Antisense Therapeutics ANP Wednesday_ 1 August 2007 Passed Halfway

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Antisense Therapeutics ANP Wednesday_ 1 August 2007 Passed Halfway Powered By Docstoc
					Antisense Therapeutics                                      ANP                   Wednesday, 1 August 2007
Passed Halfway Through Enrolment of the ATL1102 Phase II Study
Recommendation                         Speculative Buy for the High Risk Tolerant Investor
Antisense Therapeutics is Developing a New Class of MS Therapy                        Snapshot
ATL1102 is a novel type of drug referred to as an antisense compound. This is a       Last Price                     $0.04
drug targeting RNA, the biological intermediary between genes and proteins.           Market Cap (m)                 $20.3
Certain proteins cause disease and genes encode these proteins. When DNA is           52 Week High                   $0.07
read by the body’s enzymes, it is encoded into RNA and the RNA is encoded             52 Week Low                    $0.02
into proteins. By disrupting the encoding of proteins by blocking RNA, ATL1102
                                                                                      Sector                         Pharmaceuticals & Biotechnology
can inhibit the body’s production of a disease causing protein that causes a type
White Blood Cell to enter brain and destroy the myelin that protects nerve cells.     Investment Fundamentals
This results in Multiple Sclerosis (MS).                                               Year-end June               FY05A         FY06A         FY07E         FY08E
Clinical Trial Progress                                                               NPAT ($m)                       -6.3             -5.5        -3.8        -5.80

On 22 June 2007, the company reported that it was halfway through enrolment           EPS                            -1.76            -1.53       -0.70        -1.08
of an 80 patient safety and efficacy trial on patients with relapsing-remitting MS.   % Change                         NA              NA              NA        NA
This trial is underway in Germany, Poland, Romania, Bulgaria, as well as the          DPS (c)                          0.0             0.0             0.0       0.0
Czech and Slovak Republics. An additional clinical trial application has been
                                                                                      Franking (%)                     NA              NA              NA        NA
submitted to the Russian medical regulatory authority. The trials were expanded
into Eastern Europe because recruitment in Germany was too slow.                      Yield (%)                        NA              NA              NA        NA
The goal of the Phase II trial is to evaluate ATL1102’s efficacy. The trial began     PER (x)                          NA              NA              NA        NA
on 29 June 2006 and clinical data is expected to be released in the fourth            Source: Intersuisse Estimates (not accounting for future capital raisings).
quarter 2007 or first quarter 2008.                                                   The forecast NPAT is indicative only and highly variable upon the success
                                                                                      of the ALT1102 Phase II Trial and advancement of ALT1103.
                                                                                      Price Chart
Currently ATL1102 is in a Phase II Clinical Trial and Tysabri® is marketed,
generating $72m for the quarter ending July 2007. However Antisense’s stock            $0.07

price has not recovered from a fall 2 years ago when Tysabri® was temporarily
withdraw from the market and Antisense temporarily suspended the ATL1102               $0.06
Phase II Clinical Trial. Why?
We believe the price is being restrained for two key reasons.                          $0.05

• The first is the ability of ATL1102 to prove clinical efficacy, despite second
  generation ISIS antisense drugs are generating positive data. If successful,         $0.04

