Switching off inflammation - 1st program: to prevent formation of a scar Mike J. Davies, MD, FRCS - RESI ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Switching off inflammation
1st program: to prevent formation of a scar
Mike J. Davies, MD, FRCS
CEO, Carocell Bio Inc
mike.davies@carocellbio.com
+1-919-408-7121
The Problem: inflammation leads to scar formation
Nothing currently PREVENTS the
formation of a scar
It is widely known that inflammation is
the cause of scaring. Inflammation is
seen as redness after a surgical incision
$37 billion dollar market to manage
existing scars and not one solution truly
eliminates the scars
Recognized need for safe and effective
scar prevention treatment
Carocell Bio’s unique product: JEL3108
OTC creams & oils will be steroid-free and safe
2
Current standards of care to Reduce Scaring (nothing PREVENTS Scaring)
Therapy for scar treatment
Plastic surgery Scar revision surgery 2nd most common plastic surgical procedure
Skin camouflage Make-up Waterproof camouflage can stay in place for 2-3 days
Silicone gels or sheets Silicone gels or sheets should be placed over the scar Treatment for 12 hours a day for at least 3 months
Steroids Corticosteroid injections can be used to treat some keloid and Injections are usually given for several months of treatment
hypertrophic scars
Laser therapy Pulses of light can reduce the redness in a scar by targeting No long-term studies to prove the effectiveness/safety of laser
the blood vessels therapy
Cryotherapy Liquid nitrogen can be used to freeze keloid scars Can lighten the colour of the skin
Dermal fillers "plump up" pitted scars Costly and usually temporary
Skin needling Rolling a small device covered in hundreds of tiny needles Variable results
across the skin
Surgery with / without skin graft Making it appear more natural / less noticeable Invasive
Pressure dressings Aim is to flatten and soften the scars 6-12 month treatment 24 hours a day
Creams E45 cream Makes scar supple
Vitamin D cream Unproven
JEL3108 works with a novel mode-of-action and delivery method
It will be a first-in-class therapy and a short treatment for patients
3
Our Solution is…
Simplified LPS/UV
MAPK p38⍺
• Topical delivery of p38a- cascade
Feedback
inhibitor Extracellular
Stimuli
• Prevent scar formation by
stopping inflammation
cascade early on! MAPKKK MAPKKK
IL-6
Target for MAPKK IL-1β
• Stop collagen deposition MAPK p38⍺
MAPKK TNFα
that creates a scar inhibitors, MAPK p38α
high up in the
• Gives increased safety inflammatory
cascade
margin over small Nuclear MK2
IL-6
molecules by using Substrates IL-1β TNFα
peptide
p38α is a key modulator of the Inflammation
5 Cascade that blocks collagen deposition
The Proof Points – work already done
• We deliver JEL3108 into
cytoplasm of cell using Area JEL3108 binds
safe nanoparticle delivery in docking studies
• We deliver the peptide
into dermis of skin
• Docking studies show
JEL3108 with a
JEL3108 binds in the
fluorescent tag in
substrate groove of p38α the cells’ cytoplasm
• We have shown novel
modulation vs traditional
small molecule p38α
inhibitors
JEL3108 delivered into
6 dermis of skin
JEL3108 Novel Peptide Significantly Reduces Levels of the Inflammation
Index (TNF-⍺) in Cellular Studies
1400
1200
Inflammation Index
1000
TNF-α (pg/ml)
800
600
400
200
0
LPS100
+ 100 LPS10+ 10 LPS1 + 1 LPS0+ 0 Control
Control (no
Concentration of peptide (ng/ml) after stimulation with LPS LPS)
TNF-⍺ is a pro-inflammatory cytokine that is a recognized marker of inflammation.
