ingredient and registration trials as Betaseron® 250 mcg.
`0 Novartls signed an agreement with Bayer Scherlng Pharma AG that gives Novartls the rights to
`its own branded version of interferon beta-1b
`
`o
`
`The differences between the two IF N beta-1b products are that the Extavia® brand comes with a
`27-gauge needle, packaged with 15 vials for a 30 day supply, while the Betaseron® brand has
`30-gauge needles. packaged with 14 vials for a 28 day supply. The difference in package size
`correlates to 12 packages for Extavia® for a year of therapy versus 13 for Betaseron®.
`
`Introduction
`
`Interferon beta-1 b (IFN beta-1 b) is an immunomodulator used in the treatment of Multiple sclerosis
`(MS). it is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques.
`On August 14, 2009 the FDA approved Extavia®. a new branded version of interferon beta-1b, is the
`same product as Betaseron®. Extavia® 250 mcg contains the same active ingredient as Betaseron®
`250 mcg, with a separate Biologic License Agreement (BLA) filed by Novartis.
`
`Background
`0 Novartis signed an agreement with Bayer Schering Pharma AG that gives Novartis the rights to
`its own branded version of interferon beta-1b. (Media release, personal correspondence)
`0
`1993: Chiron began manufacturing Betaseron® for Berlex
`o
`2006: Novartis acquired Chiron and Bayer purchased Berlex
`o
`2007: Novartis and Bayer finalize agreements that allow Novartis to sell interferon beta-
`1b under the brand Extavia®
`
`o
`
`Extavia® will have the same production as Betaseron® (e.g., both are manufactured on
`the same production line and have similar package inserts)
`
`Generic Availabilig (Federal Trade Commission. Food and Drug Administration)
`o
`Biologic drugs do not have generic equivalents. Congress has introduced legislation to establish
`regulations to market lower cost generic bioiogics. also known as follow-on bioiogics (FOB).
`Lower-priced FOBs are like generic drugs, but with differences.
`0 According to the FDA, current technology does not allow for an exact replica of a pioneer biologic
`drug product. Technology also does not let us conclusively determine whether a FOB product is
`"interchangeable” with the original branded product such that a patient would be able to switch
`between the two products without the risk of an adverse effect. Current legislative proposals
`permit FDA approval of an FOB drug that is sufficiently similar to, but not an exact reproduction
`of, the original branded biologic product
`FOB products will not be designated as “therapeutically equivalent" with the original
`biologic drug product.
`
`0
`
`September 2010
`Updated versions may be found at hnpzl/yyM.pbm.va.ggv
`
`AMNEAL
`
`EXHIBIT NO. 1053 Page]
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`

`
`Abbreviated Drug Monograph: Interferon beta lb( Extavia®)
`
`Comparison to Betaseron
`o
`The differences between the two IFN beta-1b products are the Extavia® brand comes with a 27-
`gauge needle, packaged with 15 vials for a 30 day supply, while the Betaseron® brand has 30-
`gauge needles, packaged with 14 vials for a 28 day supply. (Package Inserts)
`
`Com ound
`Vial Size
`Needle Size
`Units er Pack
`
`EXTAVIA
`IFN beta-1b
`Sinle-use lass vial 3m|
`
`BETASERON
`IFN beta-1b
`Sinle-use lass vial 3 ml
`
`
`
`‘E-
`
`0
`
`Support Programs- Extavia® has a support program run by registered nurses similar to
`Betaseron's® Betaplus support program.
`
`Table 1: FDA-approved Indications for DMDs for MS (Package Inserts)
`Indications
`
`Decrease
`frequency of
`relapses In
`RRMS
`
`Slow the
`accumulation
`of physical
`disability
`X
`
`X
`
`Treatment
`of
`Relapsing
`Remitting
`Ms (RRMS)
`
`Decrease
`frequency of
`clinical
`exacerbation
`
`X
`
`X
`
`X
`
`X X X
`
`Route
`
`IM
`
`SQ
`
`SQ
`
`SQ
`
`SQ
`
`Drug
`IFN beta-1a
`(Avonex®)
`IFN beta—1a
`(Rebif®)
`IFN beta-1b
`(Betaseron)
`IFN beta-1b
`(Extavia®)
`Glatiramer
`acetate
`(Copexone®)
`
`September 2010
`Updated versions may be found at hfig://vaww.gbm.va.gov
`
`AMNEAL
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`EXHIBIT NO. 1053 Page 2
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`
`Abbreviated Drug Monograph: Interferon beta 1b( Extavia®)
`
`Table 2: Dosing and Administration of DMD for MS (Package Insert)
`IFN beta- 1a
`IFN bet.a- 1a
`IFN beta- 1b
`(Avonex®)
`(Reblw)
`(Extavla®IBetaseron®)
`30 mcg IM weekly
`8.8 mcg SC three/wk
`0.0625 mg SC
`same time
`every other day
`same days (M-W—F)
`aftemoonlevening
`at least 48 hr apart
`
`Inltlal Dose
`
`Glatiramer acetate
`(Copaxone®)
`20 mg SC daily
`
`Recommended
`Titration
`
`Weeks 1-2
`Weeks 2-4
`Week 5+
`
`8.8 mcg Weeks 1-2 0.0625 mg
`22 mcg
`Weeks 2-4 0.125 mg
`44 mcg
`Weeks 5-6 0.1875 mg
`Week 7+ 025 mg
`
`Maximum Dose
`
`30 mcg IM weekly
`
`44 mcg SC threelwk
`
`0.25 mg SC
`every other day
`
`20 mg sc daily
`
`Special
`considerations
`
`Special
`populations
`
`Storage
`
`Pt training on inject
`
`Pt training on inject
`
`Pt training on inject
`
`Pt training on inject
`
`Not approved <18 yrs
`Not studied > 65 yrs
`
`Not approved <15 yrs
`Not studied > 65 yrs
`
`Not approved <18 yrs
`Not studied > 65 yrs
`
`Refrigerate at 2—8°C
`
`Refrigerate at 2-8°C
`Can be stored up to
`30 days at room temp
`
`Store at room temp. If
`not injected after mbdng.