  ATL1102 would be one of the first antisense therapies to demonstrate clinical
  efficacy. Therefore, the market has discounted the stock due to a higher             $0.03
  perceived technical risk associated with the antisense technology.
• The second is the market’s perception of Tysabri’s first mover advantage.            $0.02
                                                                                           Aug-06         Nov-06             Feb-07           May-07          Aug-07
   There is a view that a neurologist would prefer to prescribe an antibody
   instead of an antisense compound. We do not hold this view. As ATL1102 is          Business Description
   a novel compound; it is likely to have characteristics that are favourable for
   some MS patients over Tysabri®, plus it is expected to have a lower COGs           Antisense Therapeutics is involved in the development
   than Tydabri®.                                                                     and commercialisation of novel antisense
Antisense Therapeutics with its lead compound in Phase II trials has an               pharmaceuticals, a class of drug based on small
enterprise value of about $11.0m, compared to an average and median of $73m           synthetic genetic molecules that interfere with the
and $21m for other companies whose lead drug is in Phase II studies.                  production of target proteins. Advanced projects target
                                                                                      Multiple Sclerosis (ATL1102) and Acromegaly and
The release of the forthcoming Phase II data will be the point where the first
                                                                                      Diabetic Retinopathy (ATL1103). Only ATL1102 for
indication of the clinical efficacy of ATL1102 is expected. At this point, the
                                                                                      the management of MS will be the focus of this report.
market will know if ATL1102 is commercially viable. If the data is positive, we
expect strong appreciation of the valuation of the company.                           Analyst: Darren J. Grubb PhD MBA GDipAppFin
We rate Antisense as a Speculative Buy, for the investor willing to accept the
binary risk associated with the outcome of the forthcoming Phase II Clinical Trial
anticipated in Q407 – Q108.
                                                                  In March 2005, Antisense voluntarily suspended the trial due
What is Multiple Sclerosis?                                       to a safety issue with Tysabri®. Based on the
                                                                  recommendation of the company’s Medical Advisory Board
First recognised in the 19th Century, MS is a crippling           and rectification of the issue of Tysabri’s toxicity, safety
condition that mostly impacts women in the peak of their          related protocols were changed and the trial size increased
lives. There are about 400,000 and 2,000,000 sufferers in         to 80 patients.
the US and worldwide respectively.
                                                                  Recruitment rate was slower than expected because,
About 90% of MS cases are the relapsing-remitting form of         amongst other factors, patients now have access to
MS, characterised by acute attacks separated by symptom-          Tysabri® (which is reimbursed in Germany) and given the
free periods for up to ten years. The remaining 10% are in        opportunity to take this drug instead of entering the ATL1102
the primary progressive form of the disease, where                clinical trial. In January 2007, the company received
neurological damage and disability continues to worsen.           approval to begin recruitment in Bulgaria, Slovak Republic
MS is caused by inflammatory demyelination of axons.              and Romania centres. In June 2007, the company reported
Damage to the myelin sheath, which coats nerve fibres,            that it was now conducting the trial in 6 European countries
interferes with the ability to transmit impulses to surrounding   and was halfway through completing recruitment of the
nerves, causing problems with muscle control and                  Phase II trial.
The cause of the disease remains elusive, yet the
occurrence of acute demyelinating has been associated with        MS Management and Current
a variety of infections, vaccinations and environmental           Therapies
agents .
                                                                  Although there is no cure for MS, disease-modifying drugs
                                                                  affect the course of the disease, helping to reduce relapses.
ATL1102                                                           These are3;

ATL1102 is a modified DNA oligomer of the VLA-4 (α4β1                                                                                                     Costs in
Integrin, Very Late Antigen-4) CD49d subunit.                                                                                  Year of       Sales          US$
                                                                      Compound         Brand name          Company
                                                                                                                              approval      Revenue       (patient /
ATL1102 is a second generation antisense inhibitor targeting                                                                                                year)
production of VLA-4, a receptor on the surface of
lymphocytes. VLA4 mediates adhesion of immune cells to                  IFN b1a          Rebif®             Serono             2002        $1,452m#        20,553
blood vessel walls and subsequent migration of lymphocytes
into the tissue, which is a pivotal event in inflammatory              IFNa-b1a         Avonex®           Biogen Idec          1996         $910m*         16,608
diseases. In MS, excessive amounts of VLA-4 are thought to
allow the inappropriate entry of lymphocytes into the central                          Betaferon® /       Berlex Lab.
                                                                        IFN-b1b                                                1993          €991m         17,827
                                                                                       Betaseron®         (Schering)
nervous system (CNS)2. In clinical studies, blocking VLA-4
has been associated with a reduction of new MRI lesions in             Glatiramer
patients with MS. VLA-4 has also been clinically validated                             Copaxone®        TEVA Neurosci.         1996        $1,414m#        16,026
by approval of Tysabri®.
                                                                                                          Biogen Idec,          2004
                                                                      Natalizumab       Tysabri®                                             $77m*         28,400
                                                                                                              Elan             (2006)
In August 2003, Antisense Therapeutics began Phase I
testing of ATL1102 in 54 healthy volunteers. This double-             Mitoxantrone     Novantrone®          Serono             2000          $9.1m          1,200
blind, dose-escalation, placebo-controlled, randomised study
suggested that 6mg/kg/week of ATL1102 appeared to be              * = Half Year ending July 2007
well tolerated and would be an appropriate dose for Phase II      # = Full Year 2006
development.                                                      The patent for Novantrone® for the oncology indication expired in April 2006. The exclusivity for
                                                                  the multiple sclerosis indication does not expire until October 2007. However, since generic
In December 2004, Antisense announced the intention to            alternatives to Novantrone® are available in the United States market for the oncology indication,
                                                                  erosion of both segments (oncology and multiple sclerosis) is significant
conduct a Phase II study of ATL1102 in approximately 60
patients with relapsing-remitting MS. These subjects were to
receive subcutaneous ATL1102 twice weekly at a dose of
400 mg per week (or placebo) ant the formation of brain
lesions measured by MRI.

