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Harnessing the Therapeutic Power of Plants
Plants as Providers of Fine Chemicals Conference
2012
Andrew Gallagher
Programme Manager
Introduction
Who is Phynova?
An innovative life science company based near Oxford
with research facilities in China that uses its plant
chemistry platform to develop patented and well-
characterised
botanical
actives
for
use
in
pharmaceuticals, nutraceuticals, and personal care
products
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Plants as a Source of Medicines
•
Plants contain a wide array of secondary metabolites with inherent
biological activity
•
As plants can’t evade or fight back against predators, they rely on
these chemical defences to fend off animal and micro-organism
attack
•
The ability to synthesize secondary metabolites has been selected
throughout course of evolution and address specific needs of the
plant, e.g.:
– Volatile scents to attract pollinators to enhance fertilization rates
– Toxic chemicals to ward off pathogens and herbivorous browsers
– Compounds to suppress the growth on neighbouring plants
•
This diversity of chemical compounds makes plants a valuable
source of new medicinal compounds
Schmidt et al. (2007). Revisiting the ancient concept of botanical therapeutics. Nature
Chemical Biology; 3 (7): 360-366
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Plants as a Source of Medicines - Continued
•
A large proportion of small-molecule drugs today are either:
– Natural products
– Derived from natural products (semi-synthetically), or
– Have a natural product inspired pharmacophore
•
Abundance of natural product-based drugs begs the question of
whether plant secondary metabolites & their derivatives perform better
than randomly synthesized compounds?
•
Plant metabolites, enzymes, receptors, and regulatory proteins have
common evolutionary roots and they co-evolved to interact with one
another
– Structures and functions may have diverged over time but, on average,
natural products make better ligands for human clinical targets than
randomly synthesized compounds
Schmidt et al. (2007). Revisiting the ancient concept of botanical therapeutics. Nature
Chemical Biology; 3 (7): 360-366
4
Magic Shotgun vs Magic Bullet
•
Modern drug discovery has traditionally had a magic bullet approach,
i.e. one molecule, one receptor
•
More and more often this approach is seen as inadequate and
diseases are being treated with a combination of many singlecomponent drugs
– Combination therapies are particularly suited for complex chronic diseases
such as cancer, diabetes, infectious diseases
•
Plants have always relied on mixtures of biologically active molecules
to defend themselves from diseases and predation
•
Plant extracts can act as a combination therapy in a single
composition, i.e. one extract, multiple targets
Phynova embraces the magic shotgun ethos and all
its products are purified plant extracts
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Phynova’s Development Platform
10 000 plants used
in Chinese medicine
Patents
&
Regs (UK)
Discovery
Engine
(China)
Cost effective
Human use
reduces risk
Development
Path
(UK)
• Demand driven
• High value
markets
• Unmet needs
Functional
ingredients
Pharma
products
THMPs
Phynova utilises the rich history of TCM as a discovery engine to identify and
develop patented medicinal products for global healthcare markets
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Pharma Case Study - Melokinex™
The development model utilised by Phynova streamlines
the R&D process so that drug candidates in high value,
low competition markets are rapidly identified and
advanced to proof-of-concept
Identified
major unmet
therapeutic
need with $1
billion +
market
Data mining
and creative
candidate
selection
(~30 plants)
Activityguided
fractionation
and lead
candidate
selection
Preclinical
evaluation;
IP
generation
Successfully
completed
Phase 2b
clinical study
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Introduction: Postoperative Ileus
•
Postoperative ileus (POI) is a temporary dysmotility of the GI tract
following surgery
•
POI is accepted as an inevitable complication of major surgery
•
Although rarely life-threatening it is associated with:
•

Considerable patient discomfort

Increased hospitalisation

Increased hospital resource utilisation
Incidence of POI following abdominal surgery is 6.3% - 10.7%, but
some studies report incidence of up to 20%1
1. Wittbrodt E. The impact of postoperative ileus and emerging therapies. Pharmacy and
Therapeutics, 2006; 31(1): 39-59.
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Economic Burden Associated with POI
+ 4 days
hospitalisation
+ $6k
hospital
costs
Based on conservative estimates of POI incidence (6%) and the annual
number of abdominal surgeries in the USA (~12m) the increased
financial burden to US healthcare is $5 billion annually
(Taken from: Wittbrodt E. The impact of postoperative ileus and emerging
therapies. Pharmacy and Therapeutics, 2006; 31(1): 39-59).
