The Science and
Business of
a2®
University of Auckland Bioscience
Enterprise Forum
12 July 2013
Dr Andrew J Clarke
Chief Scientific Officer
A2 Corporation Ltd.
Presentation Outline
•
Introduction - A2 Corporation Ltd
•
Timeline – A2 Corporation Ltd
•
Commercial Biotech Partners
•
What is a2™?
•
Timeline and Highlights of Research
•
Commercialising the Potential of a2™
•
Consumer Response to a2™
Detailed scientific summaries and study references contained on www.betacasein.org and www.betacasein.net
Introduction - A2 Corporation Ltd
•
A2 Corporation Limited (“A2C”) is a is building a global business based on unique
intellectual property relating to a2™ branded dairy products and technology
•
Listed on the NZAX with a current market capitalisation of c.NZ$340m and achieved
FY12 sales of NZ$62.5m with a profit after tax of NZ$4.40 million
•
a2™ brand dairy products have a differentiated and unique proposition that delivers
a tangible consumer benefit aligned with the global consumer health trends
•
•
Evidenced by strong customer testimonials and a growing body of science
•
Unique, innovative and global dairy brand, positioned at a price premium
A2C is one of the fastest growing regional FMCG businesses in dairy with a2™
branded milk in NZ, Australia and now the UK; yoghurt produced under licence in
Australia; and plans to launch infant formula into China in the second half of 2013.
3
Timeline - A2 Corporation Ltd
•
August 2000 - Founded by Howard Paterson and Dr Corran McLachlan
•
April 2003 – Limited launch of a2 branded milk in Australia in NZ
•
April 2004 - Listed on the NZAX
•
April 2007 – Australian JV with Freedom Nutritional Products (ASX:FNP)
•
July 2010 – JV wholly owned by A2C, FNP becomes key A2C stakeholder.
•
November 2011 – Formed JV with Robert Wiseman Dairies (UK)
•
April 2012 –Agreement with Synlait to produce a2™nutritional products
•
October 2012 – a2™fresh milk launched in UK, China State Farm appointed as
exclusive distributor of a2™ infant formula for China
•
December 2012 - Listed on the NZX
•
February 2013 – Included on NZX 50 Index
4
Recent Activity
Commercial Biotech Relationships
•
Synlait (NZ)
•
LIC (NZ)
•
Analytica (NZ)
•
iProteome (NSW)
•
Elizabeth Macarthur Agricultural Institute (NSW)
•
Australian Proteome Analysis Facility (NSW)
•
AgResearch (NZ)
•
Weatherbys (UK)
•
LGC Laboratories (UK)
•
Van Haeringen Group (EU)
•
Texas A&M (USA)
•
UC Davis VGL (USA)
•
Neogen (USA)
•
CAIQ Test (China)
Detailed scientific summaries and study references contained on www.betacasein.org and www.betacasein.net
What is a2™?
•
a2™ products are naturally produced from cow’s milk, not a product of genetic
engineering
•
Comparable in composition to conventional cow’s milk with the sole exception of the
beta casein protein component
•
a2™ dairy products contain only the A2 type the protein beta casein
•
A2 is recognised as being the original or ancestor beta casein gene in modern cattle
•
The difference in structure between the beta casein variants can lead to a difference
in their breakdown during digestion
•
Anecdotal and consumer reports link a2™ products with improved digestive comfort
and other intolerance type symptoms relative to A1 beta casein containing milk
•
There is a strong and growing body of science supporting the reported advantages of
maximising A2 at the exclusion of A1.
7
What Is A2 Beta-Casein?
•
About 30% of the protein in cows' milk is beta-casein
•
Transports essential minerals and nutrients such as calcium and phosphorous
•
There are genetic variants of beta casein; A1 and A2, with minor variants either
classed as A1 or A2-like.
•
When digested beta casein can produce a range fragments with well characterized
biological activity
Composition of milk casein
Composition of solids in
milk
A2 is the Original type of Bovine Beta Casein
•
A2 is recognised as being the original or ancestor beta casein gene in modern
cattle.
•
Originally all domesticated cows produced milk containing only the A2 type of
beta casein, owing to natural genetic mutation, a variant of the A2 protein
appeared.
•
Termed A1, it differs very slightly in composition from the original A2 protein and
both types have since given rise to a number of minor related sub-variants, such
as those termed A3, B and C.
