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9 Δεκ 2012 (πριν από 4 χρόνια και 8 μήνες)

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GTX
-
001: A Risk Worth Taking

Victoria Clark, Kelly Fitzgerald

Minji Kim, Frederick Wang

Juliana Mastronunzio

2009 YBPS Case Competition

November 20, 2009

Licensing Proposal from Gastrex

Two drug candidates for inflammatory bowel disease:

GTX
-
001

and
GTX
-
002



RECOMMENDATION
: License only GTX
-
001


Targets relevant inflammatory pathways in
Crohn’s

disease and ulcerative colitis


Addresses unmet needs of patients
with moderate and severe disease


Larger potential market share than GTX
-
002


Positive net present value even when
accounting for long
-
term risk


Symptoms:
Abdominal pain, diarrhea, rectal bleeding, loss of appetite, growth,
extraintestinal inflammatory conditions




Small intestine and colon



Transmural inflammation
and ulceration, fistulae



Colon and rectum



Inflammation and
ulceration of mucosa and
submucosa

Crohn’s Disease

Ulcerative Colitis

Inflammatory Bowel Disease (IBD)

46%

55%

38%

30%

16%

15%

880,000 Cases

1,200,000 Cases

Crohn’s

Disease

Ulcerative Colitis

Prevalence of IBD (US and EU 2008)

No treatment

5’ASA

Steroids + 5’ASA

Steroids +

Immunomodulator

Biologics

Refractory

Mild

Moderate

Severe

Target patients for

GTX
-
001 and GTX
-
002

Immunomodulators


Oral or IV


Effective for maintenance


Affects actively cycling cells


High risk for secondary infections


Ex. 6
-
MP,
methotrexate

Biologics


IV or subcutaneous injection


Effective for induction and maintenance



Increased risk for tuberculosis, serious
infections, lymphoma


Ex.
infliximab
,
adalimumab
,
natalizumab


Current Therapies for Moderate/Severe Cases

Unmet Needs


Tolerance develops to
infliximab


Average time to flare is approximately
equal for all treatments

Peyrin
-
Biroulet L, et al. Lancet 2008;372:67
-
81.

PROS


Novel biologic that may prevent
leukocyte
extravasation

and migration


Potentially treats both CD and UC


Potentially blocks activated T cells,
natural killer cells,
monocytes
, and
macrophages

CONS


Not specific to the gut


Not specific to immune cells


Limited preclinical data


Potential side effects on gut epithelial
cell adherence



GTX
-
001

VLA
-
1

Collagen

GTX
-
001: Anti
-
VLA
-
1 Antibody

Janeway's Immunobiology . Seventh Edition. pp 469 2008

Podolsky DK. N Engl J Med 2002;347:417
-
29.

Eckmann L et al. Proc Natl Acad Sci U S A 2008;105:15058
-
63.




TLR

IL
-
1R

TNFR

IKKs

Interleukins

Cytokines

Chemokines

Survival

GTX
-
002

NF
-
κ
B

GTX
-
002: IKK Inhibitor

PROS


Targets signaling hub of NF
-
κ
B
pathway


Oral bioavailability


Decreased T
-
cell survival


Effective in rodent IBD model

CONS


Nonspecific immunomodulation


Susceptibility to bacterial infection


Exacerbates acute inflammation


Limited preclinical data


Multiple drugs under development

Phase I

-
$30

Phase 2

-
$99

Phase 3

-
$171

Marketing

Failure

Failure

Failure

Biologics: 80%

NCE: 73%

Biologics: 41%

NCE: 45%

Biologics: 74%

NCE: 58%

$15

milestone

$45

milestone

$140 milestone

Modeling the Risk of Clinical Trials

Trial Success Determinants


Lack of major adverse events


Mild side effect profile


Efficacy parameters include number of stools, stool frequency,
abdominal pain, rectal bleeding,
hematocrit
, and functional
assessment by the patient

Per drug per disease

R&D cost: $300MM

Milestones: $200MM

Biologics overall success rate: 24%

New Chemical Entity (NCE)


overall success rate: 19%

5
-
ASA only

21%

Steroid+5A
SA

14%

Steroid+IM

3%

Biologics

62%

Market size of IBD drugs (2032)

