R&D Day 12 March 2010
Presented by
Ron Long, CEO & President
Eva Arlander, VP Pharma
Bertil Samuelsson, VP Discovery & Research
Rein Piir, CFO / IR
1
Agenda
•
Welcome – Rein Piir, CFO / IR
•
Introduction – Ron Long, CEO & President
•
Window of opportunity and Xerclear™ - Eva Arlander VP Pharma
•
R&D Portfolio – Bertil Samuelsson - VP Discovery & Research
•
Sum up and conclusion
2
Introduction
Ron Long - CEO
3
Our first product will see the light of the market on March 15!
4
Rationale
HSV-1
Xerclear
Inflammatory response
The rationale for the use of a combination aciclovir and hydrocortisone in the
treatment of recurrent mucocutaneous HSV is to enable control of both the
viral replication and the inflammation
5
- a powerful package

Prevents development of cold sores

Decreases healing time of ulcerative cold sores

The Xerclear™ vehicle improves dermal delivery

Xerclear™ has a unique and compelling label text

Granted patents: covering 1) composition-of-matter and 2) formulation
6
6
Xerese™ – Xerclear™ – a differentiating label
First cold sore product with clinical data resulting in a unique and
strong indication text – both in US and EU
Indication text as approved in US
“Xerese, a combination of acyclovir and hydrocortisone, is indicated for the early
treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of
ulcerative cold sores and to shorten the lesion healing time in adults and
adolescents (12 years of age and older)”
Indication text as approved in EU
”Treatment of early signs and symptoms of recurrent herpes labialis (cold sores) to
reduce the progression of cold sore episodes to ulcerative lesions in
immunocompetent adults and adolescents (12 years of age and older)”
7
Xerese™ – Xerclear™ strategy
NORDIC
Launch Xerclear™ Rx in SE on March 15 and in FIN March 22. OTC to
follow during 2010.
EU
European partner discussion for Xerclear™ ongoing in parallel with
preparation of product launch by late H2-2010. Initially, legal status is OTC
and Rx, with an overall switch to OTC over time.
US
MEDA is the US partner for Xerese™. They are preparing for product
launch by Q3/Q4 2010. Like other cold sore pharmaceuticals, Xerese™ will
be a prescription (Rx) product
ROW
Discussions ongoing
8
US market for topical cold sore products
Market
 Topical cold sore cream market is approximately USD 150-180 MUSD/year
 Prescription status for all antiviral treatments (acyclovir, penciclovir)
 Main competitors are Zovirax cream, Denavir cream and Abreva
9
EU Market for topical cold sore products
Market
 Topical cold sore treatment value of the main European markets is
approximately 200 MUSD/year
 EU is a scattered and competitive market dominated by OTC products
 The market value for SE and FIN is 7 MUSD/year
10
Regulatory status in EU
Regulatory
Status in
RMS/CMS
Approved*
(n=10)
Pending (n=4)
2g tube OTC
2g tube Rx
6
(CZ, DK, IS, PT, SK, SE)
4
(AT, FI, FR,UK)
4
(BE, ES, PL, DE)
*Either direct or expected by a submission of a variation after the national approval
11
Window of opportunity
•
Medivir’s first product launch
•
Inhouse competence in development, marketing and sales
•
Established dermatology network in SE
•
Future products from Medivir pipeline – closer than ever
•
Business opportunities
12
13
Medivir R&D
A project pipeline with major focus on anti infective
Strong preclinical delivery
•
Validated discovery process & technology platforms generating quality development candidates
–
•
One of the largest compound libraries in the industry
–
–
•
Tools for structure based drug design
Early and extensive in vitro and in vivo DMPKT profiling
–
•
X-RAPiD, a combinatorial library of ~120 000 compounds for screening any protease
e-FOCUS software provide a map of the protease subsites, generating exquisite structure activity relationships
(SAR) for inhibitor development
X-ray crystallography & high field NMR
–
•
~4 500 nucleoside analogue
~25 000 protease inhibitors
Proprietary and specialized protease technologies:
–
–
•
HCV PI; less then 3 years from lead series (LI phase) to start of Phase IIa clinical trials (in collaboration with
Tibotec/J&J)
Focus on once daily, low dosage and orally bioavailable drugs
Large network of preclinical and clinical specialist collaborators and CROs complementing internal
drug discovery and development
14
One focused pipeline March 2010
Project
Indication
Partner
Xerclear
Cold sores
Meda / US
MIV-606
Shingels
Epiphany
TMC435
HCV
J&J
MIV-210
HBV
Daewoong
HCV-POL
HCV
J&J
MIV-710/711
OA, OP, Cancer
MIV-410
HIV
Presidio
HIV-PI
HIV
J&J
Cathepsin S
Pain
BACE
Alzheimers
Preclinical
research
Preclinical
develop.
