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Regenozene Capstone Project
- 3. PRODUCT!PROFILER:!REGENOZENE!
EXECUTIVE!SUMMARY!
Overview!
Our! therapeutic! concept! proposes! to! stop! Relapsing+Remitting! Multiple! Sclerosis!
through! targeting! oligodendrocytes! and! DR+6! receptor! specificity! which! will! enabling!
restoration! of! myelin! function! and! produce! favorable! immune+regulation! while! increasing!
efficacy!and!reducing!side!effects!common!with!the!current!and!emerging!standard!of!care.!!!!!
!
Multiple!Sclerosis!(MS)!is!an!inflammatory!disease!that!directly!attacks!and!destroys!the!
myelin!sheaths.!The!general!paradigm!has!been!that!neuronal!damage!is!irreversible!with!no!
known!cure.!
!
The!prevalent!method!to!treat!attacks!of!multiple!sclerosis!is!the!use!of!corticosteroids!
to! reduce! inflammation! that! spikes! during! a! relapse.! ! However,! the! side! effects! of!
corticosteroids!include!increased!blood!pressure,!mood!swings!and!weight!gain.!Long+term!use!
can!also!lead!to!cataracts,!high!blood!sugar!and!an!increased!risk!of!infections.!
!
Current!therapies!slow!the!progression!of!the!disease,!at!best,!and!provide!supportive!
care!for!symptoms.!!AVONEX®,!the!current!standard!treatment!for!MS,!is!an!interferon!beta!1α!
drug!that!has!been!proven!to!reduce!the!frequency!of!“relapsing+remitting!multiple!sclerosis”!
(RRMS)!symptoms,!but!side!effects!include!severe!chronic!flu+like!symptoms!and!liver!damage.!
Constant!monitoring!of!the!patient!must!occur.!!
!
A!relatively!new!MS!treatment!is!Fingolimod!(GILENYA®),!which!is!administered!orally!on!
a!daily!basis.!!This!current!therapy!creates!biological!activity!that!sequesters!immune!cells!in!
lymph!nodes,!thus!reducing!MS!attacks!and!the!short+term!disability!this!disease!causes.!Again,!
heart!rate!must!be!closely!monitored!as!well!as!other!patient!vitals.!!
!
Death! Receptor! 6! (DR+6),! a! member! of! the! TNF! receptor! class,! has! recently! been! of!
particular! interest! in! the! treatment! of! MS.! ! This! receptor! is! known! to! initiate! a! cascade! of!
events!that!cause!apoptosis!of!the!oligodendrocyte!and!increases!localized!T!cell!proliferation.!!
By!inhibiting!this!receptor,!it!may!be!possible!to!reverse!the!damage!caused!by!MS.!!
!
It!is!hypothesized!that!a!molecule!resulting!from!the!linkage!of!the!non+toxic!analog!of!
the!diphtheria!toxin,!a!target!specific!delivery!mechanism!for!oligodendrocytes,!with!a!small!
molecule!DR+6!inhibitor,!may!represent!a!potential!drug!candidate!for!treatment!of!patients!
suffering!from!Multiple!Sclerosis.!!The!recombinant!fusion!protein,!REGENOZENE,!is!projected!
to!penetrate!the!market!at!70%!at!its!peak!period!7!year!post!launch!projected!2022.!During!
this! 20! year! period,! REGENOZENE! is! expected! to! obtain! $32.3! billion! in! sales! an! initial! $26!
million!dollars!invested.!With!its!high!rate!of!return,!REGENOZENE!is!expected!to!be!a!leader!in!
multiple!sclerosis!therapy.!!
!
REGENOZENE!is!designed!to!not!only!focus!on!terminating!the!progression!of!Relapsing+
Remitting!Multiple!Sclerosis,!but!will!also!address!the!issue!of!damaged!neurons!by!allowing!the!
- 4. PRODUCT!PROFILER:!REGENOZENE!
natural! repair! mechanisms! to! occur! inside! of! the! oligodendrocyte.! The! proposed!
pharmacological!intervention!has!the!potential!to!become!a!breakthrough!therapy!providing!
hope!for!Multiple!Sclerosis!suffers!worldwide.!!!!!!!!!!!!!!!
!
!
PROJECT!OVERVIEW!
Mission&Statement&
Our!company!strives!to!develop!innovative!therapies!to!enhance!the!quality!of!life.!!!!
!
Business&Model&&
! Together! with! current! industry! trends,! we! propose! our! model! to! mimic! the! virtual!
business!models!of!today.!!This!would!assist!in!minimizing!financial!risk!and!maintaining!a!lean!
infrastructure!through!the!(1)!low!capital!intensive,!(2)!the!smaller!infrastructure,!(3)!contract!
research!organizations,!and!(4)!contact!manufacturing!organizations.!!We!also!hope!to!create!
partnerships!with!universities!and!Big!Pharma!companies!to!leverage!resources.!!!!!!!!!!
!
Our!target!market!would!be!all!newly!and!existing!diagnosed!RRMS!patients.!There!are!
potentially!10,000!newly!diagnosed!patients!each!year!who!would!consider!REGENOZENE!as!
their!primary!treatment!choice!because!it!proposes!a!reduced!symptom!profile!as!well!as!the!
possibility!of!regaining!basic!functions.!
!
! Our!position!encompasses!the!innovative!research!including!partnerships!with!academic!
institutions!that!will!facilitate!REGENOZENE!to!phase!III!clinical!trials.!We!will!retain!ownership!
of!the!intellectual!property!rights!and!the!IP!rights!of!any!other!niche!uses!that!REGENOZENE!
might! develop! during! preclinical! and! early! Phase! I! and! Phase! II! studies.! It! is! the! intellectual!
property! rights! and! our! ability! to! license! out! our! product! to! a! seasoned! pharmaceutical!
company! that! will! incur! the! bulk! of! the! costs! to! commercially! produce! REGENOZENE.! The!
royalty!payments!we!expect!from!ownership!will!offset!investment!costs!that!were!paid!during!
the!optimization!of!REGENOZENE.!!
!
! In! 2022,! we! anticipate! that! upon! commercialization! of! our! product! we! will! receive!
royalty!revenues!on!the!sales!of!the!drug.!Because!of!the!novelty!of!the!drug!and!what!value!it!
is!proposing!to!bring!to!customers,!revenue!projects!are!expected!to!be!at!the!very!high!end!of!
what!profits!other!drugs!generate.!Gross!profit!margins!are!expected!to!be!between!40!and!
46%.! The! high! gross! profit! margin! will! ensure! that! we! will! be! able! to! pay! back! the! initial!
investors,! but! also! will! assess! the! possibility! of! moving! forward! with! any! other! applications!
discovered!during!optimization!of!REGENOZENE!optimization.!!!
!
! Current! leading! competitor! of! REGENOZENE! is! the! therapy! GILENYA®! because! of! the!
once!daily!oral!administration.!REGENOZENE!would!be!easily!managed!through!the!use!of!a!
pump!containing!a!once!a!day!cartridge!that!administers!a!daily!dose.!In!the!future,!we!may!
collaborate!with!a!stem!cell!company!that!can!generate!new!oligodendrocytes!for!the!afflicted!
which!would!enhance!our!therapeutic!approach!for!customers!who!have!passed!the!point!of!
use!for!REGENOZENE!due!to!the!severe!oligodendrocyte!damage.!
- 5. PRODUCT!PROFILER:!REGENOZENE!
!
! Our!competitive!edge!will!strive!on!closely!monitoring!new!therapeutic!approaches!to!
RRMS! and! to! investigate! the! possibility! of! our! product’s! ability! to! enhance! other! proposed!
drugs.!Because!there!is!already!building!evidence!indicating!the!use!of!our!model!drug,!there!is!
potential! to! treat! other! neurodegenerative! disorders.! Because! our! concept! proposes! a!
relatively!safe,!efficient!way!to!target!and!alter!cellular!functions,!the!possibility!to!utilize!this!
approach!in!other!target!areas!looks!promising.!!
&
!
Disease&Overview&&
MS!is!characterized!as!a!complex,!autoimmune!disease!that!progressively!disables!the!
central! nervous! system.! ! It! affects! over! 2.1! million! people! worldwide,! with! an! estimated!
400,000!persons!actively!living!with!the!disease!in!the!United!States.1
!!The!demyelination!and!
death! of! the! oligodendrocytes! manifest! into! a! multitude! of! visible! symptoms! that! resemble!
nervous!system!disorders!including!fatigue,!balance!and!coordination!problems,!bladder!and!
bowel! dysfunction,! visual! and! cognitive! impairment,! and! pain.1
! Currently! there! is! no! known!
cure!for!MS!only!approved!therapies!to!address!slowing!the!progression!of!this!disease.1
!!
!
The! challenges! that! current! Relapsing! Remitting! Multiple! Sclerosis! patients! are!
encountering!are!that!the!pharmaceutical!therapies!currently!relied!upon!as!the!standard!of!
care! reduce! the! quality! of! life! due! to! the! constant! monitoring! of! a! patients! vitals.! ! ! These!
therapies! also! do! not! possess! the! ability! to! stop! or! reverse! the! disease.! The! proposed!
therapeutic,! REGENOZENE,! has! the! potential! to! halt! the! symptoms! of! the! disease! and! also!
reverse!the!effect!of!demyelination!by!allowing!for!the!process!of!remyelination!to!occur!and!in!
effect,!!allow!for!the!potential!of!regained!cognitive!ability,!improved!balance!and!coordination,!
and!better!control!of!urinary!and/or!bowel!incontinence.!Regaining!a!fraction!of!these!abilities!
would!allow!for!an!increased!quality!of!life!through!the!independence!of!performing!normal!
everyday!tasks!such!as!unassisted!bathroom!visits!or!the!ability!to!walk!without!the!use!of!a!
mobility!aid.!!
! !
!
!
(Additional!information!regarding!Disease!Overview!located!in!Appendix!A)!
!
- 6. Category! Target*Product*Profile!
Indication! A!disease!modifying!therapy!in!adults!for!the!treatment!of!patients!with!relapsing!Multiple!Sclerosis!to!
halt!the!experience!of!relapses!and!slow!the!progression!of!disability!