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Multiple Factors Contribute to POI
Anaesthesia
Hormones and
neuropeptides
Endogenous opiate
release
Surgical trauma
Exogenous opiates for
pain relief
Autonomic nervous
system
Inflammation
Enteric nervous system
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Current Treatments Approaches for POI
•
Only one approved pharmaceutical treatment for POI – alvimopan
(Entereg®), a peripherally acting μ-opioid receptor antagonist
•
Treatments in development include
– ghrelin receptor agonists,
– 5HT4 receptor antagonists
– opioid receptor antagonists
•
Other treatment options include
– use of nasogatric tubes,
– early postoperative ambulation and feeding,
– epidural analgesia,
– Rescue medication such as laxatives, and anti-inflammatories
Even though there are treatment options
available, benefit is often marginal
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MelokinexTM: Data Overview
•
In vivo studies show that Melokinex™ improves mechanically-induced
and drug-induced bowel immotility in mice and rats
•
Promotes motility in normal mice
•
Long history of safe human usage of the constituent plant – used
traditionally as an emetic
•
Clean acute toxicology in mice (LD50 not detectable)
•
MTD is 229x clinical dose
•
Causes no skin irritation or sensitization (allergic reaction)
•
Clinical data shows it significantly alleviates POI
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Promotion of GI Motility in Normal &
Hypofunction Animals
Atropine & surgery induced hypofunction
100
**
**
**
**
250
Normal control
Neostigmine
(0.15mg/kg)
99.2 mg/kg
198.4 mg/kg
Melokinex
*
20
**
**
15
10
5
0
49.6 mg/kg
Normal control
Neostigmine
(0.15mg/kg)
99.2 mg/kg
Melokinex
198.4 mg/kg
Impelling percentage (%)
**
25
**
200
80150
**
*
**
**
**
**
**
70100
60 50
50
49.6 mg/kg
30
Quantity of faeces
90
Time to first excretion (min)
160
140
120
100
80
60
40
20
0
Impelling percentage
Time to first excretion (min)
Normal mice
0
Normal
Normal
Control
group
100
90
80
70
60
50
40
30
20
49.6mg/kg
mg/kg 99.2
49.6
99.2 mg/kg
mg/kg 198.4
198.4mg/kg
mg/kg
Atropine Neostigmine
Neostigmine
Melokinex
Atropine
Melokinex
Treated
Control
Treated
Control
**
**
49.6 mg/kg
Pseudosurgery
Mechanical Neostigmine
Injury
Control
**
**
99.2 mg/kg 198.4 mg/kg
Melokinex
A single administration of Melokinex™ significantly (**p<0.01;
*p<0.05) shortened excretion intervals and increased the quantity
of the faeces in normal, and chemically & surgically induced
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hypofunction mice
Effective Agent Throughout the GI Tract
Impelling percentage (%)
Intestine enterokinesia in the small intestine (n=10)
100
90
80
70
60
50
40
30
**
**
**
** P<0.01
49.6 mg/kg
Normal control
Neostigmine
Group
99.2 mg/kg
198.4 mg/kg
Melokinex
Impelling percentage (%)
Intestine enterokinesia in the large intestine (n=10)
90
80
70
60
50
40
30
20
**
**
**
**
** P<0.01
30.5 mg/kg
Normal control
Neostigmine
Control
61 mg/kg
122 mg/kg
Melokinex
Melokinex™ was shown to be effective in increasing
enterokinesia in both the small and large intestine
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Effects Colon Enterokinesis
Proximal colon constriction in anaesthetised rats (n=5)
Positive control
(neostigmine)
200
180
160
140
120
100
80
60
40
20
0
##
**
##
**
#
（0~30min）
##
**
0~30min
Before
Medication
##
**
##
**
##
**
##
**
#
30~60min
##
**
60~90min
After Medication
Notes:
Melokinex 5mg/kg
##
**
##
*
#
*
90~120min
Contraction strength (mV/min)
No. of contractions
Negative control
Melokinex 10mg/kg
90
80
70
60
##
**
##
**
50
40
##
**
30
##
**
##
**
#
*
##
**
20
##
**
##
**
#
*
#
*
10
0
（0~30min）
Before
Medicaiton
0~30min
30~60min
60~90min
90~120min
After Medication
Compared with self, before medication: # P<0.05, ##P<0.01
Compared with negative control: * P<0.05, ** P<0.01
The contraction waves and amplitude indices significantly increased
within 30 minutes after a rectal administration of Melokinex in
anaesthetised rats (peak between 30-60 minutes)
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Phase II Safety & Efficacy Study Design
Objective
Investigate the efficacy and safety of
Melokinex
Randomised, double blind, placebo
Design controlled, multicentre
End Primary: First flatus/stool after surgery
points Secondary: First bowel sound
Sample
Size
Active dose 72 patients
Placebo 72 patients
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Efficacy Analysis – Primary Endpoints
First passing flatus after
surgery
Active
Placebo
Rate (%)
– Data evaluated using KaplanMeier survival curve
– Median time to first passing
flatus after surgery was 87hrs
hours on placebo and 58
hours on active (P<0.0001)