1   N Engl J Med. 2003 Jan 2;348(1):15-23
2   Bioorg Med Chem Lett. 2004 May 3;14(9):2323-6                 3   Drug Discovery Today: Therap. Strateg.3(3) 2006
Tysabri                                                                                                                                                            Compounds in Clinical Trials Targeting MS
Tysabri® is an approved monoclonal antibody targeting VLA-                          Strategy                                                         Target             Compound          Company       State         Comment
4. Long term administration of Tysabri® has produced

                                                                                                                                                     VLA-4               ATL1102          Antisense       II        Not specific and


statistically significant benefits in reducing neurological                                                                                           S1P1
                                                                                                                                                                                           Novartis       III
lesions and reduction in the risk of exacerbations4,5.                                                                                                                 (Fingolimod)
                                                                                                                                                     CCR1               ZK811752                           II
Though the initial success of Tysabri® was hindered by                                                                                                                                    (Schering)
cases of progressive multifocal leukoencephalopathy in                                                                                               VLA-4                683699             GSK           II
some MS patents, suggesting that long term blockade of α4-

                                                                                    Suppression of
                                                                                    autoreactive B
integrins might prevent trafficking of non-pathogenic                                                                                                                   Rituximab                                    B-cell specific
lymphocytes that are essential for immunosurveillance. This                                                                                                              (Rituxan,                                 therapy and does

                                                                                                                                                     CD20                                Genentech       II/III
                                                                                                                                                                      monoclonal anti-                             not affect T cells,
event resulted in Elan and Biogen Idec voluntarily                                                                                                                    CD-20 antibody)                             not antigen-specific
withdrawing the drug from the market. Tysabri® was re-
issued by the FDA in June 2006 conditional that patients are                                                                                                          BHT-3009 (DNA
not co-prescribed interferon and for patients refractory or                                                                                                                                Bayhill
                                                                                                                                                                          vaccine                          II

                                                                                                 Induction of antigen-specific T cell tolerance
intolerant to conventional treatments6.                                                                                                                               encoding MBP)
                                                                                                                                                                      Tovaxin (myelin-
                                                                                                                                                                       reactive T cell                     II
MS Therapies in Development                                                                                                                         Myelin-
                                                                                                                                                  specific T (B)
                                                                                                                                                                       (trivalent TCR
                                                                                                                                                                                                                  Antigen-specific and
                                                                                                                                                                                          Response                   well tolerated
                                                                                                                                                      cells           peptide vaccine)
Although reports 128 MS clinical trials                                                                                                            NBI-5788
recruiting patients, most relate to combination therapies of                                                                                                          (altered peptide   Neurocrine       T
existing therapeutics, that treat inflammation with                                                                                                                         ligand)
compounds to treat the symptoms such as anti-spastics. In                                                                                                                 MBP8298
                                                                                                                                                                      (synthetic MBP                     II/III
addition, there are a number of compounds in development                                                                                                                   peptide)
to treat the symptoms. Examples included Sativex (GW                                                                                                                                      Angiogen
Pharmaceuticals) a cannabis extract and Fampridine SR                                                                                                                    Tranilast                       PC
                                                                                      Induction of protective T cells, suppression

(Acorda Therapeutics), which retard MS induced spasticity .                                                                                       Tryptophan
                                                                                            of autoreactive T cell immunity

