1. 1
New Organic Germanium
Molecules for Therapeutics
Core Technology Platform for New
Molecules
July 2013
R&D project

2. 2
WDS Pharma LLC
 Synthesis, R&D of new organic germanium molecules for perspective use in medicine,
health care, veterinary and cosmetic
Researches are going on since 2005. The proprietary core technology platform for
chemical synthesis of Germanium and different organic substances was developed. The
technology allows purposely to construct a variety of unique bioactive molecules based
on organic germanium compounds, perspective for medical therapies.
 The current foresights are:
 Antiviral (antiherpetic) therapy
 Anticancer therapy
 Anti-acne
 Diabetes type 2
 New water-soluble vaccine adjuvant
 Anti-infection therapy etc.
 IP: 5 Russian patents (2 patents received in 2013), 4 PCT (2 PCT issued in 2012 г)
 Since September 2012 WDS Pharma is a resident of Skolkovo Innovative Cluster

3. 3
1. One of the main advantages of the developed technology platform is its technological
and technical simplicity, universality (variety of initial organic molecules can be used),
and availability of main synthesis reagents, which are biogenic. This excludes the
possibility of contamination of final product with unwanted toxic or hazard impurities
(green chemistry).
2. The chemical purity of new synthesized compounds is >99% and totally free of
germanium dioxide.
3. We are able to create a variety of new organic molecules with different bioactivity and
perspective for new drug development (novel drug candidates) see Suppl. 1
4. We are also able to create the new unique molecules with improved characteristics and
activity on the base of different generic substances (me-too drugs). See Suppl. 2
5. All new molecules are patentable
Core Technology Platform

4. 4
Carboxylic acids,
aminoacids, their
derivateves and
other organic
molecules
Organic
germanium
molecules
GeO2
New bioactive
organic
germanium
molecules
Generic
New
ME-TOO
DRUG
NOVEL
DRUG
Proprietary Technology Platform

5. 5
Our current researches help us to believe and demonstrate that the new molecules have the
following key advantages:
 High water and biopharmaceutical solubility resulting to higher bioavailability.
 Safe for Human (acute, cumulative and mutagen non-toxicity etc).
 Small molecule’s size allows to penetrate physiological barriers
 The therapeutic effect of me-too drugs is higher (comparing with the initial generic) due
to synergism and better pharmaceutical characteristics
 Allows to use less dosage of me-too drug with the same or higher therapeutic
efficiency, that also lead to decreasing of general and organ’s human medication
intoxication and side effects.
Advantages of New Molecules

6. 6
Pipeline
Compound Indication Discovery Preclinical Phase 1
WDS-1 (gel, suppositories) Genital Herpes, Cold Sore & Oral
Herpes
WDS-1 (capsules) Herpesviruses infections
WDS-3 (gel) Dermatology (Acne, Rozacea)
WDS-10 Solid Tumors
WDS-11 Solid Tumors
WDS-9 Immunotherapy
Water-soluble Vaccine Adjuvant
WDS-HGC Immunotherapy
Water-soluble Vaccine Adjuvant
WDS-HGC Diabetes type 2
WDS-18 Osteoporosis, calcium
metabolism

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 Ivanovskiy Virology Institute (prof. Igor Barinskiy, Dr. Ludmila Alimbarova),
Moscow;
 Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer
ITEM) (Dr. Jochen Buschman), Hannover (Germany)
 Pasteur Institute of Epidemiology and Microbiology (prof. Areg Totolyan, Dr.
Irina Lavrentieva), Sankt-Peterburg
 Petrov Oncology Institute (prof. Vladimir Anisimov), Sankt-Peterburg
 Mechnikov Vaccines and Serum Institute (prof. Vsevolod Lyashenko, prof.
Ludmila Krasnoproshina, prof. Nelly Akhmatova), Moscow
 Molecular System Ltd. (Dr. Valery Ossovskaya), SF (USA)
R&D Cooperation

8. 8
New Organic Germanium molecule
Russian Patent № 2293086 dated 27.12.2005 (PCT # WO/2007/075122)
in vitro & in vivo initial studies
Nano-size bioactive molecule
Supplement 1

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№ Parameter Data
1 Name 1-hydroxygermatranil citrate (HGC)
2 Category Small molecule
3 Appearance White powder
4 Solubility in water 200C > 60%
5 pH 4
6 Solubility in organic solvents Insoluble
7 Solubility in pH 1.2/4.4/6.8 >500 mg/ml / >500 mg/ml / >500 mg/ml
8 Solubility in FaSSIF / FeSSIF > 500 mg/ml / 500 mg/ml
9 Chemical purity >99.5%
10 Odour Odourless
Main Characteristics