– Lower and upper quartiles
(25%, 75%) were 65 hours and
94 hours for placebo
– Lower and upper quartiles
(25%, 75%) were 42 hours and
76 hours for active
Kaplan-Meier Survival Curve: 1st Flatus (FAS)
P < 0.0001
Hours post-surgery
Patients receiving Melokinex on
average experienced first flatus
29 hours earlier than those who
received the placebo
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Efficacy Analysis – Primary Endpoints
First passage of stool after
surgery
Placebo
Rate (%)
– Median time to first bowel
movement after surgery was
111 hours on placebo and 77
hours on active (P<0.0001)
– Lower and upper quartiles
(25%, 75%) were 88 hours and
128 hours for placebo
– Lower and upper quartiles
(25%, 75%) were 43 hours and
92 hours for active
Kaplan-Meier Survival Curve: 1st Bowel
Active Movement (FAS)
P < 0.0001
Hours post-surgery
Patients receiving Melokinex on
average had a 1st bowel movement
34 hours earlier than those who
received the placebo
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Weak Affinity for Typical GI Motility Targets
Melokinex has shown a
limited (significant
response >±50%) in a
series of GI-related
enzyme and radioligand
binding assays
Data does not however
support the strong
pharmacological effect
seen and suggests that
the promoting of GI
motility might be
contributed by a
multivalent mechanism
of action
Functional Ingredients Case Study IminoNorm™ & PhynoRadiance™
The multiple secondary metabolites not only make
plants excellent therapies for complex, multivalent
diseases, but also allows them to be used for different
conditions
Research
began for
anti-diabetic
drug
candidate
Activity assays
suggested
cosmetic
applications in
addition to
diabetes
PhynoRadiance
now marketed as
cosmetic
ingredient for
skin lightening
Collaboration with
global soft drinks
company for use
of IminoNorm for
soft drinks
industry in China
From one
plant have
pharma,
nutraceutical
and
cosmeceutical
products
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The Convergence of Food and Pharma
•
Global shift from reactive treatment of health disorders through the
use of drugs, to proactive, preventative approach by consumers
•
Two big trends are shaping the health and wellness markets:
– Natural movement that centres on a healthy balanced diet
– Nutraceutical movement that focuses on adding beneficial active
ingredients to achieve specific health functions
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IminoNorm™ - Solution for ‘Diabesity’
● IminoNorm is a functional ingredient that
significantly reduces blood glucose levels and
improves the glycaemic index of carbohydrate
rich goods
● IminoNorm acts on multiple biochemical
pathways including
 Inhibiting carbohydrate digestion
 Output of glucose from glycogen stores
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IminoNorm™ In vivo Activity
Plasma glucose (mmol/L)
Impact on postprandial blood glucose levels in rats
(n=10)
3.50
Placebo
ig 25mg/kg
ig 50mg/kg
3.00
ip 15mg/kg
ip 30mg/kg
2.50
ig 25mg/kg miglitol
2.00
0
30
60
90
120
150
Time after starch administration (minutes)
•
IminoNorm™ was shown to potently reduce post-prandial blood glucose
levels in vivo
•
ig 50mg/kg test sample is as effective as miglitol (Glyset®) at lowering
blood glucose levels
•
Interestingly, the ip route also reduced blood glucose levels, supporting
the multiple mechanism of actions suggested by enzyme studies
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Human Glucose Tolerance Study
•
Co-ingestion with 50g soft sugar resulted in a reduction of the AUC 2hr
and AUC 3hr by 53.5% and 50.8% respectively compared with placebo
•
•
Activity comparable with the control, 50mg miglitol
The strong efficacy supports the magic shotgun approach as lower levels
of synergistically acting compounds work together to produce a potent
result
AUC (% of control)
Glucose Absorbtion_ZZ
110.00
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
AUC2h
AUC3h
Placebo
BCME
Miglitol
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Other Roles of α-Glucosidase in the Body
CNX/CR
T
Folding
α-glucosidase I
α-glucosidase II
α-glucosidase II
Copper
incorporation
Cu2+ Cu2+
Glucosidase plays a key role in the glycan processing and maturation of the
enzyme tyrosinase
• The glycan is sequentially trimmed by α-glucosidase I and II allowing the
attachment of molecular chaperones calnexin (CNX) and calreticulin (CRT)
through their recognition on monoglucosylated N-glycans of tyrosinase
• Tyrosinase is folded by the chaperones resulting in active tyrosinase
• α-Glucosidase inhibitors prevent the necessary oligosaccharide trimming required
for chaperone attachment and folding.