On exposure to the peptide, TNF-⍺ levels significantly reduced in cellular studies
indicating a significant reduction in inflammation
LPS, lipopolysaccharide; TNF, tumor necrosis factor
7
JEL3108 Peptide Inhibits the Activation and Activity of p38⍺ in Cellular Studies
Activation of p38⍺ is a critical step in the inflammation cascade
Levels significantly reduced in cellular studies when exposed
to the Jel-3108 peptide and NP combination
Prevention of activation of MAPK
1.4 All doses tested - [100nM (the
1.2 minimum effective dose - prevent
Activated MAPK
the activation of inflammation
Phospho/p38α
1
(Phospho/p38a)
0.8
0.6
0.4
0.2
0
0 100 300 1000
Concentration of peptide (nM)
Cells were analyzed for active (phospho)-MAPK p38α by immunoprecipitation and immunoblotting using Sigma p38 MAPK activity assay kit (product number CS02050)
MAPK, Mitogen-activated protein kinase
8
Demonstrates High Specificity and Selectivity of lead peptide for p38⍺ in
Biochemical Assays
JnnK Cdk2 Prak Chk1 EGF Src Fak Mek Akt
Selectivity over related enzymes
(kinases) very important in
>10 >10 >10 >10 >10 >10 >10 >10 ~10
preventing unwanted side effects
Kdr Jak3 Egfr ZAP70 CSK IGFR p38β p38⍺
7 7 4 4 3 0.95 0.450 0.003
Kinase inhibition (uM)
The Jel-3108 peptide was screened against a panel of 30 kinases in biochemical assays. Results
showed high selectivity and specificity for p38α
Akt, protein kinase B; CDK2, cyclin-dependent kinase 2; CHK1, checkpoint kinase1; CSK, C-terminal Src kinase; EGF, epidermal growth factor; EGFR, epidermal growth
factor receptor; FAK, focal adhesion kinase; IGFR, insulin-like growth factor receptor; JAK3, Janus kinase 3; JNK, c-Jun N-terminal kinase; KDR, kinase insert domain; MEK,
mitogen-activated protein kinase; p38, p38 mitogen-activated protein kinase; PRAK, p38-regulated/activated protein kinase; Src, Src kinase; ZAP70, zeta chain-associated
protein kinase 70
9
Crystal structure of diphosphorylated
p38α ‘ACTIVE’ MAP kinase (pdb: 3py3)
The Detail
• Novel Binding
Phosphorylation • Novel Mode of
Action
Phosphorylation
• Novel delivery into
cells
• Complete & ‘local’
shutdown of the
p38α pathway
JEL3108 Novel nanoparticle delivery system will get our payload into cells
Novel binding mode blocks the inflammation three-fold:
(1) JEL3108 locks p38α autoactivation by TAB1
(2) Blocks p38α activation by MKK3, MKK4, and MKK6 (upstream)
(3) JEL3108 sterically blocks p38α substrates getting phosphorylated (downstream)
10
The Carocell Bio Product
• Safe, sterile, spray formulation applied at the time
of incision closing and used daily, on the site, for
up to a week – so it is a short and painless
treatment cycle
• Nanoparticles in the spray promote skin
absorption and uptake by cells to release the
unique, patented, novel binder which adhere to
the target
• Release the unique, patented, novel peptide
binder which adheres to the target
• Ameliorates the inflammatory process, reduces &
stops the collagen deposition thus preventing the
formation of a scar
11The Current Market - what people spend on scar reduction
$37bn
234-million
operations
world-wide
(2019)
12Traction
• 3 Patents issued
• USA, EU, Japan (Pending – China)
• Cellular studies completed
• Human tissue biopsies ongoing
• Big pharma excited – we need your help to get there
14Team
Mike Davies John Nicholson Ann Mackey Graham Combe
MD, University of Edinburgh MA, University of Cambridge BA, Vanderbilt University BSc (Hons), University College London
Founder & CEO Chairman CFO Business Development
Developed drugs 2 exits
on market 55 years pharma
$200M raised experience
15Financials – potential exits within 5 years
Investment Novartis pay $310M for IFM Therapeutics’
inflammation-focused unit
Novartis is handing over $310 million up front and up
to $1.265 billion in milestones. Clinical Proof
of Concept
April 2019
Exit
Regulatory Approval
for Clinical Trials
DeepBridge Capital ~ 50%
$20M
$6.5M
$1.5M $3.5M
2021 2022 2023 2024 2025 2026
16$10M Investment over 2 years
Toxicology
GMP manufacture
GMP stability
Regulatory engagement (IND/CTA)
Grow team
2024
Formulation development
Pig scar prevention study Regulatory
Regulatory engagement (pre-IND)
Patents
approval for
2023
Cellular studies Grow team clinical trials
IUK grants $6.5M
Patents
Deepbridge Capital investment ask
Personal investment 2022
$3.5M
2021
ask
$1.5M
raised
17See you in
BREAKOUT Room 1
Thank You
Dr Mike Davies
NC Biotechnology Center
Durham, NC 27709
mike.davies@carocellbio.com
+1-919-408-7121You can also read