Efficacy! No! direct! comparator:! When! administered! alone,! significant! improvement! over! GILENYA®’s!
annualized!relapse!rate!(ARR)!and!disability!progression!(EDDS)!studies!
Safety! At!least!as!safe!as!GILENYA®!(alone!and!in!combination!with!GILENYA®),!safe!for!use!by!pregnant!and!
nursing!mothers,!improved!safety!as!compared!to!ONTAK®!diphtheria!shuttle!baseline!
Contraindications! Patients!who!have!not!been!vaccinated!against!diphtheria!toxin,!persons!exhibiting!hypersensitivity!to!
the!DTP!vaccine!or!any!of!the!drug!components.!!Special!caution!should!be!taken!with!patients!with!
preQexisting! cardiovascular! disease.! ! Risk! of! infectious! complications.! ! Complete! reversal! of! lesions!
would!result!in!removal!of!patient!from!medication!and!maintenance!using!other!approved!Multiple!
Sclerosis!therapies.!
Drug*Interactions! None!
Route*of*Admin! Insulin!style!pump!(subcutaneous)!
Treatment*Regimen! Chronic!!disease!modifying!lifetime!treatment!
Convenience! Continuous!basal!administration;!daily!dose!provided!as!a!cartridge!
(sterile,!frozen!solution!in!a!sterile,!singleQuse!vial)!!
Shelf*Life! Room!temp!30!hours,!refrigerated!(2Q8C)!up!to!4!weeks,!frozen!(at!or!below!Q10C)!up!to!1!year!
Target*Regions! United!States,!Canada!
First*Launch! 2023!
Price! $48K/year!+!10%!premium!($53K/year)!
Reimbursement! Expect! 80%;! two! improved! parameters! over! GILENYA®! (improved! disease! progression,! reduced!
relapse!rate)!
Other*Indications*(future)! Other! forms! of! MS,! other! autoimmune! demyelinating! disorders! (Progressive! Multifocal!
Leukoencephalopathy,!PostQInfectious!Encephalitis)!and!radiation!injury!
!
!
(See!Appendix!B!for!further!details)
- 7. PRODUCT(PROFILER:(Regenozene
5
Current'Treatment'Options'
There(are(two(main(competitors(in(the(multiple(sclerosis(drug(market:(interferon(βC1a(and(
fingolimod.( Interferon( βC1a,( a( first( line( treatment( for( MS,( and( is( theorized( to( inhibit( TCcell(
proliferation(and(block(migration(of(immune(cells(across(the(blood(brain(barrier.(2,3
((Interferon(
β(has(been(marketed(as(AVONEX®(and(REBIF®.(Interferon(therapy(has(shown(to(produce(an(18C
38%(decrease(in(the(amount(of(relapses(and(slow(the(progression(of(disability(in(MS(patients.4
(((
AVONEX®((Biogen(Idec,(Inc.)(has(about(40%(of(the(overall(market(in(the(United(States(and(30%(
in(Europe.((In(the(US,(AVONEX®(and(REFIB®(costs(between($24,000C$31,000(per(year,(and(is(
covered(by(most(insurance(plans.5(
Although(these(therapies(account(for(a(large(portion(of(the(
market,(they(are(not(with(out(their(side(effects,(including:(cardiovasular(events,(liver(disorders(
and(severe(fluClike(symptoms(often(leading(to(depression.6,7(
Even(though(these(drugs(are(not(a(
cure,(interferon(therapy(can(beneficially(alter(the(natural(course(of(MS(for(patients(that(start(
treatments(early(in(their(disease(progression.((
( (
Fingolimod( (GILENYA®)( is( the( first( oral( drug( indicated( for( the( slowing( the( progression( of(
disability(and(decreasing(the(frequency/severity(of(symptoms.((Commercialized(by(Novartis((its((
mechanism( of( action( lies( within( the( activity( of( one( of( the( five( sphingosinC1Cphosphate(
receptors,( S1PR1.8
( Through( this( characteristic( fingolimod( can( sequester( lymphocytes( in( the(
lymph(nodes(and(prevents(the(white(blood(cells(from(migrating(to(the(central(nervous(system.9
((
Fingolimod( has( many( sideCeffects,( the( most( serious( including( bradycardia,( potentially( fatal(
infections,(inflammation(of(the(brain(with(bleeding,(and(skin(cancer.((This(treatment(has(annual(
costs(of($48,000(and(is(also(reimbursed(through(most(insurances.9(
(
Glatiramer(acetate(or(COPAXONE®,(manufactured(by(Teva,(is(a(standardized(mixture(of(the(
acetate(salts(of(synthetic(polypeptides((LCglutamic(acid,(LCalanine,(LCtyrosine,(and(LClysine).(Its(
mechanism(of(action(in(multiple(sclerosis(is(not(fully(elucidated(but(is(thought(to(be(related(to(
alteration( of( TCcell( activation( and( differentiation( as( it( appears( to( preferentially( bind( to( and(
activate(inflammatory(reducing(Th2(cells(as(opposed(to(the(inflammatory(inducing(Th1(cells.10(
It(
has(been(clinically(shown(to(reduce(the(frequency(of(relapses(and(increases(the(time(between(
relapses(in(multiple(sclerosis(patients((results(seen(in(three(placeboCcontrolled(clinical(trials).(
Adverse(effects(of(glatiramer(acetate(include(injectionCsite(reactions(such(as(indurations(and(
masses,(as(well(as(depression.11
(This(drug(is(an(appropriate(choice(for(patients(who(are(unable(
to( tolerate( fluClike( symptoms( or( have( coexisting( depressive( disorder.( As( another( firstCline(
treatment(for(multiple(sclerosis,(is(available(as(a(subcutaneous(injection(given(once/day.(It(does(
not(require(refrigeration.(It(costs(between($23,000C$34,000(a(year;(most(insurance(plans(will(
cover(the(cost.(
Lastly,(with(the(advent(of(stem(cells,(it(promises(for(another(treatment(for(MS.(In(one(study,(
autologous(peripheral(blood(stem(cells(were(used(to(treat(MS(in(humans(and(produced(mixed(
results.12
(Another(study(transplanted(neural(stem(cells(into(MS(disease(model(mice(and(found(
that(the(animals(had(a(reduction(in(demyelination(and(axonal(loss.13
(In(addition,(the(functional(
impairment(caused(by(the(disease(model(was(almost(abolished(both(neurophysiologically(and(
clinically.13
( Further( research( still( needs( to( be( conducted( regarding( the( use( of( stem( cell(
- 8. PRODUCT(PROFILER:(Regenozene
6
transplantation(for(use(in(the(treatment(of(MS(in(order(to(validate(their(safety(and(efficacy(for(
the(mass(market.(
(
(Additional(Information(regarding(Current(Therapies(located(in(Appendix(A)(
Comparison*of*the*proposed*optimized*novel*recombinant*protein*to*main*first*line*RRMS*
therapy*competitors,*AVONEX*®,*COPAXONE*®*and*GILENYA*®.(Our(product(will(directly(
compete(with(all(the(injectables(and(the(sole(approved(oral(capsule(evaluated(below.(However,(
the(proposed(optimized(fusion(protein(will(potentially(encompass(the(efficacy(of(the(current(
leading(therapeutic,(AVONEX®,(and(the(regenerative(properties(of(DRC6(inhibitor,(resulting(high(
efficacy,(reduced(side(effects,(and(the(return(of(physical(control(to(the(end(user.(
(
Rx*Name*
(Company)(
AVONEX®*
(Biogen)*
COPAXONE®*
(Teva)*
GILENYA®*
(Novartis)*
REGENOZENE*
(Capstone)*
Class* Recombinant(
Interferon(β(
(
mixture(of(the(
acetate(salts(of(
synthetic(
polypeptides(
sphingosine(1C
phosphate(receptor(
modulator(
(
Recombinant(
protein(
Target( TChelper(cell(
response(
suppressor(
alteration(of(TCcell(
activation(and(
differentiation(
sphingosine(1C
phosphate(receptor(
(
Oligodendritic(DRC6(
Receptor(
Patients*
relapse*free*
at*2*years*
38%(
Placebo:(26%(
34%(
Placebo:(27%(
70%(
Placebo:(~20%(
(
<70%(
Adverse*
Effects*
flulike(symptoms(
after(injection,(
depression,(and(
liver(enzyme(level(
abnormalities.(
InjectionCsite(
reactions(such(as(
indurations(and(
masses,(as(well(as(
depression(
(
Bradycardia(&(
macular(edema(
TBD(
Dosing* intramuscular((
once/week(
subcutaneous(
once/day(
Oral(
Once/day(
Intravenous(
Once/day(
Pricing* $24,000C($30,000(
Annually(
$23,000C$34,000(
Annually(
$48,000(
Annually(
(
(
(
(
- 10. PRODUCT(PROFILER:(Regenozene
8
Market(Analysis(
Industry( (
The(market(for(the(proposed(novel(recombinant(protein(drug,(REGENOZENE,(is(males(and(
females( diagnosed( with( relapsingCremitting( Multiple( Sclerosis.( It( is( disease( that( is( more(
prevalent(in(the(northern(hemisphere(and(also(most(common(to(those(of(Northern(European(
decent.17
(The(clients(for(REGENOZENE(will(be(the(physicians(in(hospitals(and(clinics(treating(MS(
patients.(Ultimately,(the(end(user(is(the(patient(diagnosed(with(MS.(
(
Current(therapies(for(MS(have(been(effective(in(reducing(frequencies(of(clinical(relapses,(
however,( side( effects( are( undesirable( and( use( of( combination( therapy( results( in( more(
inconvenience.(There(is(an(opportunity(to(be(successful(with(the(introduction(of(an(optimized(
fusion(protein(with(equivalent(efficacy(and(better(safety(profile(compared(to(AVONEX®(in(the(
treatment(of(MS.(((
(
Newly(introduced(to(the(market(in(2010(is(Novartis’s(GILENYA®,(the(first(oral(drug(providing(
much( hope( for( MS( patients( by( constraining( lymphocytes( to( the( lymph( nodes,( reducing( the(
overall(attack(of(the(immune(system(against(the(myelin(and(delay(the(progression(of(physical(
disability.18
(The(side(effects(of(GILENYA®,(may(be(something(to(note(such(as(bradycardia(and(
atrioventricular(blocks.19
(Long(term(safety(and(efficacy(is(still(to(be(seen(as(it(is(relatively(new(
however,(it(can(be(safely(said(that(GILENYA®(will(be(the(standard(treatment(of(care(for(RRMS(
unless(serious(adverse(events(are(implicated.((
(
There( is( an( opportunity( to( develop( an( optimized( drug( candidate,( REGENOZENE,( with( a(
better(safety(profile(compared(to(AVONEX®(and(with(a(restorative(power(that(is(absent(with(
GILENYA®,( thereby( proving( more( desirable( to( physicians( and( patients.( Due( to( its( mode( of(
mechanism(and(thereby(specificity,(RENGENOZENE(will(have(fewer(side(effects(than(AVONEX®(
and(with(proof(of(concept(of(providing(reCmyelination(through(targeting(of(DRC6,(REGENOZENE(
proposes(a(more(restorative(potential(than(any(other(therapy(on(the(market(or(in(the(pipeline(
today.(
(
Total'Market'
The(total(market(for(multiple(sclerosis(is(2.1(million(people(in(the(world.(It(is(more(prevalent(
in( the( northern( hemisphere( with( the( highest( concentration( in( North( America.( In( the( United(
States,(MS(has(a(growth(rate(of(approximately(2.5%(and(has(not(seen(decreasing(numbers(in(
decades.20(
(
Worldwide( sales( in( 2009( were( over( $8( billion( dollars( for( the( 4( leading( drugs.( This( only(