Phase I
Clinical development
IIA
IIB
Phase III
NDA Market
HCV - targets HCV
Anti infective
Other indications
15
Valomaciclovir - licensed to Epiphany Biosciences
Agreement
– Equity in Epiphany
– Milestone payments to USD 24.5 M
– Royalty from world wide sales
– Medivir has the marketing rights for the Nordic countries
– Epiphany responsible for the clinical development
Valomaciclovir (EPB-348)
•
A broad-spectrum herpes antiviral with high commercial prospects
•
Lead indication: Varicella Zoster (Shingles). Shingles sales in the major markets exceeded
0.8 billion USD in 2008
•
Develoment status:
– Completed Phase IIb trial, met primary endpoint, time to complete crusting, at once daily dosing
• Randomized, double-blind, active-controlled, multi-center, parallel-group (non-inferiority with
Valtrex as comparator) at 46 U.S. clinical centers including 373 patients
– Phase 2b data show reduction in incidence of PHN
– Data suggestive of wider treatment window
– Targeting 2012 regulatory submissions and 2013 launch in US and EU
•
EBV (infectious mononucleosis) – Phase IIa complete, met primary endpoint
16
MIV-210 (lagociclovir valactate) licensed to Daewoong
•
Agreement
– China, South Korea, Japan and Taiwan territories for HBV
– Daewoong responsible for the clinical development
– Medivir has the marketing rights for the rest of the world
•
Lagociclovir valactate:
– Potent inhibitor of HBV in vitro and in animal models
– Active against all tested HBV mutants, e.g. to lamivudine, adefovir, and entecavir
– Is synergistic with lamivudine and adefovir in vitro
•
Dose in HBV patients expected to be 10-20 mg q.d.
•
News flow and events in the upcoming 12 months
– Start of Phase 2a in HBV patients
17
Main partner – three programs:
HCV PI, TMC435
HCV-Pol
HIV-PI
Profile
A potent second generation protease inhibitor, QD dosing
Profile
A nucleoside NS5B inhibitor
Profile
Highly competitive CD target profile protease HIV inhibitor
Status
Phase IIb-trials in treatment naive patients ongoing
Phase IIb-trials in treatment experienced patients ongoing
Status
In preclinical development (IND) phase
Status
In preclinical lead optimization
Next step
Start of phase III-trials in treatment naive patients
Next step
Initiation of phase I trials
Next step
Selection of CD
Summary of the licensing agreements
All development costs covered by Tibotec / J&J
Remaining milestone payments for these programs of € 200m
Royalties on global sales
Nordic marketing and sales rights retained by Medivir
18
Hepatitis C (HCV) - background
Disease & market
• ~180 million worldwide infected with hepatitis C virus
• ~12 million infected in the US, Europe and Japan
• Immense medical need: only 40-50% of patients with genotype 1
respond to current SoC therapy (48 weeks of PEG-IFN/ribavirin)
• Estimated market value of 10.5 billion USD in 2015
The need for new drugs
• Increased SVR rates (cure rates)
• Improved safety and side effect profile
• Shorter duration of treatment
• Higher compliance
– lower drug burden and simplified dosing (once daily, no food
interaction and large “forgiveness” factor)
19
HCV- Future of new DAA agents; New treatments evolving
Programs in collaboration with Tibotec/JNJ
Directly Acting Antiviral (DDA) Agents
•
New oral agents will dramatically
increase SVR and shorten treatment
duration
•
Initially as “add-on” therapy but in
combination eventually displace one or
both of ribavirin and Peg-IFN
•
New anti viral agents with different MOA
will be used in combination with each
other, similar to HIV, to improve efficacy,
shorten treatment duration and minimize
development of resistance
- Combinations of Protease Inhibitors
with other direct antivirals will drive
the future market
•
Medivir, with TMC435 as a front runner of
this new wave, is strongly positioned to
become part of these future DAA
combination treatments
Kwong A, et al. Drug Discovery Today: Therapeutic Strategies 2006;3:211-220 Schmitz U, Tan SL. Recent Pat Antiinfect Drug Discov 2008;3:77-92
In-house HCV programs
20
Hepatitis C - Nucleoside NS5B Polymerase Inhibitors
Status
• Partnership entered with Tibotec/J&J May 2008
• Presently in late preclinical development phase
towards phase I clinical trials
Next step
• Start of phase I
Licensing agreement
• Remaining milestones of €137m + royalties on
sales for one product reaching market.