                                                                                                                                                  catabolism                               Aventis
ATL1102 is targeting an anti-inflammation strategy to treat                                                                                                                                 TEVA                  Orally available and
                                                                                                                                                                        Laquinimod                         II       few side effects.
MS. This places it within the most active space for MS                                                                                                                                    Neurosci.
                                                                                                                                                                                                                   Probably multiple
investigational drug development. Yet to our knowledge, it is                                                                                      HMG-CoA
                                                                                                                                                                        Atorvastatin        Pfizer         II      cellular targets as
the only compound using the oligonucleotide strategy to                                                                                                                                                              these are non-
                                                                                                                                                                                           Takeda                   specific, general
induce an anti-inflammatory response against MS.                                                                                                    PPAR-γ
                                                                                                                                                                       Rosiglitazone         GSK           II
The key issue with all anti-inflammatory strategies that
                                                                                                                                                     PDE IV              MN-166          MediciNova        II
modulate T-Cell migration, regulation and activity is the
                                                                                                                                                                                         Biogen Idec,
increased probability of opportunistic infections and retarded                                                                                      Unknown            Fumaric acid
autologous cancer surveillance. These two issues are highly                                                                                                             Daclizumab
                                                                                                                                                                                                                   Appears to induce
likely to require active management during therapy by any                                                                                            CD25
                                                                                                                                                                                           Roche          III     regulatory NKf cells
strategy that causes immuno-suppression.                                                                                                                                 anti-CD25
                                                                                                                                                                                                                   and is non-specific
                                                                                                 Suppression of autoreactive T cells

The Company’s Medical Advisory Committee believes that                                                                                                                 Alemtuzumab
                                                                                                                                                                                                                     Effective after a
ALT1102 is likely to not be broadly immuno-suppressive, as                                                                                                                                                          single application.
                                                                                                                                                     CD52                                 Genzyme         T       Immunosuppressive
was experience with Tysabri®. The Committee postulates                                                                                                                   anti-CD52
                                                                                                                                                                                                                     and severe side
that ALT1102 could possibly be more cellular specific as it                                                                                                                                                                effects
targets VLA-4 to a different binding site compared to                                                                                                                    ABT-874         Abbott Lab.       II        Targets key pro-
Tysabri®. Nevertheless, the issue with Tysabri® suggests                                                                                              IL-12                                                            inflammatory
                                                                                                                                                                        CNTO-1275         Centocor         II             cytokine
that ALT1102 will need to be monitored through its                                                                                                                                                                      Specifically
development for potential adverse side-effects.                                                                                                                                                                   targeting activated T
                                                                                                                                                     CD154               IDEC-131        Biogen Idec      T          cells and severe
The table below summarises anti-inflammatory strategies for                                                                                                                                                           thromembolic
the treatment of MS.                                                                                                                                                                                                  complications
                                                                                                                                                     mTOR             Temsirolimus         Wyeth           II        Orally active,

