Transcript ISIS Pharmaceuticals

ISIS PHARMACEUTICALS
Making Antisense
Cumzain Malika
Irakoze Vanessa
Arvin-Berod Clémence

Overview of Isis Pharmaceuticals

Antisense Technology

Pipeline

2 drugs: Kynamro and ISIS-Apo CIII

Business Model and Funds.
Isis Pharmaceuticals, Inc.,
was created in1989 by Dr
Crooke, CEO and President
of Isis pharmaceuticals)
ISIS Pharmaceuticals incorporated in California in 1989
 In January 1991 they changed their state of
incorporation to Delaware
 Their principal offices are in Carlsbad, California

CA:1 10 Millions $
Based on an
Antisense
technology
322 employees
31 Drugs on their
pipeline
Isis pharmaceuticals: A unique paternships
plazomicin
1998
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2005 2006 2007
2008
EXC 001
Vitravene
2010 2011
2012
ISIS-AATR
ISISSTAT3
CURTISEN
ICO-007
PCSK9
MACUGEN
alicaforsen
ISISSMNRx
ANTISENSE TECHNOLOGY
«ANTISENSE » TECHNOLOGY
5’
3’
Bind sens
ADN
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Bind
antisens
WHY «ANTISENSE » TECHNOLOGY?
3’
5’
Bind sens
ADN
3’
ARN
5’
5’
3’
3’
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Bind
antisens
Bind sens
Bind
antisens
HOW ANTISENSE TECHNOLOGY WORK?
It is possible to synthesize a strand
of nucleid acid (DNA, RNA or a chemical
analogue)…
HOW ANTISENSE TECHNOLOGY WORK?
…that will bind to the messenger RNA (mRNA)
produced by that gene and inactivate it, effectively
turning that gene "off". This is because mRNA has to
be single stranded for it to be translated
ROBUST MULTIPLE MECANISMS
ANTISENSE TECHNOLOGY
Avantage


Diseases are often
connected to to excess or
insufficient production of
certain « proteins » so if
the production of these
proteins is disputed many
diseases can be treated or
cured.
Antisense drugs inhibit
or increase the
production of specific
disease-related proteins
Problem


Antisense technology has not
been perfected. It is still
difficult to express aRNA only
in targeted tissues.
Is difficult to insert the
antisense molecule into the
cell.
REVOLUTIONIZING DRUG DISCOVERY
REVOLUTIONIZING DRUG DISCOVERY :
PIPELINE
KYNAMRO° MIPOMERSEN
FDA Approval Date: January 2013
Indication:


Approved as adjunct to lipid lowering medication and
diet to reduce LDL cholesterol, apolipoprotein B, total
cholesterol, and non-HDL cholesterol in patients with
homozygous familial hypercholesterolemia.
Dosing: 200mg subcutaneous once weekly

Missed doses can be administered up to 3 days
prior to the next weekly dose
SIDE EFFECT
Contraindications:
Moderate to severe hepatic impairment
 Active liver disease, including unexplained persistent
elevations in transaminases

Warnings (and Black Box warnings)
BBW: Risk of hepatotoxicity
 Injection site reactions can occur
 Flu like symptoms can occur

TARIF

Dosing: 200mg subcutaneous once weekly
Cost:

$4,000/dose or $16,000/month
Financial assistance is available through the Kynamro
CornerstoneSM program
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Homozygous familial hypercholesterolemia (HoFH) is
a rare genetic disorder affecting ~1 in 1,000,000
people in the US.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
•
Cause is a genetic
mutation that leads to
LDL receptor dysfunction
•
Result is the inability to
remove LDL cholesterol
from the bloodstream
•
Survival past the age of 30
is rare if untreated
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

HoFH is managed with statin therapy which may be
ineffective even at high doses

LDL apheresis is an option for therapy, however, it is
expensive, invasive and often unavailable

Targeting the basic building block of LDL cholesterol –
apolipoprotein B – is an effective means to decrease
production of LDL ultimately eliminating the need for a
mechanism of LDL clearance
Mechanism of action
ApoB-100 is an important structural and fonctional component of
lipoproteins
Blocking ApoB100 production blocks VLDL and LDL production
CLINICAL TRIALS
resultat
Study design
Randomized, double blind, placebo controlled
Phase 3 clinical trial
Enrollment
Between September 2007-August 2009
Enrolled 51 patients
34 assigned to mipomersen,
17 assigned to placebo
Duration of Study
26 weeks
Primary Endpoint
Percent change in LDL cholesterol
concentration from baseline
Secondary endpoints
Percent change from baseline in
apolipoprotein B, total cholesterol, and nonHDL cholesterol
CLINICAL TRIAL
SAFETY