• Additional €130m for second compound and
indication reaching market + royalties on sales.
• All development costs covered by JNJ
• Nordic rights retained by Medivir
21
Development stage of HCV nucleosides
Ph I
Pre-clin
Ph Ib/IIa
Ph IIb
Ph III
NM-283
MK-0608
Biocryst
R-1626
First
generation
Biota/BI
Tibotec/Medivir
R-7128
Inhibitex
Idenix (IDX-184)
Roche
Second
generation
TMC619688 TMC651755
& prodrugs
PSI-938
PSI-879
Pharmasset PSI-7851
22
HCV Nucleoside program News flow and events in the upcoming 12 months
• Start of Phase I clinical trials
• Presentation of Phase I clinical trial data
• Presentation on antiviral potency, mechanism of action
and DAA synergy data
23
Cathepsin K inhibitors – for the treatment of osteoporosis,
osteoarthritis and metastatic bone disease (MBD)
Cathepsin K inhibitors intervene in
disease states where there is excessive
bone loss, e.g. osteoporosis,
osteoarthritis and metastatic bone disease
Osteoclast
Market value estimates:
• Osteoporosis: Global sales for 2010
estimated at 7.9 billion USD
•
Osteoarthritis: Global sales for 2010
estimated at 4.4 billion USD
•
MBD: Global bone metastasis market
was 1.3 billion USD in 2008. Deutsche
Bank projects a denosumab SRE
market of 2.1 billion USD in peak
sales
24
Medivir Cathepsin K inhibitor program
•
Two Candidate Drugs selected in 2009 (MIV-710 and MIV-711)
•
MIV-710 and MIV-711:
–
–
–
–
•
Dose in human
–
•
•
An efficacious dose of ~50 mg once daily anticipated
Strong IP position
A broad program targeting multiple indications of great unmet medical need
–
–
–
•
display superior pharmacokinetic properties compared with MIV-701 (discontinued) which
showed “proof-of-principle” in phase I clinical trials during 2007
exhibit potent and reversible anti-resorptive activity on bone
does not suppress the beneficial bone formation, as other anti-resorptives
furnish long duration of activity
osteoporosis, OP
osteoarthritis, OA
metastatic bone disease
News flow and events in the upcoming 12 months
–
–
Upscale of CD and completion of preclinical development phase
Partnering discussions
25
Medivir Cathepsin K Inhibitor CDs MIV-710 & MIV-711
% of baseline CTX-I
High efficacy predicted from biomarkers of osteoporosis
Reduction in plasma CTx-I, a biomarker of bone
breakdown, in cynomolgus monkeys after:
- Oral administration
- Single low dose
Treatment
Max
inhibition
(%)
Inhibition at
24h
(%)
Vehicle
56
2
MIV-701
64
22
MIV-710
75
51
MIV-711
95
75
140
120
Almost 100%
suppression of
osteoporosis bone
breakdown over 8h
100
80
Vehicle (n=10)
MIV-701 (n=5)
60
MIV-710 (n=7)
MIV-711 (n=4)
MIV-701
40
MIV-710
20
MIV-711
0
0
4
8
12
16
20
24
• Highly advantageous plasma exposure for
MIV-711 (128 fold higher compared with MIV-701)
• Almost complete inhibition of bone erosion with
extended effect duration (8h) after a single oral dose
• 75% of effect maintained after 24h
Time (h)
A clinical efficacious once daily dose of ~50 mg – low cost of gods
26
PPI-801/802 (MIV-410):
For the treatment of HIV – licensed to Presidio Pharmaceuticals
•
Agreement
–
–
–
–
•
PPI-801/802 (formerly called MIV-410):
–
–
•
Nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action. PPI-801
is a non-obligate chain terminator being incorporated into the nascent cDNA chain and
terminates at a penultimate position following the addition of at least one additional
nucleoside
Broad-spectrum activity: is effective at inhibiting a wide variety of NRTI resistant mutants
Indication
–
–
•
Milestone payments of maximally USD 41.75m
Royalty from world wide sales