                                                                                                                                                                      Mycophenolate                                 generally well

                                                                                                                                                     IMPDH                                 Roche           II       tolerated. Not
                                                                                                                                                   Nucleoside                                                        specific and
4 CNS Drugs. 2005;19(11):909-22                                                                                                                                          Cladribine          NIH          III     immunosuppressive
5 Eur J Immunol. 2005 Aug;35(8):2268-73
6 Expert Opin Biol Ther. 2007 Jan;7(1):123-36                                       Modified from Drug Discovery Today: Therapeutic Strategies Vol. 3, No. 3 2006 (Anti-inflammatory
7 Summarised in Clinical Trials in Multiple Sclerosis 2007: Planned, In Progress,   strategies for the treatment of multiple sclerosis – tryptophan catabolites may hold the key)
Recently Completed
Main Advances in MS Drug Development
                                                                 ATL1102’s Competitive Advantages
•   Novartis is undertaking Phase III trials on FTY720
    (fingolimod). It is a novel immunosuppressant drug that      In the event ATL1102 successfully completes all clinical
    causes lymphopenia by redirecting lymphocytes from           development, the question is why will ATL1102 be
    the circulation to the lymph nodes. The molecular            successful in the market place?
    biology of this biological function lies in FTY720's
                                                                 Often with other disease indications, the patient would be
    activity upon sphigosine-1-phospate receptor one
                                                                 administered a combination therapy to target the causative
    (S1P1). It is currently in trials as monotherapy for MS,
                                                                 agent. In the example of HIV, a cocktail of antiviral drugs
    after failing Phase III trials for Kidney Cancer.
                                                                 targeting the same causative agent via different mechanisms
•   The marketed anti-cancer anti-CD20 antibody Rituximab        are used. A similar strategy is used to manage cancers.
    is in Phase II/III development as a MS therapeutic.          We believe that MS cannot be treated by a cocktail of drugs
    Rituximab causes B-Cell depletion and treatment with         to prevent demyelination through inhibition of the immune
    Rituximab reduced the number of areas of brain lesions       system results in major complications. Because of the
    in MS patients and the number of relapses.                   severe consequence of increased tumour growth and
•   BioMS Medical is in Phase II/III testing of MBP8298, a       opportunistic infections caused by reducing T-Cell activity, it
    17 amino acid Myelin Basic Protein peptide that reduces      is unlikely that the two or more immune modulators will be
    production of MBP-antibodies. High doses of MBP8298          used in combination to manage MS. Only anti-spastics
    causes immune tolerance to this peptide and a Phase II       would be used in combination with immune suppressants or
    clinical trial showed statistically significant clinical     modulators.
    benefit in patients with the HLA haplotypes DR-2 or DR-      As a result, there would be a high level of competition on
    4. About 65% of MS patients have these HLA                   ATL1102 if it enters the market.
                                                                 Despite the high competition, ATL1102 is expected to have
•   Active Biotech/Teva Pharmaceutical completed Phase II        some competitive advantages that could provide commercial
    development of the oral immunomodulatory agent               success. Tysabri® has demonstrated that inhibition of
    laquinimod and a Phase III commenced in June 2007.           leukocyte transmigration is a successful strategy for the
    A Phase II study demonstrated a statistically significant    management of MS, although caution is needed with its use.
    reduction in new brain MRI lesions and patients with the     Thus, prescribing neurologists are familiar with the
    disease at the beginning treatment had a 52% decrease        application of its clinical utility and prescribe Tysabri® when
    in new lesions.                                              a patient is refractory to the interferon’s and Copaxone™.
•   ABT-874 is a fully human anti-interleukin-12 (IL-12)         There are only two indirect competitive compounds and two
    monoclonal antibody. Abbott Laboratories has begun a         direct competitors to ATL1102 that are inhibitors to leukocyte
    Phase II trial to evaluate the efficacy of ABT-874 in        transmigration.
    reducing MS brain lesions.
                                                                 •   The indirect competitors are FTY720 (Novartis) and
•   Alferon N (interferon α-n3) is in testing by Hemispherx          ZK811752 (Berlex). These compounds have the same
    Biopharma. In a retrospective study, brain MRI was               cellular application (inhibition of leukocyte
    performed on 69 MS patients, where 31 were treated               transmigration), but undertake this via a different mode
    with interferon α-n3 and 38 declined interferon α-n3             of action to Tysabri® (Biogen Idec), 683699 (GSK) and
    therapy. MRI identified lesions in two (6%) of the 31            ATL1102.
    treated patients and 14 (37%) of the 38 untreated
    patients. The results also showed improved muscular          •   Tysabri® and 683699 are direct competitors as these
    coordination in the treated patients.                            inhibit leukocyte transmigration via the same
                                                                     mechanism as ATL1102. Although we can hypothesis
•   NeuroVax (IR208) is a synthetic T-Cell receptor peptide          at what the different clinical uses of these three VLA-4
    vaccine developed by Immune Response Corporation.                inhibitors could be, only with further clinical and
    NeuroVax™ contains three peptides (BV5S2, BV6S5                  ADMETox data can an accurate assessment of the
    and BV13S1) expressed by T-Cells in over 90% of MS               different utilities be made.
    patients. NeuroVax™ is currently undergoing Phase II
    studies in a 200-patient trial.                              As a leukocyte transmigration inhibitor; ATL1102 would have
                                                                 second mover advantage if clinical trials prove successful
•   Genzyme was undertaking Phase II testing of Campath-         because of clinical application familiarity. This is assisted by
    1H (alemtuzumab, anti-CD52 monoclonal antibody),             Tysabri® being the most effective therapy on the market for
    which reduces the number of T-Cells. In earlier trials, it   the management of MS.
    was identified that Campath-1H therapy is more
    effective if given early. However, the issue with this       Another key advantage would be the cost of ALT1102 over
    drug is it causes Graves Disease in one third of patients    Tysabri®. At about US$28k for an annual course of
    and causes more aggressive disease progression once          Tysabri®, we believe the cost of ALT1102 would be cheaper
    off the drug. As a result the trial was terminated.          as oligonucleotides are relatively inexpensive to synthesis.
Oligonucleotide synthesis is routine and can be easily
scaled-up. Therefore, if ALT1102 enters the market, we
                                                                 Financial Position
expect the pricing to be exploited to capitalise on its second
                                                                 For the Year Ending June 2007, the company held $7.6m
mover advantage.
                                                                 cash. The main expense for the year was Staff Costs
A further potential advantage of ALT1102 over Tysabri® is        representing $1.2m and Research and Development Costs
that ALT1102 does not appear to generate neutralising            at $1.1m. Total expenses represented $2. 7m.
antibodies or cause anaphylaxis. Tysabri® decreases the
                                                                 For the forecast year end June 2008, we anticipate Staff
number of relapses and new brain lesions in MS patients,
                                                                 Costs to remain stable at about $1.2m, but R&D costs are
when administered IV every 4 weeks, yet anaphylaxis can
                                                                 anticipated to increase to about $4.0m per annum due to the
occur and persistent neutralising antibodies were reported in
                                                                 Phase II clinical trial costs. Total expenditure is anticipated
6% of patients. In these patients, the relapse of MS was the
                      8                                          to be in the range of $6.0m
same as the placebo .
                                                                 The company has enough cash to complete the current
Further advantages and limitations of using an antisense
                                                                 Phase II Clinical Trials, but further capital will have to be
compound over an antibody or small chemical entity can
                                                                 raised should the company undertake larger human clinical
only be established after further clinical trials.
                                                                 trials and advance its development pipeline.
We are of the opinion that, if ALT1102 is successful in
clinical trials, it would initially enter the market as an
alternative for patient’s refractory to Tysabri®. Once
familularity of the use of ALT1102 becomes adopted by the
medical community, price competition could be the key
factor that could allow ALT1102 to challenge Tysabri’s           An investment into Antisense is appropriate for investors
market share.                                                    who are tolerant to the binary risk associated with the
                                                                 outcome the Phase II clinical trial. The results of this trial are
                                                                 anticipated to be release late 2007 or early 2008.