Ipomersen have an acceptable safety profile
[no significant liver blood test abnormalities that
met stopping criteria or intolerable injections
site reactions/flu-like symptoms (FLS)],no new
or worsening conditions that interfered with
study completion,
RISK EVALUATION AND MITIGATION
STRATEGY
 Mipomersen
is only available through
REMS

BBW for risk of hepatotoxicity (counsel on
hepatotoxicity)
EUROPE APPROVAL

The negative recommendation was based on the
committee’s concerns about the safety of mipomersen
ISIS-APOCIIIRX
Treatment for Patients with Familial Chylomicronemia Syndrome
ISIS-APOCIIIRX:


is an antisense drug designed to reduce
apolipoprotein C-III(apoC-III) a protein
production and lower triglycerides.
is for patients with familial chylomicronemia
syndrome, or FCS, and patients with severely
high triglycerides.
FAMILIAL CHYLOMICRONEMIA SYNDROME
(FCS)


FCS is a very rare orphan genetic
disease that affects an estimated
3,000 to 5,000 patients worldwide
FCS patients are unable to break
down triglycerides correctly causing
fat particles called chylomicrons to
build up in the blood.

Triglyceride levels often above 2,000
mg/dL .

Extreme risk for acute pancreatic
events and other serious conditions.

Current therapies, like fibrates, are
not effective to reduce triglyceride
levels and risk of serious events.
APOC-III INHIBITS CLEARANCE OF
TRIGLYCERIDES FROM BLOOD


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The Committee for Orphan Medicinal Products
(COMP) has issued a positive opinion for Orphan
Drug Designation for ISIS-APOCIIIRx for the
treatment of patients with familial
chylomicronemia syndrome (FCS) on jan 13,2014.
Isis is also developing ISIS-APOCIIIRx for
patients with severely elevated triglycerides,
greater than 880 md/dL, that affects an
estimated 50,000 patients in the United States
and Europe.
These patients have a high risk of pancreatitis
but also have a high risk of type 2 diabetes and
cardiovascular disease
REVOLUTIONIZING DRUG DISCOVERY
Business model
A 25 years old biotechnology company
CONCEPT OF ISIS


Technologic platform based on RNA-targeting as
opposed to traditional protein targets.
Investment in R&D / no marketing power of its
own.

Partnerships with big pharma

Consortium of satellite companies
BUSINESS STRATEGY
SATELLITE COMPANIES
CLOSEST COMPETITOR AEGERION
VS



Created in 2005.
Biopharmaceutical company of innovative, lifealtering therapies for patients with debilitating
often fatal, rare diseases.
Direct competitor of ISIS: Lomitapide VS ISISAPOCIIIRx for treatment of FCS.
Juxtapid VS Kynamro in HoFH.
KYNAMRO VS JUXTAPID

Limited population (1 in a million)

Cost

Side effects profiles

Marketing power
LICENCES, MILESTONES PAYMENTS

$25M milestone payment from Genzyme

$7.5M milestone payment from GSK.

$7.5M from Alnylam

$9M milestone payment from Biogen
FINANCIAL STRENGTH


Isis announces Positive Decision On
European Orphan Drug Designation
For ISIS-APOCIII Rx (treatment of
FCS).
After this news, the price of share of
ISIS went up, and ISIS is considered
by the Deutsche Bank as a
risk/reward trade-off remains
particularly attractive.
FINANCIAL DATA


Revenue:
2012
2011
2010
$102M
$99M
$108.5M
2012
2011
2010
$158M
$157M
$145M
R&D expenses:
CASH POTENTIAL
In 2012: $124M in cash
 Expenses in 2012: $65M


Can live up to 2 years without any cash in-flow.
CURRENT RATIO
Total assets in 2012: $545M
 Total liabilities in 2012: $362M

Current ratio in 2012: 1.5
 In 2011: 1.54


Recent data: 2013’s current ratio is expected to
be high ( around 7).
SHAREHOLDER’S EQUITY


Obtained when subtract total liabilities from
assets.
Give an idea of the sharholder’s stake in the
company.
2012
2011
$182M
$171M
ISIS FINANCIAL RECENT DATA
EXPECTED REVENUE
SWOT ANALYSIS
S
W
TRENGTHS
EAKNESSES
• Expertise in antisense
technology
• Partnership strategy
enhancing drug
developtment process
O
PPORTUNITIES
• Successful launch of
Kynamro in US could
provide for growth
• Expanding startegic
collaborations with
major biopharma
companies
Positive
• Can’t treat
multifactorial
pathology
Internal
factors
• Based on an unique
technology
T
HREATS
• Lengthening
regulatory process
• Cost containment
pressures would
negatively impact
drug sales and profit
Negative
External
factors