Figure from: MILK PROTEIN POLYMORPHISM: DETECTION AND DIFFUSION OF THE GENETIC VARIANTS IN BOS GENUS,
Annali della Facoltà di Medicina Veterinaria, Vol. XIX, 1999. Università degli Studi di Parma ]
Breed Evolution and Beta Casein type
bos indicus
Ancient bos
(Auroch )
Asian bos indicus eg.
Brahman (A2)
bos taurus
African bos taurus eg.
Kuri (A2)
European bos taurus e.g.
Holstein, Jersey, Guernsey (A1
and A2 in all breeds)
>100,000 yrs ago
taurus and indicus species
evolve from bos genus
African bos indicus e.g.
Africander (A2)
~5,000 yrs ago
Variant A1 evolves through
natural mutation from beta
casein A2 in bos taurus
Figure adapted from information reported in:
1. Advanced Dairy Chemistry: Volume 1 - Proteins, Second Edition, edited by P.F. Fox and P. L. H. McSweeney pp 424 & 430
2. MILK PROTEIN POLYMORPHISM: DETECTION AND DIFFUSION OF THE GENETIC VARIANTS IN BOS GENUS, Annali della Facoltà di Medicina
Veterinaria, Vol. XIX, 1999. Università degli Studi di Parma
3. Daniel G. Bradley, Ronan T. Loftus, Patrick Cunningham, David E. MacHugh (1998) ‘Genetics and domestic cattle Origins’ Evolutionary Anthropology
V6;3 pp79-86
10
Difference in Structure and Digestion of A2 vs. A1
Tyr
Pro
Phe
Pro
Gly
Pro
Ile
Pro
Asn
A2 release BCM - 9
digestion
Amino Acid position 67
a2 beta casein
protein chain (209aa)
Val
Tyr
Pro
Phe
Pro
Gly
Pro
Ile
Pro
Asn
Ser
Leu
Pro
a1 beta casein
protein chain (209aa)
Val
Tyr
Pro
Phe
Pro
Gly
Pro
Ile
His
Asn
Ser
Leu
Pro
digestion
Amino Acid position 67
A1 releases BCM - 7
Reported as strong exorphin
Tyr
Pro
Phe
Pro
Gly
Pro
Ile
Adapted from: Gobbetti M, Stepaniak L, De Angelis M, Corsetti A, Di Cagno R. Latent bioactive peptides in milk proteins: proteolytic activation and significance in dairy processing.
Crit Rev Food Sci Nutr. 2002;42(3):223-39. & Jinsmaa, Y & Yoshikawa, M. 1999. Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein. Peptides
V20(8), pp 957-962.
11
Beta Casein of Other Species
•
Human1, goat2 and sheep3 beta caseins are more comparable to A2 than A1 with
respect to the amino acid that flanks their corresponding BCM-7 sequence
•
It has been reported that human beta casomorphin 7 may be yielded in very low
quantities (1-10% of theoretical yield) by the in vitro digestion of human beta casein4
•
Bovine casomorphins are reported to have up to 10x the affinity to opioid receptors
compared to the human equivalent, additionally bovine casomorphins have a
significantly longer biological half-life than their human equivalents5
•
Simply put, A1 containing bovine milk has potential to impart up to 10x or more BCM7 bioactivity than an equivalent volume of other mammalian milks
1.
2.
3.
4.
5.
embl accession X55739.1
embl accession AJ011019.3
embl accession X16482.1
Norris CS, Darragh A, Booth C, Boland MJ, Hill JP. 2003. Human milks release beta-casomorphin-7 during simulated digestion. Poster paper
presented at the 2003 International Dairy Federation Conference.
Brantl V, Teschemacher L. 1994. Beta casomorphins and related peptides.Weinheim: VCH.
Timeline of Research around a2™
1994 – 2001: Epidemiological Studies
• Link A2 with a lower risk of heart disease and type 1 diabetes
• Undertaken and published by 3 groups from independent data across developed
countries
• Hypotheses around mechanism derived from animal and BCM-7 centered studies
1980’s – current: Studies around BCM-7
• Established as an exorphin with potential to interact with a range of cell and tissue
types. Including digestive, immune and neural.
• Unique production from incomplete A1 digestion established with potential
transport mechanism into circulation and across the blood brain barrier reported.