accounts(for(the(36%(of(those(that(do(take(MS(therapy.(However,(this(value(is(expected(to(
reach(56%(by(2015.21(
(
Target'Market'
The(target(market(is(defined(as(all(the(people(the(United(States(and(Canada(diagnosed(with(
relapseCremitting( Multiple( Sclerosis( and( all( physicians,( hospitals,( research( centers( treating(
- 11. PRODUCT(PROFILER:(Regenozene
9
patients( with( relapseCremitting( multiple( sclerosis.( As( of( 2010,( there( are( 400,000( people(
diagnosed(with(MS(in(the(U.S.(In(addition,(there(are(10,000(new(people(diagnosed(every(year(in(
the(United(States(alone.5(
(
'
'
Addressable'Market'
With(a(target(market(of(400,000(patients(in(the(United(States,(this(business(plan(will(focus(
its(addressable(market(to(those(with(relapseCremitting(multiple(sclerosis(in(the(United(States.(
This(accounts(for(85%(of(the(Target(Market,(which(are(360,000.(By(the(forecasted(target(launch(
date(at(2021,(the(addressable(market(is(projected(to(have(increased(more(than(75%(to(about(
half(a(million(patients.(
(
(
- 13. PRODUCT(PROFILER:(Regenozene
11
GAP(Analysis(
(
The(GAP(analysis(was(used(to(thoroughly(compare(our(product’s(actual(and(potential(
performance( against( AVONEX®( and( GILENYA®( for( the( treatment( of( MS.( The( GAP( analysis(
revealed(the(areas(of(highest(importance(to(the(customers(and(how(REGENOZENE(falls(into(
each(category(allowing(for(a(direct(comparison(of(its(performance(with(the(leading(product(in(
the(same(market.(This(analysis(should(demonstrate(safety(and(efficacy(as(well(as(reversal(of(
physical(disabilities(as(the(criteria(for(commercialization.(
(
The(dosing(of(the(proposed(fusion(protein(is(set(as(a(continuous(basal(administration(
subcutaneously(via(an(insulin(style(pump.(This(is(not(the(most(convenient(dosing(therapy(for(
multiple(sclerosis,(but(it(is(predicted(to(be(the(most(effective(for(therapeutic(purposes.(Safety(is(
currently(one(of(the(biggest(concerns(with(leading(therapies(for(multiple(sclerosis.(AVONEX®,(as(
a(leading(MS(therapy(is(plagued(with(side(effects(such(as(chronic(fluClike(symptoms(that(leads(
to(depression,(suicide,(liver(damage,(effects(on(white(blood(cells,(and(many(more.(GILENYA®(is(
associated( with( bradycardia,( macular( edema,( and( suspected( increased( risk( for( opportunistic(
infection.(
(
REGENOZENE(is(proposed(to(be(very(effective(at(targeting(the(major(problems(that(lies(
in( multiple( sclerosis.( As( mentioned( previously,( AVONEX®( and( GILYENA®( helps( reduce( the(
frequency( of( exacerbations( and( diminishes( the( progression( of( physical( disability( that( is(
progresses(with(the(disease,(but(does(not(do(anything(to(reverse(the(patients(condition(and(
only(maintains(the(status(quo.(
(
Based( on( this( comparison,( several( market( opportunities( were( highlighted( on( certain(
levels(ranging(from(mode(of(delivery,(dosing,(indications(and(side(effects.((Intravenous(delivery(
offers(many(advantages(over(AVONEX®(and(GILENYA®(based(on(increased(target(cell(uptake,(
improved(bioavailability(and(improved(regenerative(ability(with(a(potential(reduction(of(side(
effects(leading(to(an(overall(improved(safety(profile.(So(with(the(proposed(recombinant(protein(
drug,(REGENOZENE,(dosing(convenience(is(envisaged(to(be(compromised(in(order(to(achieve(
maximum(gains(in(disability(reversal(and(reduction(of(lesions.(This(projected(convenience(vs.(
efficacy(tradeCoff(of(attributes(is(planned(to(be(further(validated(during(a(market(research(study(
to(support(the(marketing(plan(as(discussed(above.(
(
- 15. PRODUCT(PROFILER:(Regenozene
13
Intellectual(Property(
(
Intellectual(property(experts(and(patent(lawyers(will(complete(the(analysis(of(the(claims(
that(already(exist(in(the(patent(databases(regarding(DR6,(CRM197(and(also(MOG.(These(three(
entities(have(various(patents(surrounding(them(but(do(not(seem(to(have(a(claim(for(the(method(
with(which(we(intend(to(use(these(entities.(It(is(necessary(to(obtain(the(intellectual(property(
rights(of(our(proposed(therapeutic(and(the(method(of(use(for(our(novel(therapeutic.(If(we(are(
not(able(to(obtain(the(exclusivity(that(we(are(seeking,(then(the(project(will(be(modified(in(order(
to( obtain( the( rights( for( the( proposed( therapeutic( entity.( We( intend( to( have( all( information(
surrounding(all(patents(that(currently(exist(regarding(DR6,(CRM197(and(MOG.(There(does(not(
seem(to(be(any(patents(currently(in(existence(that(envelope(the(sheer(novelty(of(our(drug,(so(
patent(infringement,(expiration(and(generics(are(not(a(concern(at(this(time.(Because(we(will(be(
creating( both( the( small( molecule( inhibitor( and( the( conjugated( molecule( we( expect( to( have(
patents(issued(and(assigned(to(the(company(that(will(give(us(Exclusive(Worldwide(Rights(to(all(
applications( of( the( toCbeCpatented( product( However,( the( isolation,( purification( and(
manufacturing( of( the( nontoxic( mutant( diphtheria( toxin( (CRM197)( may( potentially( pose( a(
hindrance(to(the(success(of(patenting(our(drug,(since(this(model(is(already(in(use.22(
(
A(search(on(the(USPTO(website(showed(the(following(data:(
DR6:(398(hits(
CRM197:(153(hits(
MOG:(248(hits(
DR6(and(Multiple(Sclerosis:(60(hits(
(
'
Strategy(
The(steps(in(carrying(out(the(product(development(plan(to(launch(REGENOZENE(includes(
creating(a(recombinant(fusion(protein((CRM197CMOG(mAB(fusion)(which(is(covalently(linked(to(
a(small(molecule(DRC6(inhibitor.(Both(recombinant(fusion(protein(small(molecule(DRC6(inhibitor(
will( require( sufficient( StructureCActivityCRelationship( (SAR)( guided( protein( and( medicinal(
chemistry( optimization( studies( in( order( to( identify( a( molecule( with( optimized( efficacy( and(
ensure(its(novelty(to(increase(the(ability(to(patent(this(specific(molecular(entity.(
(
(The(novelty(of(this(hypothesized(product(is(the(fusion(of(CRM197,(a(shuttleClike(vesicle(
to(specifically(target(oligodendrocytes,(and(the(small(molecule(DR6(inhibitor.(It(is(the(fusion(of(
these(two(separate(entities(and(the(method(of(use(that(could(be(patented.(This(patent(should(
be(applied(for(in(2012,(potentially(with(additional(supporting(data(to(be(filed(during(the(patent(
review(process.(Assuming(product(launch(in(2024,(there(is(sufficient(amount(of(time(for(market(
exclusivity(since(there(is(yet(to(be(a(product(similar(to(the(proposed(drug,(REGENOZENE,(on(the(
market(for(the(treatment(and(potential(reversal(of(RRMS.(Closer(to(launch,(and(extension(of(
market( exclusivity( by( applying( for( other( certificates( or( patents( on( our( product( may( be(
considered.(In(the(event(that(a(patent(cannot(be(obtained,(the(project(will(not(be(continued.(
Following( the( identification( and( purification( of( the( drug( development( candidate,( additional(
- 18. PRODUCT(PROFILER:(Regenozene
14
Overview(of(Potential(Clinical(Development((
Preclinical)Development:((
Before( the( testing( on( animals,( there( are( certain( key( areas( related( to( drug( that( needs( to( be(
answered.(Some(of(them(are:(
• Chemical(properties(of(each(component(and(the(proposed(drug(as(a(whole(in(vitro(and(
in(solution.(Some(of(the(questions(that(need(to(be(answered(include(if(toxin(part(A(and(
DR6(works(in(solution(and(if(part(A(binds(at(the(desired(position.(After(that(toxin(part(A(
and(DR6(would(be(tested(in(vitro.(We(would(also(focus(on(checking(if(A(or(B(on(its(own(
affect(oligodendrocytes.(
(
• Diphtheria( toxin( is( the( other( thing( that( needs( to( be( studied( in( detail.( Some( of( the(
specific(questions(that(need(to(be(answered(with(respect(to(diphtheria(toxin(include:(
o If(diphtheria(toxin(is(capable(of(entering(cells(and(disrupting(DR6.(
o If(diphtheria(toxin(reduces(the(rate(of(demyelination.(
(
• Well( defined( steps( for( synthesis( and( purification( of( the( drug.( This( would( involve( the(
various(methods(to(efficiently(scale(up(the(production(of(the(drug(for(manufacturing(
purposes.(
After(these(aspects(are(known,(animal(studies(would(be(carried(out.(Some(of(the(key(questions(
that(will(be(answered(during(animal(studies(are:(
• Animals( would( be( immunized( with( diphtheria( toxin( vaccination( and( then( diphtheria(
toxin(with(component(A(and(B(would(be(used(to(challenge(cells.(We(would(need(to(look(
for(any(cross(reactivity(and(effect(on(therapeutics.(This(is(important(because(naturally(
humans(are(vaccinated(for(diphtheria.(Control(animals(without(diphtheria(immunization(
would( also( be( used( for( comparison.( If( the( immunized( animals( have( reduced( uptake,(
then(the(dose(to(overcome(immune(response(would(be(determined.(
(
• Whether(each(component(is(safe(in(animals?C(Safety(levels(would(be(compared(against(
control(animals(receiving(placebo(and(other(sets(receiving(alternate(MS(therapeutic(like(
AVONEX®( and( GILENYA®.( ONTAK®( which( uses( other( diphtheria( shuttle( would( also( be(
used(for(comparison(studies.(Safety(measures(would(include(looking(for(changes(in(TC(
cell(proliferation,(inflammatory(markers,(MRI(of(lesions(and(relapse(rate.(
(
• The(effect(on(changing(the(dosage(on(safety(and(efficacyC(To(study(efficacy(MS(would(be(
induced(in(vaccinated(animal(models.(These(animal(models(would(be(then(challenged(
with(diphtheria(toxin(components(A+B.(Combination(therapy(with(other(drugs(for(MS(
like(GILENYA®(would(also(be(tried(to(study(the(effects(on(safety(and(efficacy(in(animal(
models.(Some(of(the(things(that(would(be(measured(across(multiple(times(which(can(
help(study(changes(in(efficacy(would(include:(
(
o Mobility(study(
o Sensory(loss(study(
o Urinary(frequency(study(
- 19. PRODUCT(PROFILER:(Regenozene
15
o Balance(study(
o Labeled( localization( studyC( for( all( major( organ( systems( using(