Presidio responsible for the preclinical & clinical development
Medivir has the marketing rights for the Nordic countries
Treatment failures from HAART
First-line therapy for newly infected individuals
News flow and events in the upcoming 12 months
–
Completion of preclinical development phase
27
HIV-PI Program
Disease & market
• An estimated 35 M people worldwide were infected by HIV, of which a total of
approximately 2 M people in Western Europe and North America
• In an increasing number of patients, HIV is developing resistance
• There is no cure
• Estimated market value for HIV/AIDS: 12.7 Bn USD in 2010
R&D collaboration with Tibotec/J&J Collaboration
•
•
•
Agreement entered in June 2006
Research funding at Medivir up to December 2008
Development milestones & royalties similar to
HCV PI license agreement
•
Highly competitive CD target profile
Extensive non-limiting patent portfolio
•
News flow and events in the upcoming 12 months
•
Selection of candidate drug (CD) and start of
preclinical development
28
Cathepsin S Inhibitors - for Neuropathic pain and RA
•
Strong link to neuropathic pain
–
–
•
Strong link to RA
–
–
–
•
upregulated in DRG infiltrating macrophages and near
site of peripheral injury in rodent models
secreted by activated microglial cells in CNS in rodent
models
crucial role in MHC Class II antigen presentation
performs final step in processing of invariant chain
antigen presentation is key to establishing an immune
response
Medivir Cathepsin S program
–
–
–
Strong IP (patent) position
Potent, selective and orally bioavailable inhibitors
developed
Proof-of-principle has been demonstrated for Medivir
lead inhibitor in a preclinical rodent model of
neuropathic pain
•
News flow and events in the upcoming 12 months
–
–
Candidate Drug Selection
Start licensing discussions
A cathepsin S inhibitor acting by reducing microglial activation
leads to decrease in the pain signal transduction and eleviate
neuropathic pain.
29
BACE Inhibitors for the treatment of
Alzheimer’s disease (AD)
Disease and market
• Around 35 million AD cases world-wide today with a
three fold increase to 105 million AD cases expected
by 2050
• Life expectancy from diagnosis: Approx. 10 years
• The annual costs for AD is estimated to 148 billion USD
Reduced brain volume
Neuronal cell death
Synaptic degeneration
Plaque (Amyloid β-peptide)
Drugs available today
 No available drugs cures/prevents the disease
 A few drugs cause transient symptomatic relief
– Acetylcholine esterase inhibitors
– Glutamate antagonist
30
BACE Inhibitors - The leading hypothesis for next generation AD drugs
•
Project status: lead optimization stage
•
Novel and patentable lead series developed
•
Focus on two validated lead series
•
Strong IP (patent) position
•
Potent and selective BACE inhibitors
•
•
•
•
Lead inhibitors display robust potencies
Ki values <1 nM against BACE and IC50 values < 1 nM in cell-based assays
measuring Aβ40 release
orally bioavailable and displaying drug-like properties
News flow and events in the upcoming 12 months
•
•
•
Demonstration of high central exposure after oral administration in rodents
Afford substantial efficacy in AD disease models after oral administration
Start licensing discussions
31
Main partner – three programs:
HCV PI, TMC435
HCV-Pol
HIV-PI
Profile
A potent second generation protease inhibitor, QD dosing
Profile
A nucleoside NS5B inhibitor
Profile
Highly competitive CD target profile protease HIV inhibitor
Status
Phase IIb-trials in treatment naive patients ongoing
Phase IIb-trials in treatment experienced patients ongoing