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 Low acute toxicity
 According to LD50 (> 5000 mg/kg mice I.P.) the compound belongs to the V class
of hazard (Hodge, Sterner)
 Allergic and skin-resorptive action (in guinea pigs and CBA mice)
 No immediate or delayed hypersensitivity reactions were documented
 No changes in nonspecific immunity or numbers of leucocites and eosinophiles
 Mutagenic action:
 Ames test: the compound can not induce mutations of genes in test strains of
Salmonella typhimurium
 Count of chromosomic abberations in mice bone marrow: the compound does not
have mutagenic action
Studies by Russian Scientific Center of Biological Substances Safety and Sysin
Institute of the Human Ecology and Environmental Hygiene, Moscow
Toxicological Safety

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The laboratory screening studies showed the folowing biological activities:
 Immunomodulatory and immunostimulatory action; possible effect on stem cells
activity;
 Strong adjuvant action;
 Anti-infection (antiviral, anti-bacterial)
 Antihypoxic and nootropic action;
 Antitoxic action (decrease the side effects of some drugs);
Biological Activities Perspective for
Medicinal Use
Due to nanosize HGC demonstrates
o Interacion with TLR-receptors, including extracellular (TLR4, TLR2) and intracellular
(TLR9)
o Activation of the intrinsic immunity.
o Stimulation globulin-forming cells (demonstrated in vivo, in intact, as well as in
immunized animals).
o Ability to permeate the BBB and act on processes in brain

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Study by Mechnikov Institute of Vaccines and Serums, Moscow
The similar dynamics was
registered for T,
CD19, CD5 and other
markers
0
10
20
30
baseline ГОС 24 ч ГОС 7сут
CD3
0
5
10
15
baseline ГОС 24 ч ГОС 7сут
NK
0
1
2
3
4
baseline ГОС 24 ч ГОС 7сут
CD3/NK
0
1
2
3
4
baseline ГОС 24 ч ГОС 7сут
CD4/CD25/Foxp3
0
5
10
15
20
25
baseline ГОС 24 ч ГОС 7сут
CD8
Action of immune status changing in
immunized mice
HGC 24h HGC 7 days HGC 24h HGC 7 days
HGC 24h HGC 7 days HGC 24h HGC 7 days
HGC 24h HGC 7 days

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0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
TLR2 TLR4 TLR9
Effect on TLR2, TLR4, TLR9 activation in vivo
baseline
Ваксигрипп 24 ч
В+ГОС 24 ч
ГОС 24 ч
Baseline
Flu vaccine 24 h
Flu vaccine + HGC
24h
HGC 24 h
Adjuvant action
Study by Mechnikov Institute of Vaccines and Serums, Moscow

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0
200
400
600
800
1000
1200
Amount of antibody-forming cells in mice spleen in 4 days after
injection with T-independent antigen (Dextran) (detected by ELISPOT)
N
Dex
Dex + ГГЦ
Baseline
Dex
Dex+ HGC 10
mcg
Summary: the increasing of Antibody-Forming cells in >2,4 fold.
Adjuvant Action
Study by Mechnikov Institute of Vaccines and Serums, Moscow

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Immune response in mice after administration of
erythrocites and cyclophosphamide
Av .hemagglutinin dilution
Sheep’s erythrocites and cyclophosphamide 50 mg/kg,
simultaneously
3,5±1,03
Sheep’s erythrocites, cyclophosphamide, and HGC 500
mg/kg, intraperitoneal, simultaneously
6,25±0,33 √
Control 5,12±0,61
Immune Support during
Immunosupression by Cyclophosphamide
Study by Mechnikov Institute of Vaccines and Serums, Moscow
Study model:
 Immunisation of mice by sheep’s erythrocites.
 Antybodies production increases in the case of simultaneous or consecutive
administration of HGC and erythrocites
 Prevents the immunity inhibition and demonstrates antitoxic action