Immunohistochemistry((
(
• Extent(of(reCmyelination(and(corresponding(changes(in(immunological(function.(
(
• Determine( the( maintenance( dose( in( animals( and( find( the( corresponding( dose( for(
humans.(
(
• Therapeutic( titrations( would( also( be( performed( in( animals.( This( would( involve( preC
mating( studies( in( animals( to( study( effect( of( therapeutic( on( fertility( and( offspring(
development.(The(total(and(free(bilirubin(for(generalized(toxic(lysis.(
Once( the( optimal,( minimal( and( maximal( dosages( are( known( in( animals,( the( corresponding(
dosage(can(be(calculated(for(humans.23
(Also(the(drug(would(be(enter(Phase(I(clinical(trial(only(if(
it( shows( promising( result( in( Animal( studies.( This( stage( might( take( a( lot( of( time( in(
troubleshooting(and(optimizing(drug.(
(
Estimated(time:(18C24(months.(
(
Expected(end(point:(REGENOZENE(would(be(expected(to(be(safe(and(effective(in(animal(
models.(We(would(expect(to(see(evidence(of(reCmyelination(in(the(animal(models.(Also(we(
would(have(a(clear(dosage(in(animals(
)
Phase)I)clinical)trial:*
Objectives:*
1. To(determine(the(optimal(safe(dosage(for(patients.(
2. To(determine(the(metabolic(and(pharmacological(action(of(the(drug.(
Additional(factors(that(need(to(be(identified:((
• Dose(proportionality:(This(would(involve(testing(exposure(of(different(dosages((usually(
more(than(three).(A(graph(is(plotted(to(find(out(of(the(exposure(is(proportional(to(dose,(
less(than(proportional(or(greater(than(proportional.((If(the(dose(if(directly(proportional(
to(exposure(that(implies(that(the(clearance(if(constant.(It(is(a(very(important(thing(that(
needs(to(be(determined(during(clinical(trial(phase(I.24
(
(
• Bioavailability:(This(would(involve(testing(the(administered(unchanged(drug(that(reaches(
the( systemic( circulation.( Bioavailability( fluctuates( depending( on( the( route( of(
administration( and( certain( other( criteria( and( may( even( vary( from( patient( to( patient.(
Bioavailability(is(useful(to(calculate(dosage(required(for(administration.25
(
(
- 20. PRODUCT(PROFILER:(Regenozene
16
• Bioequivalence:(Bioequivalence(is(determined(by(comparing(two(similar(products.(Since(
the(drug(is(a(novel(idea,(so(we(can(check(the(effect(of(small(molecule(against(DR6(as(
opposed(to(monoclonal(antibody(used(for(DR6(receptor.25
(
(
• Metabolism:(Metabolism(of(drug(in(the(body.((
(
• Pharmacodynamics:(This(will(involve(studying(the(various(effects(of(drugs(on(the(body.(It(
will( also( include( studying( the( mechanism( of( drug( action( and( relation( between( drug(
concentration(and(effect.26
(
(
• Pharmacokinetics:( Pharmacokinetics( basically( involves( the( study( of( absorption( and(
distribution(of(the(drug(in(the(body.(This(involves(studying(the(duration(of(the(effect,(
chemical(changes(of(drugs(in(the(body(and(route(of(excretion(of(drug(metabolites.26
(
Number(of(patients:(20C80(
Type(of(patients:(Patients(with(RRMS(and(normal(people(without(RRMS.((
Points(of(emphasis26
:((
• Vital(signs.(
• Adverse(events(
• Plasma(and(serum(levels(
Expected(time:(12C15(months(
(
Expected(end(point:(REGENOZENE(is(expected(to(be(safe(in(both(the(control(and(patients(with(
RRMS.(It(is(expected(to(be(safer(than(existing(therapies(for(RRMS.(
(
Phase)II)clinical)trials:*
Objective:(To(determine(risks(and(side(effects(pertinent(to(the(drug(X(in(RRMS(patients.(
Other(factors(that(need(to(be(identified:(
• Bioavailability:(Additional(information(about(bioavailability(with(respect(to(effectiveness(
of(drug.(Safety(and(efficacy(both(would(be(considered(
(
• DrugC( disease( interactions:( Is( the( drug( reducing( the( disease( or( slowing( the( rate( of(
progression?(
(
• DrugCdrug( interactions:( Combining( the( drug( with( the( immune( modulators( and( other(
drugs(to(see(if(the(safety(or(efficiency(improves(or(remains(constant(over(a(period(of(
time.(
(
• Efficacy(at(various(doses:(Using(multiple(doses(to(determine(the(effect(on(safety(and(
efficacy(of(the(treatment.(
(
• Pharmacodynamics:(More(in(depth(and(longer(time(studies(than(Phase(I(
- 23. PRODUCT(PROFILER:(Regenozene
19
Large(scale(production(including(synthesis(and(conjugation(of(therapeutic(components(will(be(
performed(by(a(GMP(contracting(company.(
Dosage(and(Administration((
REGENEOZENE( proposes( to( be( a( chronic( disease( modifying( lifetime( treatment( with( or(
without(combination(for(improved(immune(modulation(via(GILENYA®.((The(therapy(could(be(
administered( as( a( daily( dose( delivered( through( an( insulin( style( pump( (subcutaneous)( as( a(
continuous( basal( administration.( ( REGENOZENE( could( be( manufactured( and( packaged( as( a(
frozen(solution((in(2mL)(in(a(sterile,(singleCuse(vial(cartridge.((Cartridges(are(stable(at(Room(
temp(up(to(30(hours,(refrigerated((2C8C)(up(to(4(weeks,(and(frozen((at(or(below(C10C)(up(to(1(
year.(
(
Dosage(and(administration(is(designed(to(overcome(the(immunization(by(Diphtheria(toxin(
vaccination(through(an(initial(ramp(up(of(drug(delivery(causing(an(induced(immune(tolerance(to(
the(therapeutic.((Tolerance(maybe(induced(by(repeated(administration(of(a(small(dose(below(
the(required(threshold(for(immune(response.29,30(
(
(
(
(
(
(
(
(
(
(
(
- 24. PRODUCT(PROFILER:(Regenozene
20
Operations(
(
We(will(formulate(an(academic(partnership(with(one(or(two(universities(for(the(preCclinical(
trials( as( well( as( Phase( I( and( phase( II( trials( which( will( alleviate( the( need( to( build( a( research(
facility.( Maintaining( a( partnership( with( well( drawn( out( contracts( will( ensure( that( we( will(
ascertain(our(intellectual(property(rights(with(this(novel(therapeutic(approach.((It(is(proposed(
that(our(company(will(be(initiating(preCclinical(trials(as(well(as(phase(I(and(phase(II(trials(so(that(
we( can( be( sure( to( ascertain( our( intellectual( property( rights( with( this( novel( therapeutic(
approach.( At( the( culmination( of( phase( II( trials,( we( will( be( outsourcing( the( large( scale(
commercial(manufacturing(to(a(Contract(Manufacturing(Organization((CMO)(for(phase(III(trials(
all(the(way(through(the(lifetime(of(REGENOZENE.(There(will(be(critical(endpoints(in(place(for(the(
CMO(to(uphold(for(the(duration(of(their(contract(with(us,(including(but(not(limited(to(dosage(
formulation,( quality( manufacturing( assurance,( and( secure( distribution( of( our( product( in( the(
United(States.(We(are(opting(to(go(in(this(direction(for(the(large(scale(production(as(a(way(to(
reduce(costs(as(well(as(reduce(the(inherent(risks(in(operating(our(own(manufacturing(facility.31(
(
The(first(order(of(business(for(us(will(be(to(make(sure(that(the(contract(that(we(draw(up(
adheres(to(all(the(standards(that(we(believe(are(essential(for(our(product(to(work(in(the(way(
that( we( want( it( to.( We( will( research( and( analyze( thoroughly( before( choosing( the( optimal(
contract(manufacturing(organization,(one(that(must(be(FDA(certified(and(GMP(compliant.(After(
selecting(the(company(for(the(large(scale(production(of(REGENOZENE,(we(will(negotiate(the(
terms( of( agreement( and( sign( a( contract( for( the( lifetime( of( the( product.( Should( there( be( a(
breach( of( contract,( another( CMO( that( has( been( placed( on( standCby( will( be( immediately(
selected(and(utilized(and(legal(ramifications(for(the(previous(CMO(will(ensue.(In(the(event(that(
a(single(CMO(is(not(able(to(supply(enough(of(or(product,(we(will(sign(up(with(another(contract(
manufacturing(organization(so(that(there(is(no(shortage(of(our(product(on(the(market(at(any(
given( time.( This( should( be( determined( fairly( quickly( should( our( forecasted( sales( numbers(
appear(to(be(more(than(we(had(prepared(for(producing(within(the(first(quarter.(
(
Because(it(is(contemplated(the(proposed(therapeutic,(REGENOZENE,(could(have(potentially(
hazardous(ramifications,(we(will(be(sure(to(include(in(the(contract(with(our(CMO(to(guarantee(
that(any(impurities(or(contaminates(in(the(product(can(be(found(immediately.(We(will(ensure(
this(by(employing(improved(testing(methods,(a(rapid(detection(system(and(also(high(level(GMP(
standards.( Should( any( contamination( be( detected,( all( production( must( be( stopped( and( all(
product(quarantined(until(the(source(of(the(contaminate(can(be(pinpointed.32
(It(is(our(goal(to(
regularly( check( our( CMO( and( investigate( ourselves( the( analytical( methods( being( used( for(
testing(as(well(as(looking(through(the(raw(data(to(check(for(any(inconsistencies.(Should(any(
problems( arise( we( will( hire( some( professional( GMP( consultants( to( work( with( the( CMO( to(
ensure(that(the(proper(product(is(being(delivered(to(our(customers.(((
(
(
'
- 26. PRODUCT(PROFILER:(Regenozene
22
Risks(and(Risk(Management(
(
In(order(to(fully(service(effectively(utilize(resources(and(minimize(value(loss,(management(
and(researchers(need(to(undertake(an(enterprise(perspective(of(risk(analysis.(Risk(assessment(is(
a(necessary(method(for(dealing(with(uncertainty(through(seeking(to(describe(the(likelihood(of(
value( loss( that( may( manifest( under( relevant( conditions( throughout( the( drug( development(
process.( First( problems( must( be( formulated( and( the( exposure( and( effects( must( be(
characterized( to( fully( characterize( the( risk.( (Then( risk( actions( plans( may( be( established( to(
mitigate(risk(and(to(monitor(risk.(These(plans(rely(heavily(on(two(major(assumptions,(that(the(
product(will(reach(the(appropriate(development(stage,(and(that(the(product(will(in(fact(reach(a(
successful( launch( and( a( satisfactory( market( share.( Thus,( when( certain( situations( arise,( the(
appropriate(contingencies(may(be(implemented.