$8.3 bn



GTX
-
001

GTX
-
002

Target Segment

Biologics & Refractory

Immunomodulator

& Refractory

Price per patient

$7,000
-

$17,000

$3,500
-

$10,000

Target Patient Population

1.6%
-

10%

2.4%
-

16.5%

Potential Market Share

7%
-

50%

2%
-

20%

Potential Sales

$0.6bn
-

$4.2bn

$0.2bn
-

$1.7bn

Higher efficacy & willingness to pay drive higher sales revenue for biologics

IBD Market Analysis and Projections

GTX
-
002

Chance of success is 29% for GTX
-
001 and 22% for GTX
-
002

Conditions


10,000 Monte Carlo simulations performed


Total rNPV = valuation of CD market and UC market


Prices adjusted with 3% annual inflation rate


10% discount rate


GTX
-
001

Total rNPV

Total rNPV

Mean (
rNPV
) = $590MM

Mean (
rNPV
) = $139MM

Positive Risk
-
Adjusted Valuations

GTX
-
001: A Risk Worth Taking

Scientific Recommendation


Preclinical data insufficient to differentiate between
potential GTX
-
001 and GTX
-
002 clinical efficacies


GTX
-
001 has fewer adverse events in the rodent than
GTX
-
002


Optimal GTX
-
001 therapy must be fully humanized,
easy to administer (subcutaneous delivery), effective for
induction and maintenance

Financial Recommendation


Both GTX
-
001 and GTX
-
002 have positive
rNPV
,
but
rNPV

value is higher in GTX
-
001


Drugs would not be co
-
administered and may
compete for moderate/severe IBD markets


Biologics market is 60% of IBD drug market

Acknowledgements

Victoria Clark, Kelly Fitzgerald

Minji Kim, Frederick Wang

Juliana Mastronunzio

Yale Biotechnology and Pharmaceutical Society

Boehringer

Ingelheim

Covidien

Saul Ewing LLP

Vion

Pharmaceuticals

Taro Pharmaceuticals

McKinsey & Company

Yale Center for Customer Insights

Phase I:

ZP1848


GLP
-
2 peptide analogue

KLH
-
TNFα kinoid


vaccine

C326


IL
-
6 Inhibitory Avimer protein


Phase II:

AIN457


anti IL
-
17 Mab

KLH
-
TNFα kinoid


vaccine

rhIGF


recombinant IGF

OPC
-
6535


superoxide anion production
inhibitor

Ustekinumab


anti
-
IL
-
12, IL
-
23 human Mab

HMPL004


multiple cellular targets

SC12267



inhibits pyrimidine synthesis


Phase III:

Vedolizumab


anti
-
integrin α4β7

Phase I:

rhuMAb

Beta7


anti
-
integrin α4β7 and αEβ7


Phase II:

Golimumab


anti
-
TNF
α

Mab

Rituximab


anti
-
CD20 Mab

SC12267


inhibits pyrimidine synthesis

HMPL004
-

multiple cellular targets


Phase III:

Budesonide
-
MMX


corticosteroid

Golimumab


anti
-
TNFα human Mab

Vedolizumab


anti
-
integrin α4β7

Abatacept


binds B7 T cell receptor

Crohn’s Disease

Ulcerative Colitis

Currently Recruiting IBD Clinical Trials

http://www.clinicaltrials.gov

Monte Carlo Simulations


IF the drug is more effective, the model incorporates a higher market
capture and price charged


Probabilities for market size and price modeled with beta
-
PERT
distributions


Manufacturing costs not included due to incomplete data; the higher
cost of producing monoclonal antibodies will lower the predicted
rNPV



Continue to Phase II?
Yes/No
Freq of
proceeding
std dev
Absence of adverse events
0
0.8
0.05
Continue to Phase III?
Absence of adverse events and effective
0
0.41
0.05
Continue to market?
Absence of adverse results
0
0.74
0.05
More effective than SOC?
0
0.31
0.1
Yes=1, No=0
Determination of
relative effectiveness
to current drugs was
based on historical
FDA classification of
drugs by therapeutic
value; system
stopped in 1992

5’ASA


Oral, mild side effects, but limited efficacy in severe IBD


Ex.
Asacol
,
Liada
,
Colazal

Steroids


Oral or IV injection, rapid onset of action, severe side effects limit use
for maintenance therapy


Ex.
Predisone
,
methylprednisolone

IM


Oral, effective for maintenance, high risk for secondary infections


Ex. 6
-
MP,
methotrexate

Biologics


IV or subcutaneous injection, effective for induction and
maintenance, but increased risk of infection


Ex.
Infliximab
,
Natalizumab


?


7.85% CD and 4.21% UC cases are refractory to treatment


For any existing treatment, average time to flare is 25 months +/
-
2
for CD and 30 +/
-

2 months for UC


Goal for new therapy: significantly increase time between flares,
minimize side effects, use for induction and maintenance