• Human studies reflect a wide ranging ability to metabolise BCM-7, with
compromised ability linked to negative physiological outcomes
1995-2003 – Animal Studies
• A1/A2 rodent feeding trials provide support to epidemiological relationship
• BCM-7 studies report physiological responses in a range of exposed tissues
Detailed scientific summaries and study references contained on www.betacasein.org and www.betacasein.net
A1 β-casein supply (A1/capita) 1990 and ischaemic heart disease 1995,
20 countries
140
130
120
Dea t hs pe r 100 , 000 , 1995
110
100
90
80
70
60
50
40
30
20
0
1
2
A1 be t a case i n
3
4
g / day
Regr essi on Equat i on:
(r=0.76,
0.48-0.90),
p=< 0.0001.
i hd =(95%
41. CI
30126
+ 22. 66732*
casei n Dotted lines are the 95% confidence limits of the regression
line)
Source: NZ Medical Journal, 24 January 2003, Vol 116 No 1168
Correlation of A1/capita (A1 -casein in the per capita milk and cream
supply) with the incidence of diabetes mellitus Type 1 at age 0–14 years of
age, 1990-94, 19 countries
DM- 1 I nc i dence pe r 100 , 000 pe r yea r
40
30
20
10
0
0
1
2
A1 be t a case i n
3
g / day
Regr essi on Equat i on:
(r=0.92
(95%
to +0.97)
p <0.0001;
di abet
es = CI
- 4. 0.72
173545
11. 89631*
casei ndotted lines = 95% confidence limits of the regression line )
Source: NZ Medical Journal, 24 January 2003, Vol 116 No 1168
BCM-7 Affects Components of an Allergic Response
•
Food allergy may be confused with food intolerance,
which is a non- immunological reaction that can be
caused by enzyme deficiencies, pharmacological agents
and naturally occurring substances (NICE Clinical
Guidelines 2011)
•
A2 is NOT for patients with Milk Protein Allergy
•
BCM-7 is reported to:
• Bind Mu opiate receptors
• Trigger histamine release from mast cells
• Trigger MPO product from colonic immune cells
• Cause wheal and flare reactions on the skin of
healthy children
•
Adverse response to A1 consumption and subsequent
BCM-7 exposure is not an allergic reaction
•
Research will characterise the putative relationship
between A1 beta casein consumption and intolerance
type symptoms.
References at www.betacasein.net and www.betacasein.org
References at www.betacasein.net and www.betacasein.org
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Recent research on neuronal and gut epithelial cells
report that bovine BCM-7:
•
Inhibits cysteine uptake and promotes oxidative stress
•
Imparts changes to mRNA expression that contrasts
with that of the hBCM-7
•
Leads to changes in global methylation contrasting
with control and hBCM-7
Presented by: Trivedi MS et al. International Conference on Food Science and Nutrition 2013 (London) RISE2012(NEU, Boston)
EFSA review on BCM-7 and Disease
•
In 2009 EFSA released a report “Potential Health Impact of β-casomorphins and Related
Peptides” that examined evidence for BCM-7 causing heart disease, diabetes or
neurological conditions.
•
The report served to appraise publically available data and concluded:
“Based on the present review of available scientific literature, a cause-effect
relationship between the oral intake of BCM7 or related peptides and aetiology
or course of any suggested non-communicable disease cannot be
established.”
•
Simply put the lack of quantitative data, or that relating to the amount of BCM-7 an
individual is exposed to, disallowed a cause-effect analysis.
•
The report identified that A1 derived BCM-7 is an opioid with the potential to interact
with a wide range of cells and tissues; including that involved with digestive and
immune function.
•
A2 Corporation agreed with the outcome which was aligned with the company’s
disclosed and qualified position.
•
Significant research around BCM-7 has been published since the 2009 EFSA review.
19
Recent research on BCM-7
•
Previously studies established that:
•
Digestion of A1 but not A2 produces protein fragment beta casomorphin-7 (BCM-7)
•
BCM-7 binds opiate receptors and has the potential to interact with a range of tissues
•
Precursor protein A1 is linked to a range of negative health outcomes
•
Recent clinical trials report BCM-7 production to physiologically relevant levels in the gut of
healthy adult humans. (Boutrou et al, 2013)
•
A correlation between BCM-7 levels with delayed psychomotor function in formula fed
human infants has been reported (Kost et al, 2009)
•
Serum BCM-7 has also been linked to the compromise of breathing in infants fed A1
containing formula, potentially leading to SIDs (Wasilewska et al, 2011) .
•
The activity of the enzyme DPPIV (DPP4) which breaks down BCM-7 has been reported to
be highly variable, with low activity linked to above noted adverse outcomes in infants
•
A mechanism by which BCM-7 leads to oxidative stress and cell dysfunction has
subsequently been demonstrated (Trivedi et al, 2012).