As(an(organization(we(must(manage(the(ambiguity(of(risk(by(qualification(and(quantification(
of(whether(it(falls(within(the(three(types(of(risk:(technical,(commercial,(and(value(risk.(We(must(
ensure(that(the(team(contains(individuals(are(that(objective(with(an(ability(to(manage(their(own(
risk( acceptance( to( empathize( with( the( corporate( risk( acceptance( level( while( maintaining( a(
balance(of(subjectivity(and(objectivity.
The(first(step(is(to(qualify(risks(into(functional(areas.(Within(research,(the(risks(are(posed(in(
our(product’s(in(vitro(and(in(vivo(efficacy(performance(that(will(produce(a(sufficient(PK/PD(and(
dose(response(performance.(Also(within(the(preclinical(phase,(the(performance(of(the(in(vivo(
safety(and(toxicology(studies(to(ensure(safety(multiples(and(to(establish(target(clinical(doses(
qualifies(additional(risk.(This(evaluation(creates(a(combination(of(risk(factors(that(needs(to(be(
constantly( observed( throughout( the( entire( product( development( process( of( our( product(
REGENOZENE.(Ensuring(that(the(target(safety(and(toxicology(requirements(are(met(is(crucial(
because(of(the(nature(of(our(drug(mechanism(relies(on(a(recombinant(DNACderived(cytotoxic(
protein(composed(of(the(amino(acid(sequences(for(diphtheria(toxin(fragments(A(and(B((Met1C
Thr387)CHis(and(the(sequences(for(human(FC(antibody(regions(conjugated(with(a(DR6(small(
molecule(antagonist.(This(creates(many(decision(points(along(the(product(development(plan(to(
adequately(address(the(complex(nature(of(the(immune(response(system(that(the(human(body(
may(have.
Within(the(functional(area(of(clinical(development(and(medical(risks,(the(risk(of(standard(of(
care(changing(is(very(high(with(a(high(potential(for(several(paradigm(shifts(in(the(therapeutic(
arena(of(MS.(Currently,(GILENYA®(has(been(a(game(changer(as(it(is(the(first(oral(drug(indicated(
for( slowing( the( progression( of( disability( and( decreasing( the( frequency( and( severity( of(
symptoms.(This(presents(a(huge(risk(to(our(market(share(in(that(it(will(be(difficult(to(guarantee(
adherence( to( the( treatment( when( it( requires( constant( IV( injections.( The( convenience( that(
GILENYA®( provides( demonstrates( a( significant( advantage( over( existing( treatments( currently(
such(as(AVONEX®.(We(intend(to(use(the(same(primary(endpoints(based(on(competitor(study(
programs.
- 27. PRODUCT(PROFILER:(Regenozene
23
However,(if(our(product(maintains(its(efficacy(targets(through(the(development(process,(the(
advantage(of(REGENOZENE(is(its(ability(to(reverse(and(not(only(halt(progression(of(symptoms.(
This( is( something( that( current( lines( of( treatment( and( what( soon( to( be( launched( pipeline(
products(do(not(have.(On(the(other(hand,(the(efficacy(of(gene(therapy(and(stem(cell(therapy(
research(for(the(treatment(of(MS(has(shown(incredible(promising(results(with(large(implications(
of(little(or(no(side(effects.((It(is(noted(however,(that(these(therapies(may(have(difficult(with(FDA(
regulatory(requirements(to(be(approved(as(the(risks(are(still(not(fully(established.
Commercial( risks( that( may( hinder( our( ability( to( market( REGENOZENE( involve(
manufacturing,(regulatory(approval(and(funding(of(our(product.(In(order(to(overcome(our(lack(
of( experience( and( expertise( in( manufacturing,( it( will( be( necessary( to( outsource( clinical( and(
commercial(scale(manufacturing.(The(CMO(would(thus(be(providing(up(to(date(information(on(
“processCability”( of( API( and( the( formulation( as( well( as( any( final( product( risks.( In( regards( to(
regulatory(approval,(the(REGENOZENE(team(has(chosen(to(manage(regulatory(risks(by(pursuing(
just( a( segment( of( our( total( market( of( patients( by( focusing( on( just( Northern( America( until(
efficacy(and(safety(are(fully(characterized.(This(will(allow(the(team(to(build(a(close(relationship(
with(FDA(throughout(the(drug(development(process.(By(getting(approved(in(the(FDA,(it(also(
allows(us(future(opportunity(to(break(into(other(markets(more(quickly.(Another(risk(we(must(
avoid(with(regulatory(approval(is(to(avoid(submitting(for(approval(in(the(fourth(quarter(as(the(
FDA( gets( a( large( volume( of( submissions( and( the( approval( rate( significantly( drops( for( that(
quarter( according( to( Booz( Allen( Hamilton.( The( team( should( either( aim( for( a( first( quarter(
submission(and(at(the(latest(a(third(quarter(submission.((Managing(the(risks(successfully(in(our(
development( plan( will( position( us( to( strategically( maneuver( into( a( higher( chance( getting(
approval(and(launching(our(product(on(time.