Status
In preclinical development (IND) phase
Status
In preclinical lead optimization
Next step
Start of phase III-trials in treatment naive patients
Next step
Initiation of phase I trials
Next step
Selection of CD
Summary of the licensing agreements
All development costs covered by Tibotec / J&J
Remaining milestone payments for these programs of € 200m
Royalties on global sales
Nordic marketing and sales rights retained by Medivir
32
Lead HCV compound TMC435 in phase IIb
A leading, second generation protease inhibitor
• > potency than 1st generation PIs (telaprevir,
boceprevir)
• Potent anti-viral activity shown in Phase IIa clinical
trials
• Low pill burden: convenient one pill, once daily
• No food interactions
• No significant adverse events over current SoC
Licensing agreement
•
Remaining milestones of EUR 47m
•
Royalties on market sales
•
All development costs covered by Tibotec
•
Nordic rights retained by Medivir
33
HCV PI – the competitive landscape
Pre-clin
Ph I
Ph Ib/IIa
TMC435
J&J/ Medivir
Protease Inhibitors
VBY 376
ABT-450
ACH-1625
Ph III
Telaprevir
J&J/Vertex
ITMN-191/R7227
Roche/ITMN
Vertex-813
PHX-1766
Ph IIb
BI 201335
Boceprevir
Merck
BMS650032
Vaniprevir
MK7009
Merck
SCH900518
TMC435 - the leading second generation HCV PI: 1) potent 2) well tolerated 3) low dose 4) one pill and 5) once daily
34
TMC435 C201:
A phase 2a study in treatment-naïve and treatment-experienced patients
(2008/09)
A once daily (QD) treatment of TMC435 in doses from 25 to 200 mg + SoC
Four-week triple therapy, then followed by SOC alone up to week 24 or 48
35
35
TMC435 C201: Potent antiviral activity in treatment-naïve patients
achieved at week 4 (RVR) and at week 12 (EVR)
<10
IU/mL
>10 - <25
IU/mL
100
At week four:
• 8/9 and 7/10 patients were undetectable in the
75 and 200 mg groups respectively (Panel B)
Patients (%)
80
60
8/9
7/10
75 mg
200 mg
40
At week 12:
• 100% of the patients in the once daily 75 mg and 200 mg
arms (Panel B) had HCV RNA <10 IU/mL (undetectable)
20
0
Placebo
n=8
25 mg
n=9
Panel B
n=9
n=8
4-week treatment = 4-weeks of TMC435 + SoC
12-week treatment = 4-weeks of TMC435 + SoC,
then followed by 8-weeks of SoC alone
TMC435 QD
36
TMC435 C201: Results in treatment-experienced patients
- Solid antiviral activity achieved at week 4 (RVR)
7/9 patients levels below LLQ (<25 IU/mL) at 150 mg & 8/10 for 200 mg at day 28
37
TMC435 C201: Results from Cohort 5 in treatment experienced
patients; an open label study
Cohort 5 comprised prior non-responders and
relapsers to interferon (IFN)-based therapy who
had previously received 5 days of monotherapy
with TMC435 200 mg once daily (QD) in a Phase Ib
trial (Study C101).
4/5 patients completed triple therapy
with TMC435 200 mg QD whilst one patient
discontinued due to increased blood bilirubin
(patient with high bilirubin levels at entry)
No viral breakthroughs (defined as >1 log10 IU/mL
Increase from nadir in HCV RNA) were observed
within 4 weeks
Results at Day 28:
•
Potent antiviral activity
•
All four patients who completed treatment achieved HCV RNA below the limit of quantification (<25 IU/m)
•
Three of four patients had HCV RNA below the limit of detection (<10 IU/mL)
38
C201: Conclusions from the phase 2a study
In both treatment-naïve and treatment-experienced patients infected with HCV
genotype-1, TMC435 once daily in combination with SoC over 4 weeks of
treatment.
• Demonstrated potent antiviral activity
• Was generally safe and well tolerated
• Was not associated with AE-related treatment discontinuations.
