Cowen Healthcare presentation March 13th 2018 - Silence ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Cowen Healthcare presentation March 13th 2018
Disclaimer
The information contained in this presentation is being supplied and communicated to you on a Securities in the Company have not been, and will not be, registered under the United States
confidential basis solely for your information and may not be reproduced, further distributed to Securities Act of 1933, as amended (the “Securities Act”), or qualified for sale under the law of
any other person or published, in whole or in part, for any purpose. any state or other jurisdiction of the United States of America and may not be offered or sold in
the United States of America except pursuant to an exemption from, or in a transaction not
The distribution of this presentation in certain jurisdictions may be restricted by law, and subject to, the registration requirements of the Securities Act. Neither the United States
persons into whose possession this presentation comes should inform themselves about, and Securities and Exchange Commission nor any securities regulatory body of any state or other
observe, any such restrictions. Although reasonable care has been taken to ensure that the jurisdiction of the United States of America, nor any securities regulatory body of any other
facts stated in this presentation are accurate and that the opinions expressed are fair and country or political subdivision thereof, has approved or disapproved of this presentation or the
reasonable, the contents of this presentation have not been verified by Silence Therapeutics securities discussed herein or passed on the accuracy or adequacy of the contents of this
plc (the “Company”) or any other person. Accordingly no representation or warranty, express or presentation. Any representation to the contrary is unlawful.
implied, is made as to the fairness, accuracy, completeness or correctness of the information
and opinions contained in this presentation and no reliance should be placed on such Safe Harbour statement: this presentation may contain forward-looking statements that reflect
information or opinions. None of the Company, or any of its respective members, directors, the Company’s current views and expectations regarding future events. In particular certain
officers or employees nor any other person accepts any liability whatsoever for any loss statements with regard to management’s strategic vision, aims and objectives, the conduct of
howsoever arising from any use of such information or opinions or otherwise arising in clinical trials, the filing dates for product licence applications and the anticipated launch of
connection with this presentation. No part of this presentation, or the fact of its distribution, specified products in various markets, the Company’s ability to find partners for the
should form the basis of or be relied upon in connection with any contract or commitment or development and commercialisation of its products as well as the terms for such partnerships,
investment decision whatsoever. This presentation does not form part of any offer of securities, anticipated levels of demand for the Company’s products (including in development), the effect
or constitute a solicitation of any offer to purchase or subscribe for securities or an inducement of competition, anticipated efficiencies, trends in results of operations, margins, the market
to enter into any investment activity. Recipients of this presentation are not to construe its and exchange rates, are all forward looking in nature.
contents, or any prior or subsequent communications from or with the Company or its
representatives as investment, legal or tax advice. In addition, this presentation does not Forward-looking statements involve risks and uncertainties that could cause actual results to
purport to be all-inclusive or to contain all of the information that may be required to make a full differ materially from those expressed or implied by the forward looking statements. Although
analysis of any transaction. Further, the information in this presentation is not complete and not exhaustive, the following factors could cause actual results to differ materially from those
may be changed. Recipients of this presentation should each make their own independent the Company expects: difficulties inherent in the discovery and development of new products
evaluation of the information and of the relevance and adequacy of the information in this and the design and implementation of pre-clinical and clinical studies, trials and investigations,
document and should make such other investigations as they deem necessary. delays in and results from such studies, trials and investigations that are inconsistent with
previous results and the Company’s expectations, the failure to obtain and maintain required
regulatory approvals, product and pricing initiatives by the Company’s competitors, inability of
the Company to market existing products effectively and the failure of the Company to agree
beneficial terms with potential partners for any of its products or the failure of the Company’s
existing partners to perform their obligations, the ability of the Company to obtain additional
financing for its operations and the market conditions affecting the availability and terms of
such financing, the successful integration of completed mergers and acquisitions and
achievement of expected synergies from such transactions, and the ability of the Company to
identify and consummate suitable strategic and business combination transactions and the
risks described in our most recent Admission Document.
By participating in this presentation and/or accepting any copies hereof you agree to be bound
by the foregoing restrictions and the other terms of this disclaimer.