(
(
(
- 28. PRODUCT(PROFILER:(Regenozene
24
Financial(Analysis(and(Revenue(Stream(
Cost(Analysis
The(proposed(product,(REGENOZENE,(will(be(administered(continuously(via(an(Insulin(basal(
pump(device(that(uses(cartridges(to(deliver(a(continual(basal(level(of(REGENOZENE.(A(single(
cartridge(will(last(approximately(24(hours.(Based(upon(the(analysis(conducted(for(this(plan,(it(is(
anticipated(the(proposed(therapeutic(regimen(would(be(once(a(day,(every(day,(for(a(dosage(
rate(of(365(per(year.((
(
The(price(is(based(on(current(standards(of(care.(A(one(year(treatment(with(ONTAK®(costs(
approximately( $50,000/yr( and( GILENYA®( is( around( $48,000/yr.( A( year’s( worth( of( treatment(
($50K)(with(those(products(equates(to(about($137(per(day.(REGENOZENE(is(similar(to(GILENYA®(
in(that(they(all(address(the(progression(of(RRMS,(but(only(REGENOZENE(has(been(theorized(to(
regenerate(the(myelin(sheath(surrounding(the(nerves.(We(feel(strongly(that(a(10%(premium(
product( increase( over( the( current( method( of( treatment( is( in( line( with( the( benefits( of( our(
improved(product(without(gouging(patients(or(insurance(companies.(The(current(treatment(of(
$137(plus(our(10%(premium(product(increase(puts(the(cost(of(REGENOZENE(at($150(per(day.(
(
The(revenue(stream(for(REGENOZENE(is(calculated(from(the(when(the(product(becomes(
commercially(available(through(Year(10.(The(first(prescribers(of(REGENOZENE(will(most(likely(be(
those( physicians( that( have( been( involved( in( the( Clinical( Trails( (Innovators).( They( represent(
about(2%(of(the(total(market.(The(product(is(such(an(improvement(over(the(current(standard(of(
care(that(we(are(confident(that(in(the(first(year(alone,(we(will(capture(90%(of(the(Innovator(
market(and(that(we(will(maintain(90%(of(that(market(through(year(7(and(begin(to(see(a(decline(
in(the(Innovator(market(at(a(rate(of(15%(per(year(until(Year(10(as(potentially(new(products(for(
RRMS(become(available.(((((((((((((((((
(
The(next(section(of(the(market(that(will(come(“on(line”(is(that(of(the(Early(Adopters,(who(
make(up(14%(of(the(physician(pool.(We(expect(that(60%(of(those(physicians(will(come(onboard(
in(Year(1,(increasing(to(90%(of(the(Early(Adopter(physicians(in(Year(2(through(Year(7,(declining(
by(15%(yearly(through(Year(10.(
(
The(Early(Majority(is(one(of(the(largest(segments(of(the(physician(population((34%)(and(we(
do(not(expect(to(have(any(of(those(physicians(until(Year(2((starting(with(25%(of(that(segment),(
growing(by(30%(annually(to(Year(6,(stabilizing(through(Year(8(and(declining(by(10%(for(Year(9(
and(10.(
(
Late(Majority(is(the(other(large(segment((also(at(34%)(and(we(will(see(them(come(online(in(
Year(3(at((25%(of(that(market),(growing(at(30%(annually(through(Year(7(and(decreasing(by(10%(
each(year(for(Years(8,(9(&(10.(
(
The( final( market( segment( expected( to( prescribe( REGENOZENE( to( their( patients( is( the(
Laggards( (16%( of( Market).( Because( of( their( belief( in( making( sure( that( their( patients( have( a(
- 29. PRODUCT(PROFILER:(Regenozene
25
proven(therapeutic,(we(do(not(expect(any(revenue(from(this(segment(until(Year(4,(and(even(
then,(only(25%(of(that(market,(growing(30%(yearly(through(Year(8(and(declining(15%(for(each(
of(Year(9(and(10.(
(
Although( we( are( looking( at( United( States( and( Canada( as( the( target( markets,( the(
percentages( of( users( should( be( the( same( for( each.( The( revenues( generated( will( be( unique(
based(upon(the(actual(volume(of(product(prescribed(and(sold(in(each(Target(Market.(
(
(
(
Revenue'Assumptions'
• Revenue(was(calculated(as(cost(per(patient(times(the(number(of(patients(
• Treatment(is($150(per(day,(365(days(per(year(for(a(total(of($54,750(
• Capture(70%(of(market(by(Sales(Year(7(
COGS'Assumptions'
• By( the( time( any( significant( COGS( are( incurred,( there( will( be( partnerships( established(
with(Big(Pharma(
R'&'D'Assumptions'
• R(&(D(costs(are(based(on(the(clinical(development(costs(outlined(in(the(PTRS(
• R(&(D(for(REGENOZENE(will(stop(after(year(9(
Sales'&'Marketing'Assumptions'
• No(Sales(&(Marketing(costs(in(yrs(1(&(2(
• We(will(incur(Sales(&(Marketing(costs(for(years(3C6(only(
• Post(year(6,(Sales(and(Marketing(costs(will(be(absorbed(by(the(Big(Pharma(Partner(
G'&'A'Assumptions'
• G(&(A(costs(will(be(minimal(as(REGENOZENE(will(be(produced(using(the(Virtual(Business(
Model(with(very(little(overhead.(
• Office(Staff(will(receive(5%(raises(annually(
• Office(Rents(and(Utilities(will(increase(3%(annually(
• “Incidentals”(will(remain(static(at($6000(annually(
IP'&'Legal'Costs'
• Legal(fees(higher(prior(to(launch(for(Patent(Lawyers(and(Legal(Fees(
• IP(Maintenance(fees(remain(flat(from(Year(5(at($500,000((10%(of(Licensing(Fee)(
Depreciation'&'Amortization,'Interest'Expense/Cost'Assumptions'
• None(
(
(
( (
(
(
- 30. PRODUCT(PROFILER:(Regenozene
26
Sales(Forecast(
(
( Sales(are(expected(to(peak(in(year(7((post(launch)(at(just(over($5.0(Billion.(Cumulative(
sales(over(the(course(of(the(Sales(period((Launch(plus(20(years)(is(targeted(to(be($35(Billion.(
Minimal(projections(for(Cumulative(Sales(is(just(under($30(Billion(and(Optimally(they(would(be(
$40(Billion((Target(+/C(15%)(for(the(same(time(period.((See(table(below)(
(
(
(
(
$0
$5,000
$10,000
$15,000
$20,000
$25,000
$30,000
$35,000
$40,000
$45,000
$0
$1,000
$2,000
$3,000
$4,000
$5,000
$6,000
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Sales&(Millions)
Years&After&Launch
Sales&Forecast
Target
Optimal8(+15%)
Target
Minimum8(@15%)
Cumulative&Sales&
(Millions)
(
'
'
'
'
'
'
'
- 31. PRODUCT(PROFILER:(Regenozene
27
Risk'Adjusted'Net'Present'Value'
In( using( a( Risk( Adjusted( Net( Present( Value( (rNPV)( as( our( Valuation( Model,( we( are(
staying(true(to(the(current(industry(practice.(By(applying(the(various(probabilities(of(success(at(
the(various(stages(of(the(Product(Development(and(Launch(Cycle(as(well(as(the(current(discount(
rate(of(15%,(we(are(able(to(estimate(the(value(of(those(funds.(Our(overall(rNPV(is(valued(at(
$648(million.(
(
(
!$10
$0
$10
$20
$30
$40
$50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
rNPV%(Millions)
rNPV%=%$648%million
(
(
(
(
( (
(
(
(
- 32. PRODUCT(PROFILER:(Regenozene
28
Appendix(A(
(
Additional'Information'
Incidence*and*Prevalence*
Multiple( sclerosis( is( characterized( as( a( complex,( inflammatory( autoimmune( disease( that(
progressively(disables(the(central(nervous(system,(including(the(brain,(spinal(cord,(and(optic(
nerve.( This( disease( affects( more( than( 2.1( million( people( worldwide.( Currently( in( the( United(
States( alone,( there( is( an( estimated( 400,000( persons( actively( living( with( this( disease,( while(
10,000(newly(diagnosed(cases(emerge(per(year.((Onset(of(symptoms(usually(begins(in(early(
adulthood( with( ages( of( initial( diagnosis( typically( occurring( between( 28C33( years.( ( Multiple(
sclerosis( has( an( incidence( ratio( of( 2:1( women( to( men( and( is( most( prevalent( in( Caucasian(
populations(above(the(equator.1,2
(((((
(
Etiology*
Despite(all(efforts,(an(etiology(for(this(disease(has(yet(to(be(identified.((It(is(speculated(that(
many( factors( are( involved( to( cause( this( disease.( ( Because( MS( is( an( autoimmune( disease,(
researchers( pursue( the( hypothesis( of( why( the( immune( system( malfunctions.( ( As( we( move(
forward(into(the(age(of(technological(advances,(many(questions(regarding(a(patient’s(genetic(
profile(are(visited(when(researching(possible(predisposition(to(MS.((Other(causative(factors(such(
as(infectious(diseases(or(environmental(elements(encountered(during(childhood(are(plausible(
considerations.1,2
((((
*
Pathophysiology*
Study( of( its( pathogenesis,( MS,( results( in( the( inflammatory( response( and( sclerosis( of( the(
neuron.((T(cells(are(activated(and(infiltrate(the(bloodCbrainCbarrier(into(the(CNS,(thus(attacking(
the( myelin( sheaths( that( protect( the( axons.( ( As( the( demyelination( occurs,( it( stimulates( the(
inflammatory(response(that(signals(cytokines(and(chemokines(to(the(site(of(penetration.((This(
cyclical(effect(occurs(and(eventually(more(immunological(cells(are(incorporated(until(the(death(
of(the(oligodendrocyte(occurs.((The(demyelination(and(death(of(the(cell(manifests(into(visible(
symptoms(that(the(patient(experiences.1
(((((
(
Oligodendrocytes*
Two(major(types(of(cells(make(up(the(tissue(of(the(brain:(neural(cells(and(glial(cells.(Neural(
cells(relay(signals(in(the(form(of(electrical(impulses(throughout(the(entire(body.(Glial(cells(role(is(
to(support(the(neural(cells.(An(oligodendrocyte(is(a(type(of(glial(cell(that(wraps(its(membrane(
around( the( axon( of( a( neuron( to( form( a( substance( called( myelin.( Myelin( acts( as( a( form( of(
insulation(which(helps(the(neuron’s(axon(to(transmit(its(signal(to(the(rest(of(the(body.(Myelin(is(
composed(of(80%(lipid(and(20%(protein.32
(Myelin(increases(the(speed(at(which(impulses(travel(
and(acts(as(a(salutatory(propagation(of(the(action(potentials(that(occur(at(the(gaps(in(between(
the(myelin(sheathes.(The(oligodendrocytes(provide(a(similar(function(to(axons(as(the(rubber(
insulation( on( the( outside( of( a( wire.( The( myelin( prevents( the( neurons( signal( from( being(