ISIS Agreement                                                   The company’s share price is currently low relative to its
                                                                 peers because of the perception the company carries higher
                                                                 risk than other ASX quoted biotechnology companies. The
The company acquired an exclusive license from ISIS to
                                                                 company is exposed to
undertake development of ATL1102. The financial terms of
the licensing deal are undisclosed.                              •   Clinical risk – The risk that ATL1102 is an effective
ISIS has 1,500 issued patents that broadly cover antisense           inhibitor of leukocyte migration and demonstrates
and RNA patent estates. Patents cover antisense                      clinical activity against MS and
mechanisms, biology, chemistry, inhibitors of gene               •   Technical risk -The risk that the antisense technology
expression and the manufacturing of antisense drugs.                 can be used as a platform to develop a viable
ISIS is internally taking 6 antisense compounds through              therapeutic compound.
development with antisence compounds targeting ApoB-100          In the event ATL1102 is successful in the Phase II clinical
and PTP-1b for the treatment for Cholesterol and Diabetes        trial the risk of both of these perceptions will be diminished
management in Phase II Clinical Trials. The company also         and we believe the company’s valuation should move closer
has 11 antisense compounds in development with partners          to comparable Australia companies. Currently the company
including OncoGenex, Eli Lilly, Merck, ALSA, iCO, ImQuest        is about one half the value of a comparable Australian
and Atlantic Healthcare. Antisense molecules targeting           company and one-fifth the value of a Comparable that has
Clusterin (OncoGenex), HCV (Merck), ICAM-1 (Atlantic             completed some efficacy trials.
Healthcare) and VLA-4 (Antisense) are in Phase II clinical
trials. Novartis formally marketed Vitravene®, but it has        We recommend a Speculative Buy for the high risk / high
been superseded in the market place.                             reward tolerant investor knowledgeable and accepting of the
                                                                 risks associated with investing into a speculative opportunity
                                                                 that will have a binary outcome within 6 to 9 months.

8   Med Lett Drugs Ther. 2005 Feb 14;47(1202):13-5.
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be relied upon without advice from a securities adviser as to the appropriateness to you given your individual investment
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securities or the issuer; and that no part of his remuneration was, is, or will be, related to the recommendations or views expressed
by him in the report.
Prepared by Darren J. Grubb PhD MBA GDipAppFin