© Silence Therapeutics 2018 2
Silence Therapeutics - Overview
> Developing RNA interference (RNAi) therapeutics, a highly innovative, specific, new class of
medicines with life-saving potential for patients with serious and rare diseases
> Only quoted European RNAi drug development Company
> Proprietary platform technology builds on years of scientific research and in-house know-how
> Liver focussed – >7,000 genes are expressed in hepatocytes, many of which are therapeutic
targets
> Validating licensing agreement with Quark Pharmaceuticals
> Lead pre-clinical development programme for iron overload disorders (IOD)
> Led by an international, sector-experienced Board and Executive Team
> 30 people in Berlin (R&D) and 15 people in London (Corporate and R&D)
> Explore options to expand our international capital market presence, including the potential for a
NASDAQ listing
> Traded on the LSE:AIM – £138 million/$190 million mkt cap* with strong cash runway (£43
million as of 2 January 2018)
* 5 March 2018 price & conversion
© Silence Therapeutics 2018 3
Experienced Leadership Team: Strong Background
in Discovery & Development of RNA Therapies
Ali Mortazavi, Torsten Hoffmann, Ph.D. David Ellam,
Chief Executive Officer Chief Operating Officer Chief Financial Officer
Since 2012 Since 2017 Since 2016
Dmitry Samarsky, Ph.D. Laura Roca-Alonso, Ph.D. Michael Mulqueen,
Chief Scientific Officer Head of Corporate Head of BD & Licensing
Development
Since 2016 Since 2014 Since 2017
Alison Gallafent, Ulrich Zugel, Ph.D. Linnea Elrington,
Head of Intellectual Head of Pre-Clinical Drug Head of Human Resources
Property Discovery
Since 2017 Since 2016 Since 2017
© Silence Therapeutics 2018 4
GalNAc-siRNA Platform Technology © Silence Therapeutics 2018 5
GalNAc-siRNA Medicines
Schematic structure of our therapeutic molecules:
Linker
Binds siRNA to delivery moiety
Chemical A C G U U C G A C C G A A G U C A
modifications U G C A A G C U G G C U U C A G U
siRNA GalNAc (N-Acetylgalactosamine)
Mediates gene silencing Mediates targeted delivery to hepatocytes
How do we ensure that our medicines are protected and free to use?
> GalNAc as a targeting ligand per se is free to use
> We have a robust position for our foundational chemical modification technology
> We patent our linker chemistries
> We patent our potent and highly specific siRNA constructs and lead sequences
© Silence Therapeutics 2018 6Platform Performance
Platform technology: GalNAc-siRNA, able to mediate highly specific
gene silencing in hepatocytes (liver) – “Specificity upon specificity”
~7,000 genes operate in the liver. We can target any of them by adapting
the siRNA sequence, using the same technology
Target 1 Target 2 Target 3 Target 4
N o r m a lis e d ta r g e t m R N A
N o r m a lis e d ta r g e t m R N A
N o r m a lis e d ta r g e t m R N A
N o r m a lis e d ta r g e t m R N A
1 .0 1 .0 1 .0 1 .0
0 .5 0 .5 0 .5 0 .5
0 .0 0 .0 0 .0 0 .0
CTRL s iR N A 1 PBS s iR N A 2 CTRL s iR N A 3 CTRL s iR N A 4
We are able to reproducibly silence disease-causing genes using our platform technology
Single SC dose of 2-3 mg/kg in healthy mice; analysis after 1-2 weeks
© Silence Therapeutics 2018 7Advantageous Properties of Medicines
> Subcutaneous administration, patient friendly
> Long duration of action (variable depending on target gene)
> Well tolerated
> Our GalNAc-siRNA medicines are suitable for a wide range of indications
Target KD induction
Trend toward
recovery to
baseline levels
NADIR
© Silence Therapeutics 2018 8SLN124 for the treatment of Iron Overload Disorders A case study of our platform © Silence Therapeutics 2018 9
Treatment of Ion Overload Disorders (IOD)
GOAL
> Provide an effective and safe novel treatment option for patients with iron
overload conditions, such as β-Thalassemia
RATIONALE
> Target a key modulator in iron regulation with a GalNAc-siRNA molecule
providing a highly specific, effective & safe option through inhibition of a
disease relevant target gene expressed in hepatocytes
CURRENT STAGE
> Preclinical development with plans to enter clinical development in
Q4/2018
© Silence Therapeutics 2018 10TMPRSS6 is a Negative Regulator of Hepcidin and
Plays a Key Role in Iron Homeostasis
Normal hepcidin levels control iron release hepcidinlevels,