dissipated( into( the( solution( of( ions( and( water( that( is( inside( of( the( body.( ( Impulse( speed( is(
dramatically(faster(in(myelinated(axons(than(unmyelinated(cells.(((
- 33. PRODUCT(PROFILER:(Regenozene
29
(
Oligodendrocytes,(like(all(cells,(have(a(variety(of(receptors(and(proteins(that(can(be(very(
specific(to(certain(cell(type.((MOG((Myelin(Oligodendrocyte(Glycoprotein)(is(a(transmembrane(
protein(that(is(specific(to(these(glial(cells.((Increasing(evidence(illustrates(that(MOG(upregulates(
the(proinflammatory(system(as(well(as(immunological(cytokines.33
(((
(
Clinical*Presentation*and*Evaluation*
Because(this(disease(can(affect(a(variety(of(areas(in(the(brain,(it(can(produce(an(array(of(
symptoms(which(presents(a(challenge(for(the(clinician(to(diagnosis.((Some(of(these(symptoms(
include(fatigue,(numbness,(balance(and(coordination(problems,(bladder(and(bowel(dysfunction,(
visual(and(cognitive(impairment,(pain,(depression,(or(spasticity.(((
(
Using(a(comprehensive(neuropsychological(assessment,(known(as(a(cognitive(dysfunction(
test,(scientists(can(determine(if(a(patient(has(the(cognitive(impairments(associated(with(MS.2
(
The(screening(has(a(high(degree(of(sensitivity,(specificity,(
and(diagnostic(accuracy.2
(Magnetic(
resonance(imaging((MRI)(is(also(utilized(to(screen(for(multiple(sclerosis.36
(((MRIs(can(detect(
areas(of(neurological(damage(and(where(damage(to(the(myelin(has(occurred.((Another(method(
of(testing(is(extracting(cerebral(spinal(fluid((CSF)(via(lumbar(puncture.((Observing(CSF(has(been(
used(to(screen(for(MS(through(the(detection(of(immune(cells(and(proteins(present(in(the(fluid.2
(
Another(common(procedure(to(assess(nerve(impulses(is(the(evoked(potential,(which(measures(
the(electrical(signals(sent(out(by(the(brain(in(response(to(stimuli.36
(((
(
Research( has( been( conducted( for( other( methods( of( screening( for( MS.( Elevated( levels( of(
sVCAMC1( and( sECSelectin( was( found( in( the( serum( of( primary( progressive( MS( patients.34
( In(
another(study,(MRPC8/14(was(found(to(be(in(higher(than(normal(concentrations(in(active(MS(
patients.35
(There(were(also(elevated(levels(of(serum(amyloid(A36(((
and(immunosuppressive(acidic(
protein6
( in( MS( patients.( One( of( the( more( recent( findings( pertaining( to( MS( screening( is( the(
correlation(between(certain(genetic(markers(and(MS.7
(A(study(found(that(29(genes,(particularly(
genes(that(play(important(roles(in(the(immune(system,(are(associated(with(MS.7
(Detecting(for(
any(of(the(aforementioned(molecular(markers(or(genetic(markers(could(possibly(help(to(catch(
the(disease(at(an(early(stage(so(that(treatment(can(be(administered(and(disease(progress(can(
be(slowed(early.(
(
(
Remyelination*Detection**
While(these(current(therapies(are(effective(at(controlling(symptoms(and(they(have(limited(
ability( to( regress( the( disease.( Remyelination( is( the( ultimate( goal( for( any( MS( drug.(
Remyelination( is( the( process( in( which( the( myelin( sheaths( on( axons( are( regenerated.37
( One(
challenge(when(dealing(with(remyelination(is(how(to(detect(and(quantify(it’s(occurrence(in'vivo.(
Recently( there( have( been( several( possible( developments( that( may( serve( to( rectify( this(
challenge.( A( technique( by( which( measuring( magnetization( transfer( ratios( (MTR)( through(
magnetic(resonance(imaging((MRI)(has(been(used,(has(proven(to(be(successful(in(measuring(
both( demyelination( and( remyelination( in' vivo.38
( ( Magnetizing( transfer( imaging( exploits( the(
exchange(of(magnetization(between(the(hydrogen(nuclei(of(semisolid(macromolecules(and(free(
- 34. PRODUCT(PROFILER:(Regenozene
30
water(protons(to(enable(MRI(of(semisolid(components(of(tissue(such(as(myelin(membranes(that(
cannot( normally( be( imaged( directly.38
( There( was( another( study( that( used( positron( emission(
tomography((PET)(to(detect(and(quantify(myelin(content(inMvivo.39
(Using(a(carbonC11(labeled(
myelin( imaging( agent( termed( Case( Imaging( Compound( or( [11
C]CIC,( myelin( was( successfully(
detected(and(quantified.39
(This(study(indicated(that([11
C]CIC–PET(can(be(used(as(an(imaging(
marker(of(myelination,(which(has(the(potential(to(be(translated(into(clinical(studies(in(multiple(
sclerosis( and( other( myelinCrelated( diseases( for( early( diagnosis,( subtyping,( and( efficacy(
evaluation(of(therapeutic(treatments(aimed(at(myelin(repair.39(
(
(
Disease*Subtypes*
After(the(diagnosis,(it(is(important(to(categorize(the(type(of(MS.((This(disease(can(manifest(
into(four(different(forms:(relapsingCremitting((RRMS),(secondary(progressive((SPMS),(primary(
progressive( (PPMS),( and( progressive( relapsing( (PRMS).( ( Diagnosis( depends( on( the( rate( of(
attacks(and(severity.((Our(focus(is(on(the(RRMS(because(it(accounts(for(more(than(80%(of(the(
MS(population.1
(((( (
(
Death*Receptor*6*
In(the(cases(of(myelin(degeneration,(suppression(of(DR6(has(been(linked(with(a(promotion(
of( myelination( and( an( improvement( of( oligodendrocyte( progenitor( cell( survival( and(
differentiation.16,41
((Death(Receptor(6((DR6)(is(a(286(amino(acid,(single(pass(transmembrane(
protein( of( the( TNFR( family.( ( DRC6( exhibits( the( cysteine( rich( extracellular( domain( and(
intracellular( death( domain( characteristic( of( members( of( the( TNF( family,( although( it( has( not(
shown( responsiveness( to( the( TNFCα( ligand.42
( ( DR6( is( involved( in( cell( signaling( leading( to(
apoptosis(through(activation(of(caspaseC3,(although(the(intermediate(cascade(interactions(have(
not(been(defined.43,44
(((
(
The(DRC6(protein(is(constitutively(expressed(through(mammalian(tissues;(expression(of(DRC6(
is(thought(to(have(been(related(to(the(development(of(immunity.16
(While(maintained(in(the(
cytosol,(the(protein(requires(specific(processing(and(post(translational(modifications(including(
formation(of(the(stalk(region(and(NC(and(OCglycosylation(in(order(for(the(protein(to(be(properly(
inserted(into(a(lipid(raft(and(transported(to(the(cell(membrane.(
(
Studies(in(DRC6C/C(mice(show(a(strong(involvement(in(the(regulation(of(hematopoietic(cell(
proliferation(and(differentiation.16,42
((The(ligand(causing(this(correlation(is(unknown,(however,(
it(is(known(that(expression(of(DRC6(on(T(and(B(Lymphocyte(cells(is(significantly(lower(than(in(
other(cell(types,(approaching(zero.((Studies(have(shown(that(an(increase(in(T(cell(population(in(
an( area( causes( a( local( upregulation( of( DRC6( in( that( area( and( subsequent( apoptosis.43
(
Suppression(of(DRC6(improves(survival,(differentiation,(and(maturation(of(cells(presumably(by(
preventing(apoptosis(and(suppressing(the(immune(response(in(the(area.16
(((In(particular,(CD4+(T(
cell(migration(to(the(area(of(inflammation(is(compromised(in(the(absence(of(DR6.41,43
(((
)
Future)Treatments))
- 35. PRODUCT(PROFILER:(Regenozene
31
So(far,(the(current(approved(therapies(only(address(slowing(the(progress(of(MS.44
((Weiner44
,(
an(MS(researcher,(suggests(that(the(following(treatment(strategies(need(to(be(pursued(in(order(
to(cure(MS:(prevent(lymphocyte(trafficking,(decrease(Th1/Th17(cells,(provide(neuroprotection(
of(the(oligodendrocytes,(promote(remyelination,(induce(T(reg(cells,(deplete(BCcells(and(affect(
the(innate(immune(response.(Currently,(there(are(over(60(drugs(in(various(stages(of(clinical(
trials(or(under(investigation(for(treating(MS(new(
ref).(Few(of(the(treatments(address(the(areas(of(
remyelination( and( neuroprotection.45
( Almost( all( of( the( drugs( are( immunomodulators,(
immunosuppressants(or(general(antiCinflammatories.46(
(
Current(MS(Therapies(
(
AVONEX®(and(REBIF®(are(recombinant(forms(of(the(protein(but(their(amino(acid(sequence(
is( identical( to( the( natural( human( interferon( betaC1A.6,7
( There( is( only( one( small( difference(
between( the( recombinant( proteins( and( the( native( form,( the( recombinant( form( has( a(
substitution(of(a(serine(for(a(cysteine(at(position(17(of(the(amino(acid(sequence.8,0
(The(amino(
acid(sequence(of(The(beneficial(effect(gained(from(interferon(treatment(is(thought(to(be(due(to(
their(antiCinflammatory(properties(but(according(to(the(prescribing(information(on(interferon(
drugs,( the( mechanism( of( action( is( not( fully( understood.6,7
( ( Beta( interferon’s( are( thought( to(
inhibit(TCcell(proliferation(and(are(produced(naturally(by(fibroblasts(and(macrophages.6,46
(In(an(
inCvivo(study,(interferons(where(shown(to(improve(the(integrity(of(the(bloodCbrain(barrier.47
(
This( is( desirable( because( in( MS( patients,( the( bloodCbrain( barrier( often( degrades,( allowing(
undesirable( substances( to( reach( the( brain.( The( strengthening( of( the( bloodCbrain( barrier(
contributes(to(the(beneficial(effects(of(interferons.(Interferon(betaC1a(has(many(sideCeffects;(
the(two(most(common(side(effects(are(injectionCsite(reaction(and(fluClike(symptoms.6
(The(fluC
like(symptoms(occur(immediately(after(injection(of(the(drug(and(persist(for(about(half(a(day.48
((
These(symptoms(after(each(injection(can(persist(over(the(long(term(or(diminish(over(time.(The(
side( effects( of( interferons( are( often( uncomfortable( enough( that( many( patients( choose( to(
discontinue( taking( interferons( and( seek( out( other( methods( of( treatment.( While( interferons(