Detailed scientific summaries and study references contained on www.betacasein.org and www.betacasein.net
20
Research Highlights
Though clinical trials are required to confirm links with health conditions, the following
is established:
•
A1 but not A2 beta casein may yield BCM-7 through incomplete digestion
•
BCM-7 has the potential to bind opioid receptors expressed in cells throughout the
body, including digestive, immune and neurological
•
BCM-7 has been observed to be produced, absorbed and circulated in some humans,
particularly infants
•
Emerging research links BCM-7 to adverse effects on infant development and health,
and intolerance type reactions in adults
•
Recently a mechanism by which BCM-7 triggers oxidative stress in cells leading to
changes in short and long term function was demonstrated
•
The proportion and type of individual susceptible to BCM-7 exposure needs to be
determined
Detailed scientific summaries and study references contained on www.betacasein.org and www.betacasein.net
Consumer Response to a2™
•
“A rare instance of science playing catch up with consumer experienced benefits”
•
I assumed I was lactose intolerant but when I drank a2 milk I was surprised that it didn't give
me diarrhoea.
•
A2 milk has made an incredible difference to our 2 year old son's bowel movements and
also seems to reduced the amount of congestion…”
•
Hi, we love A2 milk. My son has a dairy intolerance, but is fine on A2 milk.
•
I am a big fan of A2 milk and find that if I drink any other milk or milk products I suffer from
sinus problems.
•
She said she no longer gets headaches or stomach pains and for some reason her sniffles
have gone. THANK YOU VERY MUCH....
•
Just to say 'thanks'. I normally can't tolerate milk as I feel bloated and sick. With the
addition of the a2 protein, I am slowly starting to consume milk again and get my daily
calcium hit.
•
my son (soon to be formally diagnosed autistic) has benefited so much from drinking a2
milk. “Hi i have noticed a big difference with my sinuses since drinking a2 milk…
Commercialising a2™
•
A2C’s core assets comprise intellectual property (IP)
•
Patent rights across the supply chain; testing through to composition and use.
•
Brands that include trade marks and trade names linked with established and
growing equity
•
Proprietary processes around operational aspects of a2™ production
•
Know-how around the effective and compliant communications around a2™ to
consumers, health care professionals and parties of consideration
Commercialising a2™ (2)
•
•
A2C has adopted a business strategy around direct involvement
•
Historical model of licensing shown to be unsuitable
•
Ownership or controlling stake in a2™ businesses shown to be effective
Current Activities
•
Australia - business wholly owned
•
NZ - single non-exclusive licensee
•
UK – JV with RWD to market a2™ fresh milk
•
China – Agreement to sell a2™ Infant Formula FOB to CSF for joint marketing
a2™ in Australia
% Share of Fresh Milk (Latest Quarter—by value)
% Market Share
Sep-2011
Sep-2012
% Growth
46.3%
7.0
6.4
6.0
5.0
15.0%
4.3
(5.3%)
4.0
15.4%
(16.7%)
3.0
25.0%
2.3
2.0
2.0
0.9
1.0
1.9
1.8
1.0
0.6
0.5
0.4
0.5
0.0
A2
Lactose Free
Organic
Plant Sterol
Goatmilk
Fresh Soy
Source: Aztec Scan Data : w/e 2/9/12
a2™ brand milk is the fastest growing and largest brand in the Australian
premium segment
25
Market for a2™ Products
Global Health and Wellness
Market (US$bn)
Consumer Trends
Less
625.9
Price conscious
66%
2%
Avoiding additives
Responsible
1%
Smarter choices
2%
52%
49%
12%
Environmentally friendly
0%
41%
38%
5%
Frugal
43%
9%
Buying to please others
•
•
45%
12%
Planned ahead
Source: Euromonitor 2011
56%
4%
Interested in promotions
FY06
70%
4%
Health focused
462.9
More
13%
20%
38%
40%
60%
80%
FY11
Source: SheSpot Consumer Survey (2012)
There is an increasing global consumer focus on health and wellbeing
This presents scope for innovation in mature and commoditised global dairy
markets
Summary
A2C has successfully evolved from a start-up biotech firm to a dairy
company with international operations
The a2™ proposition is based on a deep body of both definitive and
emerging science
The potential benefits of a2™ are reported with consistency by consumers
in current markets
There is an increasing consumer focus on health and wellbeing which
strong favours a2TM branded dairy products
A2C has a strong suite of global intellectual property supported by a
growing body of know-how and developing brand equity
A2C’s proven Australian dairy supply chain model provides a scalable
technical & commercial template for other markets
27