Low hepcidin levels, asβ-Thalassemia
as in in β-Thalassemia
from cellular stores & intestinal uptake result in high iron levels & overload in organs
Liver Duodenal
Enterocytes Liver Duodenal
Enterocytes
TMPRSS6 TMPRSS6
Hepcidin Hepcidin
IRON IRON
SLN124
Macrophages Erythropoiesis Macrophages Erythropoiesis
Red blood Red blood
cells cells
Silencing 1 Increases 2 Reduces iron 3 Improves 4 Reduces organ
TMPRSS6 hepcidin levels levels erythropoiesis iron overload
TMPRSS6 = Transmembrane Protease, Serine 6
© Silence Therapeutics 2018 11siRNA Screen and GalNAc Conjugate Testing in
Primary Hepatocytes
TMPRSS6 mRNA TMPRSS6 mRNA
N o r m a lis e d T M P R S S 6 m R N A
1° Hep (mouse)
(in vitro screen – Selected siRNAs) 1 .0 (receptor-mediated uptake)
0 .5
1.5 h Hep3B cells
Normalised TMPRSS6 mRNA
0 .0
0 .0 1 0 .1 1 10 100 1000
G a lN A c T M P R S S 6 s iR N A [n M ]
1.0
Lead 1° Hep (cyno)
1° Hep (human)
N o r m a lis e d T M P R S S 6 m R N A
N o r m a lis e d T M P R S S 6 m R N A
0.5 1 .0 1 .0
0 .5
0.0 0 .5
4 14 10 3 11 6 8 13 12 15 1 5 2 7 9
UTLuc TMPRSS6 siRNA
0 .0
0 .0
0 .0 1 0 .1 1 10 100 1000
0 .1 1 10 100 1000
G a lN A c T M P R S S 6 s iR N A [ n M ]
G a lN A c T M P R S S 6 s iR N A [ n M ]
> Lead siRNA for TMPRSS6 identified (picomolar IC50 by transfection)
> GalNAc-siRNA conjugate is functional in primary hepatocytes from different species (mouse,
human, cynomolgus)
© Silence Therapeutics 2018 12Silencing TMPRSS6 Lowers Serum Iron Levels
in Mice
Study design
d1 d4
SC, n=4-6 mice
TMPRSS6 mRNA (liver) Hepcidin mRNA (liver) Iron (serum)
4 40
N o r m a lis e d T M P R S S 6 m R N A
N o r m a lis e d H e p c id in m R N A
1 .0
S e r u m ir o n [µ m o l/L ]
3 30
2 20
0 .5
1 10
0 .0 0 0
10 1 3 1 0 m g /k g 10 1 3 1 0 m g /k g 10 1 3 1 0 m g /k g
CTRL TMPRSS6 s iR N A CTRL TMPRSS6 s iR N A CTRL TMPRSS6 s iR N A
> Single subcutaneous administration results in specific KD of TMPRSS6
> Upregulated Hepcidin causes reduction of blood iron levels
> Proof of mechanism demonstrated
© Silence Therapeutics 2018 13SLN124 Lowers Iron Levels for at Least 6 Weeks
After Single Administration in Mice
Study design
d1 wk 1 wk 3 wk 6
SC, n=4 mice, 3 mg/kg
TMPRSS6 mRNA (liver) Iron (serum)
40
N o r m a lis e d T M P R S S 6 m R N A
1 .0
S e ru m iro n [µ m o l/L ]
30
20
0 .5
10
0 .0 0
1 1 3 6 w eeks 1 1 3 6 weeks
PBS T M P R S S 6 s iR N A PBS T M P R S S 6 s iR N A
> Long-lasting functional mRNA KD in liver
> Reduction of serum iron levels for at least 6 weeks
> Well tolerated with long duration of action in mice
© Silence Therapeutics 2018 14Therapeutic Activity of SLN124 in Iron Overload
Model (HFE -/- mice)
Collaboration with Study design
d1 wk 3
Prof. Dr. Martina Muckenthaler
University of Heidelberg, Germany SC, n=6-7 mice
TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum)
2 .0 800
N o r m a lis e d T M P R S S 6 m R N A
S e r u m H e p c id in [ n g /m L ]
300
S e r u m Ir o n [ µ g /d L ]
1 .5 600
200
1 .0 400
100
0 .5 200
0 .0 0 0
3 1 3 m g /k g 3 1 3 m g /k g 3 1 3 m g /k g
PBS CTRL TM PRSS6 s iR N A PBS CTRL TM PRSS6 s iR N A PBS CTRL TM PRSS6 s iR N A
Iron (kidney) > Dose-dependent and robust silencing of TMPRSS6
240 mRNA in the liver
[ µ g Ir o n /g d r y t is s u e ]
220
> Increase in serum hepcidin levels
200
180 > Reversion of serum and kidney iron levels to
100 physiological values
0
3 1 3 m g /k g
PBS CTRL TM PRSS6 s iR N A
© Silence Therapeutics 2018 15SLN124 Normalises ROS Species & Improves RBC
Parameters in β-Thalassemia Disease Model
Study design
Collaboration with d1 wk 2 wk 5
Prof. J. Vadolas & Dr. Grigoriadis
Monash Medical Centre/Melbourne, Australia SC, n=6-8 Hbbth3/+ mice
Reactive oxygen species (ROS) Reticulocyte proportion Haematocrit
800 25 60
R e tic u lo c y te s [% ]
500
H a e m a to c rit [% ]
20
50
M e d ia n F I
400
15
300
10 40
200
100 5 30
0 0 0
- PBS C T R L T M P R S S 6 s iR N A - PBS C T R L T M P R S S 6 s iR N A - PBS C T R L T M P R S S 6 s iR N A
W T m ic e T h 3 /+ m ic e W T m ic e T h 3 /+ m ic e W T m ic e T h 3 /+ m ic e
> Normalisation of ROS to levels in healthy mice
> Normalisation of reticulocyte proportion and improvement of haematocrit
> SLN124 significantly improves erythropoiesis in animal model for
β-Thalassemia intermedia
ROS = reactive oxygen species; RBC = red blood cells