`then may refrigerate for
`3hrs
`
`Not approved <18 yrs
`Not studied > 65 yrs
`
`Refrigerate at 2-8°C
`Can be stored up to 7
`days at room temp
`
`Table 3: Interferon Beta-1b Clinical Trial Summaries
`
`Reference Trial
`Design
`
`Treatments. Concomitant
`Prophylaxis
`
`Study 1
`
`The IFNB
`Multiple
`Sclerosis Study
`Group 1993
`
`MC, R, DB, PC
`
`N=372
`Study 2
`
`European study
`Group on IFN
`beta-1b in
`Secondary
`Progressive MS
`1998
`
`MC, DB, R, PC
`
`N=718
`Study 3
`
`The North
`American Study
`Group on IFN
`beta-1 b in
`Secondary
`Progressive MS
`2004
`
`IFN beta-1b
`50 mcg SQ EOD (n=111)
`250 mcg SQ EOD (n-115)
`
`Placebo SQ EOD (n=112)
`
`Duration: 2-3 years
`
`b
`b
`I
`250 mcg SQ EOD (n=360)
`
`Placebo SQ EOD (n=350)
`
`Duration: up to 3 years
`
`IFN beta-jb
`250 mcg so EOD (n=317)
`
`160 mcg/m2 of BSA so
`EOD (n=314); mean
`assigned dose=300 mcg
`
`Placebo SQ EOD (n=308)
`
`Progression of disability as
`measured by EDSS
`
`MC R DB, PC
`
`Duration: 3 years
`
`September 2010
`Updated versions may be found at httg://vaww.pbm_va_gov
`
`Annual exacerbation rate
`
`Proportion of exacerbation-free
`patients
`
`Exacerbation rate
`Plaoebo=1 .27
`50 mcg=1.17
`250 mcg=0.84
`
`Exacerbation-Frg j# of
`rats.)
`Placebo =18
`50 mcg=23
`250 mcg=36
`
`Significant time delay to
`disease progression was
`shown for IFN beta-1b
`
`Progression of disability as
`measured by EDSS
`
`Placebo: 49.7% (178 pts)
`confirmed progression
`
`Exacerbation rate
`P vs. 250 (p=0.0001)
`50 vs. 250 (p=0.0086)
`P vs. 50 (p=0.01)
`
`Exacerbation-Free
`P vs. 250 (p=0.007)
`50 vs. 250 (p=0.076)
`P vs. so (p>0.05)
`
`p=0.0008
`
`p=0.0048
`
`Relative
`reduction=21,7% in the
`proportion of pts with
`progression
`
`IFN beta-1b: 38.9% (140
`pts) confirmed
`progression
`
`Rates of progression did
`not differ significantly
`between treatment
`groups.
`
`Secondary measures in
`the IFN beta-1b group did
`show improvement
`involving clinical relapses,
`newly active MRI lesions,
`and burden of disease
`
`AMNEAL
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`EXHIBIT NO. 1053 Page 3
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`
`Abbreviated Drug Monograph: Interferon beta Ib(Extavia®)
`
`_ measuredb MRI. t
`Hazard Ratio 95%Cl
`
`.
`.
`.
`.
`(T(':”,;‘,j/,‘,“s’)°"”'°a"V °°""'‘° "'3
`
`0.50 (0.36-0.70)
`
`p<0.0001
`
`p<0.00001
`
`BENEFIT trial
`
`Kappos L, et al.
`2006
`
`DB, PC’ R’ PG ’
`Mo, phase III
`stud
`INCOMIN trial
`
`Durelll, L et al.