improve( the( results( of( diagnostic( tests( on( MS( patients,( many( patients( do( not( report( an(
alleviation(of(MS(symptoms(and(complain(that(the(sideCeffects(substantially(lower(their(quality(
of( life.( Patients( can( gain( physiological( tolerance( to( interferons( which( results( in( reduced(
effectiveness( calling( for( increased( dosage( and( accompanied( by( an( increase( in( sideCeffects.(
AVONEX®( is( commercially( available( can( be( purchased( as( a( preCmixed( liquid( syringe( kit( or( a(
lyophilized(powder(that(requires(reconstitution(and(is(administered(intraCmuslcularly.6
(REBIF®(
(Merck( Serono/Pfizer)( and( is( administered( by( subcutaneous( injection( three( times( a( week.13
(
CINNOVEX®( is( a( recombinant( Interferon( betaC1a( manufactured( by( CinnaGen( and( sold( in( a(
lyophilized(form(along(with(distilled(water(for(reconstitution(and(injection.(
(
Fingolimod(is(derived(from(a(metabolite(of(the(fungus(Isaria'sinclairii.(The(metabolite,(myriocin,(
is(an(analogue(of(sphingosine(and(is(phosphorylated(by(the(sphingosine(kinases(within(the(cell.(
This(prevents(the(lymphocytes(from(exacerbating(the(autoimmune(response(seen(in(multiple(
sclerosis.( It( has( also( been( demonstrated( that( fingolimod( has( the( ability( to( stimulate( the(
regeneration( of( glialCprecursor( cells( and( glial( cells( after( they( have( been( damaged.48
( ( During(
Phase(III(clinical(trials,(it(was(observed(that(fingolimod(reduced(the(amount(of(relapses(in(RRMS(
- 36. PRODUCT(PROFILER:(Regenozene
32
patients( by( over( 50%( when( compared( directly( with( interferon( betaC1a( and( a( placebo.48
( In(
another(doubleCblinded(randomized(control(study(that(compared(fingolimod(to(placebo,(it(was(
found(that(disease(progression(at(24(month(followCups(was(lower(in(the(groups(that(received(
fingolimod(than(the(placebo(groups.48
(
(
(
Description(
Understanding*the*Blood*Brain*Barrier*(BBB)*
The(majority(of(small(molecule(drugs(do(not(cross(the(BBB((some(sources(report(as(few(as(
2%,(those(via(passive(diffusion,(with(a(molecular(weight(cutoff(of(~400D),(few(large(molecule(
drugs(are(able(to(cross((insulin(via(receptor(mediated(transport).(Diphtheria(toxin(crosses(the(
BBB(selectively(by(interacting(with(the(Diphtheria(Toxin(Receptor((DTR)(found(on(the(capillary(
membranes(of(the(BBB.49
(DTR(is(a(constitutively(expressed(transport(protein(on(brain(capillaries(
and(in(neurons(and(glial(cells(of(the(brain.((DTR(does(not(have(a(known(natural(ligand;(there(is(
no( competition( for( use( of( the( receptor.( ( ReceptorCmediated( transport( exploiting( the( DTR(
protein(and(usage(of(diphtheria(toxin(analogues(as(molecular(Trojan(horses(to(pass(drugs(across(
the(BBB(has(increasingly(become(a(popular(avenue(for(CNSCtargeted(drug(development.16
(Eisai(
ONTAK®(((DAB(389)IL2)(to(treat(TCCell(Lymphoma,(toCBBB((2BCtrans(platform,(2B3C101)(using(
the(CRM197(nonCtoxic(diphtheria(toxin(mimetic(fused(to(a(liposome(encapsulated(ribavarin(to(
treat( Japanese( encephalitis( virus( (JEV),( and( has( been( explored( as( a( viable( method( since( the(
early(1980s(as(a(potential(therapeutic(model.50(
(
The( diphtheria( toxin( interacts( with( the( DTR( which( causes( the( entire( diphtheria( toxin(
complex(to(be(transported(across(the(membrane(via(transcytosis.((This(mechanism(of(action(
provides(flexibility(in(the(design(of(the(therapeutic(as(the(process(will(allow(for(a(range(of(sizes(
to(be(transported(into(the(cell((the(limit(being(dependent(on(the(size(of(the(endosome).51(
*
*
Diphtheria*toxin*
The( diphtheria( toxin( is( a( pathogenic( type( III( AB( toxin( encoded( by( a( bacteriophage( and(
produced(by(infected(Corynebacterium'diphtheria(bacterium.(The(A(portion(of(the(toxin(is(the(
enzymatic(active(subunit,(and(the(B(portion(is(the(binding(portion.((When(introduced(into(the(
bloodstream,(the(toxin(interacts(with(the(DTR(protein(in(the(brain(capillaries(and(is(taken(across(
the( blood( brain( barrier( via( the( endocytosis( mechanism.( ( Once( in( the( CNS,( the( B( portion(
interacts(with(the(cellular(membrane(which(then(triggers(cellular(uptake(into(a(lysosome.((As(
the(pH(increases(within(the(lysosome(a(conformational(change(occurs(in(the(B(portion(causing(
insertion( of( the( B( portion( into( the( lysosome( membrane.( The( B( portion( functions( as( a(
transmembrane(transporter(protein(and(is(able(to(move(the(A(portion(across(the(membrane(
and(deposit(it(into(the(intracellular(space,(breaking(the(disulfide(bridge(attachments(during(the(
transformation(process.((Once(the(A(portion(is(free(in(the(cytosol(it(is(free(to(interact(with(the(
cellular(processes(and(interfere(with(directed(protein(synthesis.52(
- 37. PRODUCT(PROFILER:(Regenozene
31
Appendix(B(
(
TPP(Category( Minimal(Case( Target(Case( Upside(Case(
Indication( An(adjunct(disease(modifying(therapy(in(
newly(diagnosed(adults(for(the(
treatment(of(patients(with(relapsing(
Multiple(Sclerosis(to(reduce(the(
frequency(of(relapses(and(slow(the(
progression(of(disability((
A(disease(modifying(therapy(in(
adults(for(the(treatment(of(patients(
with(relapsing(Multiple(Sclerosis(to(
halt(the(experience(of(relapses(and(
slow(the(progression(of(disability((
A(disease(modifying(therapy(in(adults(for(the(
treatment(of(patients(with(relapsing(Multiple(
Sclerosis(to(halt(the(experience(of(relapses(and(
reverse(the(progression(of(disability(
Efficacy( No(direct(comparator:(When(
administered(as(an(adjunct(with(
Gilenya;(at(least(comparable(to(
Gilenya’s(annualized(relapse(rate((ARR)(
and(disability(progression((EDDS)(
studies(
No(direct(comparator:(When(
administered(alone,(significant(
improvement(over(Gilenya’s(
annualized(relapse(rate((ARR)(and(
disability(progression((EDDS)(studies(
No(direct(comparator:(When(administered(in(
combination(with(Gilenya,(achievement(of(
lowest(annualized(relapse(rate((ARR)(and(
disability(progression((EDDS)((
Safety( At(least(as(safe(as(Gilenya(when(
administered(in(combination(with(
Gilenya,(at(least(as(safe(as(Ontak(
diphtheria(shuttle(baseline(
At(least(as(safe(as(Gilenya((alone(
and(in(combination(with(Gilenya),(
safe(for(use(by(pregnant(and(nursing(
mothers,(improved(safety(as(
compared(to(Ontak(diphtheria(
shuttle(baseline(
Superior(to(Gilenya((alone(and(in(combination(
with(Gilenya),(safe(for(use(by(pregnant(and(
nursing(mothers,(safe(for(use(in(patients(with(
known(cardiovascular(disease,(superior(to(
Ontak(diphtheria(shuttle(baseline(
Contraindications(Patients(who(have(not(been(vaccinated(against(diphtheria(toxin,(persons(exhibiting(hypersensitivity(to(the(DTP(vaccine(or(any(
of(the(drug(components.((Special(caution(should(be(taken(with(patients(with(preTexisting(cardiovascular(disease.((Risk(of(
infectious(complications.((Complete(reversal(of(lesions(would(result(in(removal(of(patient(from(medication(and(maintenance(
using(other(approved(Multiple(Sclerosis(therapies.(
Drug(Interactions( None( None( None(
Route(of(Admin( Injections(IM( Insulin(style(pump((subcutaneous)( Choice(of(Insulin(style(pump(or(Transdermal(
patches((subcutaneous)(
- 38. PRODUCT(PROFILER:(Regenozene
32
Treatment(
Regimen(
Chronic(disease(modifying(lifetime(
treatment(in(combination(with(immune(
modulation(via(Gilenya(
Chronic((disease(modifying(lifetime(
treatment((
Chronic(disease(modifying(improved(
progression(lifetime(treatment(,(maintenance(
dose(after(recovery(
Convenience( Daily(dose( Continuous(basal(administration;(
daily(dose(provided(as(a(cartridge(
(sterile,(frozen(solution(in(a(sterile,(
singleTuse(vial)((
Continuous(basal(administration;(daily(dose(
provided(as(a(cartridge(
Shelf(Life( Room(temp(1T2(hours,(refrigerated((2T
8C)(up(to(24(hours,(frozen((at(or(below(T
10C)(up(to(6(months(
Room(temp(30(hours,(refrigerated(
(2T8C)(up(to(4(weeks,(frozen((at(or(
below(T10C)(up(to(1(year(
Room(temp(up(to(1(week,(refrigerated((2T8C)(
up(to(6(months,(frozen((at(or(below(T10C)(up(to(
2(years(
Target(Regions( United(States( United(States,(Canada( United(States,(Canada,(Europe(
First(Launch( 2024( 2023( 2022(
Price( $48K/year(+(5%(premium(($50K/year)( $48K/year(+(10%(premium(
($53K/year)(
$48K/year(+(>10%(premium((
Reimbursement( expect(60%;(one(improved(parameter(
over(Gilenya((improved(disease(
progression)(
Expect(80%;(two(improved(
parameters(over(Gilenya((improved(
disease(progression,(reduced(
relapse(rate)(
100%;(three(improved(parameters(over(Gilenya(
(improved(disease(progression,(reduced(
relapse(rate,(reversal(of(brain(lesions,(
restoration(of(motor(control(and(improved(
quality(of(life)(
Other(Indications(
(future)(
Other(forms(of(MS( Other(forms(of(MS,(other(
autoimmune(demyelinating(
disorders((Progressive(Multifocal(
Leukoencephalopathy,(PostT
Infectious(Encephalitis)(and(
radiation(injury(
Other(forms(of(MS,(other(autoimmune(
demyelinating(disorders((Progressive(Multifocal(
Leukoencephalopathy,(PostTInfectious(
Encephalitis)(and(radiation(injury,(other(central(
and(peripheral(demyelinating(disorders(
including(CharcotTMarieTTooth(Disease,(Devic's(
Disease,(GuillainTBarre(Syndrome(
(
- 39. PRODUCT(PROFILER:(Regenozene
31
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34
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