© Silence Therapeutics 2018 16Feedback by Key Opinion Leaders on SLN124
International KOL workshop with clinical and regulatory experts in the
field of iron overload disorders
> High medical need to reduce iron overload and number of
transfusions in patients
> Not met by currently available therapies
> SLN124 has the potential to
> Reduce systemic iron
> Prevent organ iron overload
> Enhance erythropoiesis
... providing a significantly improved therapeutic option and better
quality of life for patients living with iron overload conditions, such as
β-Thalassemia
© Silence Therapeutics 2018 17Market Opportunity of SLN124 (US & Europe)
β-Thalassemia intermedia &
T. major (TDT)
> Combination with transfusions
& chelators to reduce
frequency & dose 40,000 20,000
> Improve erythropoiesis and TDT NTDT
reduce secondary iron overload
burden
β-Thalassemia intermedia (NTDT) >150,000
> Monotherapy to delay onset of MDS
severe symptoms
> Reduce dietary iron overload &
subsequent organ damage >3,000,000
Haemochromatosis
Other iron overload disorders
Myelodysplastic Syndrome (MDS)
Haemochromatosis *US & Europe
SLN124 for β-Thalassemia with significant upside potential for other
iron overload disorders
TDT = transfusion dependent Thalassemia; NTDT = non-transfusion dependent Thalassemia
© Silence Therapeutics 2018 18Why we are Excited about SLN124?
Science Indication Patient Market
What does the Mode of How does the science What is the patient When and where do we
action bring? connect to the diseases? benefit? want to market it?
2018: Gene silencing via siRNA is a beta-Thalassemia SLN124 has the potential to become First In Class in iron overload
proven concept Myelodysplastic Syndromes an essentialcomponent of
Potential for Haemochromatosis the future SoC High value product with peak
sales of $600 million (BT) and
SLN124 has proven to QoL parameters will be $3 billion (MDS)
Central role of hepcidin
increase hepcidin and improved such as transfusion
enables lowering of iron frequency and drug burden of chelators
reduce iron plasma levels, plasma levels, optimising Launch would be expected
thus restoring iron homeostasis
erythropoiesis Enables an early treatment option for
by 2024/25 via an Orphan
designation
the prevention of iron
The GalNAc conjugate deposition in organs
A corporate strategy is required to
targets hepatocytes in the Mechanistic claim – access geographies in the
liver, acting specifically at hepcidin’s treatment of iron overload disorders
Pediatrics and adults will middle and far east
predominant synthesis site be treated
SLN124: a treatment in the We are seeking
SLN124 is highly specific mono- or combination We will work with patient commercialisation
targeting a single gene therapy setting as new SoC organisations in 2018 partnerships
© Silence Therapeutics 2018 19Pipeline - Building a Proprietary Portfolio
Internal programmes advanced into preclinical development
Our Programmes
SLN124 4Q2018
SLN124
Mid 2019
Mid 2019
SLN226
Out-Licensed Programmes
SLN226
© Silence Therapeutics 2018 20Platform Strategy
~7,000 accessible gene targets…We have the technology and the team to discover
and develop a wide range of therapeutics
Target & Indication In silico In vitro KD POM*
Disease pPOC**
NCD, CMC, CTA*** Phase I ...
Selection selection screen in vivo models Regulatory
Cost: $ $ $ $ $
We intend to strategically partner our programmes at different stages to fully unlock
the value of our platform – Rapid path to value creation
Phase 1/Phase 2
CTA/IND enabling
Disease model (pPOC)
Healthy animals (POM)
* proof of mechanism in healthy mice
Technology deals ** proof of concept in animal disease model
*** clinical trial application
© Silence Therapeutics 2018 21Outlook: Significant Milestones for the Next 12 months 2018 will be a year of continuity and building upon success to capture value by executing on pipeline development and leveraging its platform > File clinical trial approval for iron overload by end of 2018 > Add further development expertise to the senior team as pipeline progresses > Secure further validating collaborations utilising our GalNAc platform technology > Add new targets to pipeline, and utilise next generation technology > Continue defensive UK litigation action © Silence Therapeutics 2018 22
You can also read