• Mild and reversible increases in bilirubin was observed. This was mainly
observed in the highest dose groups (200 mg), whereas the highest dose in
the ongoing phase 2b studies is 150mg. The mechanism of action has been
determined and will be presented at an upcoming conference
• No evidence of any drug-related hepatotoxicity
39
C205: A global phase 2b study in treatment-naïve HCV patients;
Study Start Date: May 2009
- Once daily (QD), 75mg and 150 mg, of TMC435 + SoC:
- 12-week triple therapy followed by SOC alone up to week 24
- 24-week triple therapy
Time (weeks)
8
12
48
24
72
Weeks
TMC 75 mg, 12W
Triple
PEG-IFN
+ RBV
Post therapy FU
TMC 150 mg, 12 W
Triple
PEG-IFN
+ RBV
Post therapy FU
TMC 75 mg, 24W
Triple Therapy
Post therapy FU
TMC150 mg, 24W
Triple Therapy
Post therapy FU
12W Triple + 12W SoC
24W Triple
SoC
PEG-IFN + RBV
Post therapy FU
48W SoC
N = 400
Primary endpoint: Proportion of patients with undetectable virus levels 24 weeks after planned end-of-treatment (SVR24)
SoC: Ribavirin 1000-1200 mg BID + pegIFNalpha-2A 180 g weekly
C206: A global phase 2b study in treatment-experienced HCV patients
Study Start Date: September 2009
- Once daily (QD), 100 mg and 150 mg, of TMC435 + SoC:
- triple therapy for 24-weeks followed by 24-weeks SOC
- triple therapy for 48-weeks
12
TMC435 100 mg, 12W
TMC435 150 mg, 12W
TMC435 100 mg, 24W
TMC435 150 mg, 24W
TMC435 100 mg, 48W
TMC435 150 mg, 48W
SoC, 48W
48
24
72
1
Triple Therapy
PEG-IFN + RBV
Post therapy FU
2
Triple Therapy
PEG-IFN + RBV
Post therapy FU
3
Triple Therapy
PEG-IFN + RBV
Post therapy FU
4
Triple Therapy
PEG-IFN + RBV
Post therapy FU
5
Triple Therapy
Post therapy FU
6
Triple Therapy
Post therapy FU
7
PEG-IFN + RBV
Post therapy FU
TMC435 100 mg q.d.
Weeks
TMC435 150 mg q.d.
N = 455
Primary endpoint: Proportion of patients with undetectable virus levels 24 weeks after planned end-of-treatment (SVR24)
SoC: Ribavirin 1000-1200 mg BID + pegIFNalpha-2A 180 g weekly
TMC435 – other phase 2 clinical trials
•
C215: a phase IIb study in Japan in treatment naïve genotype-1 HCV patients
– Study Start Date: June 2009
– Patients will receive TMC435 (50 or 100 mg) for a duration of 12 or 24 weeks.
– In treatment arms 1 and 2, subjects will receive 12 weeks of triple therapy with
TMC435 once daily plus SoC followed by 12 weeks of treatment with SoC.
– In treatment arms 3 and 4, patients will receive 24 weeks of triple therapy with
TMC435 once daily plus SoC.
– In treatment arm 5 (control group), patients will be treated with SoC treatment for
48 weeks
•
C202: in treatment naïve genotype 2 to 6 HCV patients
– Study Start Date: February 2009
– Study Completion Date: November 2009
– Patients will receive TMC435 during 7 days, once daily dosing at 200mg, as
monotherapy. Subsequently, they can continue with SoC treatment consisting of
pegylated interferon and ribavirin upon agreement with the study doctor
42
TMC435: News flow and events in the upcoming 12 months
•
C205:
Presentation of data from the phase IIb study in treatment naïve genotype-1 HCV
patients
•
Phase III
Start of phase III in treatment naïve genotype-1 HCV patients
•
C206:
EOT data from the phase IIb study in treatment experienced genotype-1 HCV patients
•
C215:
Presentation of data from the phase IIb study in treatment naïve Japanese genotype-1
HCV patients
•
C202:
Presentation of data from the phase IIa study in treatment naïve genotype 2 - 6 HCV
patients
•
Presentation of mechanism of action (MOA) behind the transient reversible increases in
bilirubin seen in some patients (mainly in the 200 mg dose arm)
•
Presentation of in vitro data on synergy between TMC435 and other DAA agents
43