Symbols: blue square = N-acetyl glucosamine, blue circle = mannose, green triangle = glucose
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Role of Tyrosinase in Melanin Synthesis
Tyrosinase, the rate-limiting enzyme in the
biosynthesis of melanin, is an ideal therapeutic
target in combating hyperpigmentation.
COOH
HO
Tyrosinase
NH2
HO
HO
Dopachrome
COOH
HO
O
COOH
NH2
O
Dopa
O
N
NH2
HO
Tyrosine
HO
COOH Tyrosinase
Dopaquinone
Tyrosinase
N
H
5,6-Dihydroxyindole
O
Melanin
O
N
H
Indole-5,6-quinone
Reduction of the activity of tyrosinase has dramatic
consequences on pigmentation.
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PhynoRadiance™ - A Novel Ingredient for
Skin Whitening
•
Produced from same plant as
IminoNorm
•
Inhibits melanin formation through
a novel mechanism of action
•
Reduces skin hyperpigmentation
•
Clinical proven safe and efficacious
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PhynoRadiance™ - Clinical Results
• The study reported that the formulation
induced a significant lightening effect after
28-days of twice-daily usage
• There was a significant increase in skin
lightness (L* parameter)
• There was a significant decrease in skin
Effect of PhynoRadiance on L*
60.8
60.6
60.4
60.2
0.20%
60
0.50%
59.8
59.6
59.4
pigmentation (ITA parameter)
• 81% of subjects reported that they found
their skin clearer
• 86% of subjects would continue to use the
product and 96% would purchase it
0.20%
Day 0
• 86% of subjects reported they perceived
their skin to be more uniform in colour
0.50%
Day 28
Effect of PhynoRadiance on ITA
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29.5
29
0.20%
28.5
0.50%
28
27.5
0.50%
27
0.20%
Day 0
Day 28
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Advantages & Challenges of Botanical Drugs
•
Botanical drugs offer many advantages over NCEs:
– Historical use reduces product failure rate
– Lower concentrations of multiple active reduces toxic burden
•
Botanical drugs are however a highly specialised field with unique
challenges
•
High cost of screening and difficulty in isolation and characterisation of
active fractions
– Prior knowledge of the plants reduces this cost
•
Product quality and batch-to-batch consistency are essential in order to
satisfy both regulatory and consumer demands
– Standardisation only possible when bulk of bioactive components is known
and their range of levels has been established
•
Products have to be produced to pharmaceutical GMP
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Strict Process Control from Plant Raw
Material to Finished Product
•
•
•
Plant growing site selection
•
Contamination tests including
heavy metals, pesticides and
aflatoxins
Application of GAP guidance
QC on raw materials including
authenticity of the plant species,
microscopic identification,
impurity tests and assay for
chemical markers
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Strict Process Control from Plant Raw
Material to Finished Product
GMP manufacturing of the
plant extracts and the finished
product
•
Batch-to batch consistency
ensured through use of:
•
– Qualitative and quantitative
fingerprinting of marker
compounds e.g. HPLC, GCMS, HPTLC
– Bioassays to ensure biological
activity (marker compound
may not be the active
component)
6.0
Initial reaction velocity
•
5.0
4.0
3.0
2.0
1.0
0.0
0
50
100
150
200
250
Concentration (µg/ml)
EU pharmacopoeial
contaminant levels
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Regulatory Support for Botanical Drugs
•
Botanical drugs represent the
third paradigm in drug
development
•
Detailed guidelines on
toxicology requirements if
previous human use
•
Shorter development times and
reduced development costs
•
Regulatory parity with
synthetics & biologicals
32
Global Interest in TCM
•
Asian medicine has been receiving a lot of attention recently:
– Dec 2011 Nature Outlook supplement on Asian medicine
33
New GSK R&D Unit Focusing on TCM
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Contact Details
Andrew Gallagher
Programme Manager
Email: agallagher@phynova.com
Tel: +44(0) 1993 880 700
PHYNOVA GROUP LTD
PHYNOVA HOUSE, 16 BLENHEIM OFFICE PARK,
LONG HANBOROUGH, OXON OX29 8LN, UK
www.phynova.com
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