`2003
`
`IFN beta-1b
`250 mcg so EOD (n=292)
`Placebo SW EOD (n=176)
`
`Duration: 2 years
`
`IFN beta-1 b
`250 mcg SQ EOD (n=92)
`
`IFN beta-1a (Avonex)
`30 mcg IM q week (n=96)
`
`Time to MS according to the
`M°°°”a'“ °"‘°""
`
`Proportion of patients relapse
`free
`
`0.54(0.43-0.67)
`
`Favorin IFN beta-1b
`Relapse free- IFN beta-
`1b 51%, beta- 1a 36%
`
`Proportion of patients free from
`new PD/T2 lesions upon MRI
`
`Free of new T2 lesions-
`IFN beta- 1b 55%, beta-
`Open label, P,
`1a 26%
`Duration: 2 ears
`R, PG, MC
`EOD=every other day, RR=relalive reduction, DB=doub|e blind, PC=placebo controlled, R=randomized,
`PG=parallel group, MC=mullicenler, P=prospective
`
`Place in Therapy (American Academy of Neurology)
`0
`Extavia® holds the same place in therapy as Betaseron®, Avonex®, and Rebif® in treating
`RRMS.
`o On the basis of several consistent Class I studies, IFN-beta has been demonstrated to reduce
`the attack rate (whether measured clinically or by magnetic resonance imaging [MRI]) in
`patients with MS or with clinically isolated syndromes who are at high risk for developing MS
`It is appropriate to consider IFN-beta for treatment in any patient who is at high risk for
`developing clinically definite MS (CDMS), or who already has either RRMS or secondary
`progressive MS (SPMS) and is still experiencing relapses.
`
`o
`
`Cost Analysis
`
`Price per vlal
`
`“°"‘5"°°
`
`Yearly
`CostIPt
`
`Conclusions
`
`There is no compelling evidence to support the use of IFN beta 1b product over another. The
`registration trials for Betaseron® were used in the approval of Extavia®. The impact of different
`needle gauges between the products may influence patient preference, though this has not been
`evaluated in any clinical trials. The safety profiles for both agents were based on the Betaseron®
`registry trials.
`
`References
`
`1) Extavia Prescribing Information. Novartis Pharmaceuticals Corporation. East Hanover, NJ. 2009.
`2) Novartis Media Release. Basel, Switzerland. March 2007
`3) Federal Trade Commission: The Competitive Implications of Generic Biologics, San Fransisco,
`CA. June 14, 2007
`4) U.S. Food and Drug Administration: The Law of Biologic Medicine. June 23, 2004
`5) Avonex Prescribing Information. Biogen IDEC Inc. Cambridge, MA. 2006
`6) Rebif Prescribing Information. EMD Serono, Inc. Rockland, MA. 2009
`7) Betaseron Prescribing Information. Berlex Laboratories. Emeryville, CA. 2003
`8) Copaxone Prescribing Information. TEVA Pharmaceuticals USA, lnc., North Wales, PA. 2009
`9) Weinstock-Guttman B, Ranshohoff RM, Kinkel RP, et al. The interferons: biological effects
`mechanisms of action, and use in multiple sclerosis. Ann Neurology. 1995; 3727-15.
`
`September 2010
`Updated versions may be found at httpzl/vaww pbm.va.gov
`
`AMNEAL
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`EXHIBIT NO. 1053 Page 4
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` AMNEAL
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`
`Abbreviated Drug Monograph: Interferon beta I b( Extavr'a®)
`
`10) Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology
`Assessment Subcommittee of the American Academy of Neurology and the MS Council for
`Clinical Practice Guidelines. American Academy of Neurology - Medical Specialty Society
`Multiple Sclerosis Council - Disease Specific Society. 2002 Jan 22 (reviewed 2003 Oct). 10
`pages. NGC:003144
`11) Rice GP, lncorvaia B, Munari LM., Ebers G, Polman C, D'Amico R, Parmelli E. Filippini G. Interferon in
`relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2007, Issue 2. Art.
`No.: CDO02002. DOI: 10.1002/14651858.CD002002
`
`12) Study 1: The interferon B Multiple Sclerosis Study Group. Interferon beta-1 b is effective in
`relapsing-remitting multiple sclerosis. I Clinical results of a multicenter, randomized, double blind,
`placebo-controlled trial. Neurology. 1993; 43:655-661.
`13) Study 2: The European Study Group on Interferon Beta-1b in Secondary Progressive Multiple
`Sclerosis. Placebo-controlled multicentre randomized trial of interferon beta-1b in treatment of
`
`secondary progressive multiple sclerosis. Lancet. 1998; 252:1491-97.
`14) Study 3: The North American Study Group on Interferon beta-1b in Secondary Progressive MS.
`Interferon beta-1b in secondary progressive MS. Neurology. 2004; 63:1788-1795.
`15) BENEFIT: Kappos L et al. Treatment with interferon beta-1b delays conversion to clinically
`definite and McDonald MS in patients with clinically isolated syndromes. Neurology.
`200626721242-1249.
`
`16) INCOMIN: Durelli L, Ferrero B, Ghezzi A, et al. The independent comparison of interferon
`(INCOMIN) trial: a multicenter, randomized trial comparing clinical and MRI efficacy if interferon
`beta-1a and beta-1b in multiple sclerosis. Neurology. 2002; 56 (supplement 3):148.
`
`Prepared: September 2010 by Kathryn Tortorice PharmD. BCPS
`
`September 2010
`Updated versions may be found at httptl/vaww.pbm.va gov
`
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`EXHIBIT NO. 1053 Page 5
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