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Effect on mice tolerance of the St.aureus infection
Test methodic:
Each mouse received 20 μkg twice daily IP. 24
hours after the 2nd administration animals received
S. Aureus Wood 46 2,5х109 CFU. Microbial
suspension was administrated intraperitoneally in
0,2% agar. Animals were followed up for 3 days,
endpoint was death.
Product
Infection
Dose
Number of
mice
Animal death %
survived
miceDay 1 Day 2 Day 3
HGC 2.5х109 10 7 1 20
Control 2.5х109 10 10 * * 0
Effect on mice tolerance of the St.aureus infection
Animals were infected by
different doses to assess
LD 50.
Result: LD50 increased >4
times
Product
Infection
Dose
Number of
mice
Animal death
LD 50
Day 1 Day 2 Day 3
HGC
3х108
10 3
3х109
6х108
10 3
1,25х109
10 4 1
2,5х109
10 7
5х109
10 9
Control
3х108
10 3 2
7х108
6х108
10 5 1 1
1,25х109
10 8
2,5х109
10 9 1
5х109
10 9 1
Anti-infection and Protective Action
Study by Mechnikov Institute of Vaccines and Serums, Moscow

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Assessment of mice survival after infection by Salmonella Typhimurium
HGC was
administrated I.P.
Immunisation
scheme
Doze (μg)
Mice
number
% death LD 50 Lifetime (days)
24 hours before
and at the day of
infection
0,1 50 16 5,0*105
51,5
Control 50 28 1.2*105
22,5
Summary: Results show that HGC stimulates the intrinsic immunity and
protects animals, the animal lifetime increased in 2+ times in using of
HGC in microdozes
Anti-Infection and Protective Action
Study by Mechnikov Institute of Vaccines and Serums, Moscow

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Study by Brain Institute, Moscow
Before
StandardExperimental Experimental Standard
Antihypoxic Activity
40 min after
The changes in cerebral acid-base balance.
The intensity of volunteer’s (male, 57 years) brain energy status by method of measuring of
omnipresent millivolt potential levels before and in 40 min after oral administration of 50 ml
HGC water solution (1 mg/ml)

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Supplement 2
New Organic Germanium
me-too molecules
in vitro & in vivo studies

20. 20
Different unique new molecules based on generics had been synthesized using
the developed chemical technology platform e.g.:
I) Based on Aciclovir* (WDS-1)
*The used approach is totally differing from previously used for valacyclovir and other
synthesis. Thus the proprietary technology platform also allows to synthesize the
new molecules with other nucleotide analogous (valaciclovir, ganciclovir,
vidarubine, penciclovir etc.) to develop the antiherpetic molecule of me-better
class.
(PCT/RU2012/000897 dated 01.11.2012, priority date 16.05.2012 .).
II) Based on Azelaic Acid (WDS-3)
III) Based on Dichloroacetic Acid (WDS-11)
(Russian Patent № 2476436 dated 27.02.2013, priority date 25.01.2012,
PCT/RU2012/000922 dated 09.11.2012)
New Organic Germanium me-too molecules

21. 21
R&D project in cooperation with
 Fraunhofer Institute for Toxicology und Experimental Medicine (Fraunhofer
ITEM), Hannover (Germany)
 HannoverImpuls, Hannover (Germany)
 Ivanovskiy Virology Institute. Moscow
I. New Anti-herpetic molecule WDS-1
 Human Herpes viruses (herpetoviridae) include: herpes simplex virus
type 1 (HSV-1), herpes virus simplex type 2 (HSV-2), varicella zoster
virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and
human herpes virus HHV-6, HHV-7, HHV-8.
 Worldwide rates of HSV infection are between 65% and 90%.
 WHO reported that the lethal cases caused by HSV are 15.8% of all
viral disease and are the world second after flu lethality (35,8 %)

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Scientific Background
 Disorders caused by herpes viruses:
 Oral herpes is the most common form of infection, the visible symptoms
of which are called cold sores or fever blisters, acute herpetic
gingivostomatitis
 Anogenital herpes, known simply as herpes, is the second most
common form of herpes overall cause of genital ulceration in the world.
 Herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral
herpes infection encephalitis, Mollaret's meningitis, neonatal herpes.
 HSV-1 has been proposed as a possible cause of Alzheimer's disease
 HSV-1 as well as HHV-6 and HHV-8 are also considered to be an
important pathogen related to epilepsy
 The major public health importance of HSV-2 lies in its potential role as
a co-factor for HIV transmission

23. 23
Scientific Background
 Patients with immature or suppressed immune systems, such as
newborn infants, transplant recipients, or AIDS patients are prone
to severe complications from herpes viruses infections.
 As neurotropic and neuroinvasive viruses, HSV-1 and HSV-2
persist in the body by becoming latent and hiding from the immune
system in the cell bodies of neurons.
 Recurrent infections (outbreaks) occur from time to time, especially
in times of immune impairment (such as HIV and cancer-related
immune suppression)
 People who have genital HSV-2 have an average of 4-6 outbreaks
per year. About 20% of people with HSV-2 have 10 or more
outbreaks per year.

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Current problems in treatment
Treatments by antiviral medications (aciclovir and other nucleoside analogous) can
reduce viral reproduction and shedding, frequency, duration, and severity of outbreaks,
prevent the virus from entering the skin, and reduce the severity of herpetic symptoms.
But
 Aciclovir is poorly water soluble and has poor bioavailability (15-20% oral
and <4% topical). Thus patients on aciclovir therapy have to use high doses
leading to general and organ medication toxicity.
 The poor water solubility cause renal impairment due to the crystallization of
aciclovir in the kidneys.
 During the recurrence the herpes viruses activate and become the factor
aggravating the immunodeficiency. The protracted virus persistence leads to the
second immunodeficiency; however second immunodeficiency promotes the
virus activation. Aciclovir also seems to inhibit immune response.
 The main potential problem is the resistance towards aciclovir which evolves
rather rapidly, especially for the patients with diminished immunity

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New Strategy in Herpes Therapy
 A new Germanium-organic/aciclovir coordination complex WDS-1 was
synthesized by using proprietary unique know-how methods and
patented chemical technology.
 The developed technology platform also allows to synthesize the new
organic germanium coordination complexes with other different organic
molecules including nucleoside analogues e.g. valaciclovir, penciclovir,
famciclovir, ganciclovir, brivudine etc.
Acute toxicity 5 000 mg/kg (mice, IP)
Repeated doze toxicity 14 days/ Mice I.P./ /1000 mg/kg/day /NOAEL
Ames test negative

26. 26
New Strategy in Herpes Treatment
WDS-1 with the similar to ACV lipophilicity has considerably better
biorelevant and biopharmaceutical solubility, which can testify to its
higher bioavailability
Solubility, mg/ml
Solution medium ACV WDS-1
Water, 200C 0.13% > 25%
рН 1,2 3,5 mg/ml > 32 mg/ml
рН 4,4 2,6mg/ml > 32 mg/ml
рН 6,8 2,4 mg/ml > 32 mg/ml
Fasted State Simulated Intestinal Fluid (FaSSIF) 1,44 mg/ml > 32 mg/ml
Simulated Intestinal Fluid (FeSSIF) 1,38 mg/ml > 32 mg/ml

27. 27
Dual Mode of Action
Mode of Action
Virus inhibiting Immune modulation
Synergetic therapeutic efficiency
2 + 2 = 5 !

28. 28
Influence of WDS-1 on HSV-1 reproduction in eye lavagates of rabbits with ocular herpes
Mode of action - 1:
Virus inhibiting
Study by Ivanovskiy Virology Institute, Moscow
* - р<0,05
№/
№
Group size, n Days after infection / Virus titer lg TCD50/0,1ml(М±м).
2nd 5th 7th 9th 12th
1 Control 2,75±0,25 4,0±0,25 2,75±0,1 1,0±0.1 0,5±0,1
2 WDS-1 2,85±0,25 1,25±0,2 0,75±0,1* 0,5±0,1 0
Detected by in vitro neutralization reaction
Data adequacy compared with reference serum of non-infected animals

29. 29
Influence of WDS-1 on production of virus-neutralizing antibodies in blood
serum of rabbits infected with HSV-1 ocular herpes
Mode of action - 2:
Immune modulating
Study by Ivanovskiy Virology Institute, Moscow
№/
№
Group size, n In 2 weeks after infection In 3 weeks after infection
Titer of
Antibodies
P*
Titer of
Antibodies
P**
1
Control, (placebo)
1/128 <0,05 1/16 – 1/32* <0,05
2
WDS-1
1/256* <0,05 1/64 – 1/128* <0,05
3
Reference normal
serum
0 0
Detected by in vitro neutralization reaction
Data adequacy compared with reference serum of non-infected animals

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New Strategy in Herpes Treatment
VERO cell culture, infection dose 100 CTD50
Scheme: 1 hour after virus absorbtion
Detection after 96 hours
Anti-Herpetic Activity against HSV-1 ACV-resistant strain L2/R
Study by Ivanovskiy Virology Institute, Moscow
№/№
WDS-1 Aciclovir Valaciclovir
Sample
concentration
equivalent to
ACV (mcg/ml)
Virus titre
reduction
comparing to
control, lg
TCD50
Sample
concentration,
mcg/ml
Virus titre
reduction
comparing to
control, lg
TCD50
Sample
concentration,
mcg/ml
Virus titre
reduction
comparing to
control, lg
TCD50
1 400 3,25 500 2 500 1,5
2 160 1,50 250 1,5 250 1,5
3 80 0,75* 100 1 100 0,75*
4 40 0,5* 50 - 50 0,75*

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New Strategy of Herpes Treatment
Resume:
The studies demonstrated that new organic germanium compound WDS-1 is
non-toxic, has good biopharmaceutical characteristics and unique antiviral dual
mode of action: herpes virus inhibiting (including aciclovir resistant stains e.g.
L2/R of HHV-1) + activation and long period support of specific humoral
immunity.
These allows to develop different new medicines effective against herpes
viruses, which will have a lot of advantages (in comparision with market
analogous) e.g. higher bioavailability, less therapeutic dose, decreasing of side-
effects etc.
Furthermore the new medicines can be developed in variety of medicinal forms
including unique in the market (gel, suppositorium, eye drops and others)

32. 32
1.The program of preclinical studies required for the performance of
„First in Man“ clinical studies was approved by bfArM (Germany) on
July 05, 2012
2.The preclinical Russian registration studies of antiherpetic gel (for
cold sore and genital herpes) are starting in May 2013.
3.The preclinical Russian registration studies of antiherpetic vaginal
suppositorium (for genital herpes) are starting in 3-4Q 2013.
New Strategy of Herpes Treatment

33. 33
* Literature data
II. New Antimicrobic (anti-acne) molecule
WDS-3
Parameter Azelaic Acid WDS-3
Category Generic New patentable molecule
Water Solubility (20oC) 0.2% >10%
pH N/A*** 5.4
Acute toxicity, class of Hazard (Hodge,
Sterner) mice oral
V*** V
Skin irritant action Yes*** Negative
Skin-resorptive action N/A*** Negative
Sensibilization N/A*** Negative
Bioavailability Very low*** High**

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Antimicrobic activity of WDS-3 vs Skinoren (azelaic acid) against
Propionibacterium acnes by in vitro agar diffusion test
(products dilution 1:5)
II. New Anti-acne molecule WDS-3
Test microorganism
Size (diameter) of P. acnes growth inhibition zone (mm)
Skinoren*
gel 15%
Skinoren*
cream
20%
WDS-3*
gel 3%
WDS-3*
gel 5%
WDS-3*
cream 3%
WDS-3*
cream 5%
Propionibacterium
acnes 5592 12,5 15,5 17,5 22 18,5 27
Propionibacterium
acnes А-1 15,5 15 25 17 24 30
The less active concentrations of WDS-3 are more efficient against
Propionibacterium acnes than commercial «Skinoren» gel 15% и «Skinoren»
cream 20%.

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Characteristic DCA (sodium salt) WDS-11
Category Generic
New patentable
molecule
Solubility
рН 1,2, mg/ml 92,62 >108,29
рН 4,4, mg/ml 100,66 >147,69
рН 6,8, mg/ml 97,05 >165,28
Mode of action Warburg effect
Warburg effect +
Immune therapy
III. New Anticancer molecule WDS-11
We developed and synthesized the new organic germanium molecule
basied on dichloroacetic acid (DCA) and perspective for anticancer
therapy.

36. 36
III. New Anticancer molecule WDS-11
DCA sodium is inhibitor of mithohondrial pyruvate dehydrogenase and
now intensively studying as potential target medicine effective against
solid cancers1,2. The DCA’s mode of action is so called Warburg effect
– changing of cancer cells metabolism from aerobic glycolisys to
glucose-oxidative mechanism following to cancer cells apoptosis.
We believe that our new molecule can have dual mode of anticancer
action 2 in 1: inducting of Warburg effect + immunotherapeutic via
citokines (interferons) and natural killers stimulating.
The laboratory in vivo studies are planning to be start in 3-4Q 2013
1. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. ED Michelakis et al., British Journal of Cancer
(2008) 99, 989 – 994
2. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology.Sutendra G, Michelakis ED. Front Oncol. 2013;3:38

37. 37
We are open to
cooperation!
For further information, please contact:
WDS Pharma LLC
Dr. Igor Ambrosov
ambrosov@wdspharma.ru
Kulakova str., 20 bld. 1G,
123592 Moscow, Russia
Tel/fax +7 (495) 781-9203
Tel +7 (985) 765-2038