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Scalp Injection of Active Embryonic-like Cell- secreted Proteins and Growth Factors Gail K. Naughton, Ph.D

Scalp Injection of Active Embryonic-like Cell- secreted Proteins and Growth Factors

Gail K. Naughton, Ph.D.

Conflict of Interest

DISCLOSURES:

Conflict of Interest DISCLOSURES: Speaker has disclosed conflict of interest. Dr. Gail K. Naughton serves as

Speaker has disclosed conflict of interest. Dr. Gail K. Naughton serves as CEO and Chairman of the Board for Histogen, Inc.

Technology Focus: Regeneration

Technology Focus: Regeneration Histogen’s technology focuses on stimulating a patient’s own stem cells by delivering

Histogen’s technology focuses on stimulating a patient’s own stem cells by delivering a proprietary complex of human proteins that have been shown to support stem cell growth and differentiation.

This multipotent cell conditioned media has a broad range of applications in both aesthetics and therapeutics:

Current and near-term: Skincare and Cosmetics

First therapeutic, no reimbursement: Hair growth

Second therapeutic: Oncology

Other Opportunities for soluble and insoluble extracellular matrix: Wound care, Device Coating, Bone and Muscle regeneration, Dermal filler

Bioactive human growth factors

VEGF

KGF

Follistatin

Stem Cell Factor

factors VEGF KGF Follistatin Stem Cell Factor Human matrix components Collagens Laminin GAG

Human matrix components

Collagens

Laminin

GAG

Decorin

Fibronectin

C-propeptide

Cells grow in suspension under low oxygen, simulating embryonic environment Stem Cell signaling proteins are
Cells grow in suspension under low oxygen, simulating embryonic environment Stem Cell signaling proteins are

Cells grow in suspension under low oxygen, simulating embryonic environment

under low oxygen, simulating embryonic environment Stem Cell signaling proteins are secreted into the growth
under low oxygen, simulating embryonic environment Stem Cell signaling proteins are secreted into the growth

Stem Cell signaling proteins are secreted into the growth medium

Cell signaling proteins are secreted into the growth medium ReGenica skincare Hair Stimulating Complex (HSC) Oncology
Cell signaling proteins are secreted into the growth medium ReGenica skincare Hair Stimulating Complex (HSC) Oncology

ReGenica skincare Hair Stimulating Complex (HSC) Oncology

ReGenica skincare Hair Stimulating Complex (HSC) Oncology Intradermal injection of HSC stimulates hair follicle stem
ReGenica skincare Hair Stimulating Complex (HSC) Oncology Intradermal injection of HSC stimulates hair follicle stem

Intradermal injection of HSC stimulates hair follicle stem cells to create new hair

Stimulating Complex (HSC) Oncology Intradermal injection of HSC stimulates hair follicle stem cells to create new

4

Phase I/II Clinical Trial Double-blind, placebo controlled, randomized, each subject acts as their own control

Phase I/II Clinical Trial

Double-blind, placebo controlled, randomized, each subject acts as their own control

randomized, each subject acts as their own control HSC Baseline + 6 wks Control Baseline +
randomized, each subject acts as their own control HSC Baseline + 6 wks Control Baseline +
HSC Baseline + 6 wks Control Baseline + 6 wks
HSC
Baseline
+ 6 wks
Control
Baseline
+ 6 wks
control HSC Baseline + 6 wks Control Baseline + 6 wks Single Treatment Site Subjects –
control HSC Baseline + 6 wks Control Baseline + 6 wks Single Treatment Site Subjects –

Single Treatment Site

Subjects

56 men (50 to complete) MPHL. 21-65 years old

Treatments (at Baseline, 6 weeks)

Control (DMEM, Dulbecco’s Modified Eagles Medium)

Hair Stimulating Complex (HSC) concentrated/conditioned

Assessment Times

– Baseline, Week 12, Wk 24, Wk 48

– Wk 36 supplemental informational visit (EC approved)

Endpoints

Primary: Safety Clinical Evaluation for SAEs or AEs Blood and urine for liver and kidney tox ADA analysis

Secondary: Safety Investigator and Subject self assessments

Primary: Efficacy (12 weeks)

Trichoscan (Macrophotography, FotoFinder) quantify change in total and non-vellus hair counts and hair thickness

Secondary: Efficacy Clinical macrophotography (hair counts, etc.)

21 CFR Part 11 compliant (closed system)

Investigators

– Dr. Julieta P. Arambulo and Dr. Theresa Reyes Cacas

5

Hair Stimulating Complex (HSC) – Phase I/II Clinical Trial

Hair Stimulating Complex (HSC) – Phase I/II Clinical Trial Subjects sites treated with HSC - representative

Subjects sites treated with HSC - representative samples

S1016

S2018

Baseline

with HSC - representative samples S1016 S2018 Baseline 3 month 3 month Hair count + 61.41%
with HSC - representative samples S1016 S2018 Baseline 3 month 3 month Hair count + 61.41%

3 month

HSC - representative samples S1016 S2018 Baseline 3 month 3 month Hair count + 61.41% Terminal
HSC - representative samples S1016 S2018 Baseline 3 month 3 month Hair count + 61.41% Terminal

3 month

Hair count + 61.41% Terminal hair + 55.63% Thickness + 63.03%

Hair count + 35.88% Terminal hair + 45.83% Thickness + 42.76%

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Total Hair Count – 12 Weeks

Total Hair Count – 12 Weeks • Phase I/II trial design produced 46.5% better results in

Phase I/II trial design produced 46.5% better results in total hair count than the pilot trial at 12 weeks

A 10.45% Increase in Mean Total Hair Count over baseline was seen

The increase in hair count is statistically significant, unlike the pilot trial, at 12 weeks

16 * 14 12 10 46.5% 8 6 4 2 0 Honduras Pilot Philippines Phase
16
*
14
12
10
46.5%
8
6
4
2
0
Honduras Pilot
Philippines Phase I/II
% Change

p=0.0013

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Terminal & Vellus Hair Counts – 12 Weeks

Terminal & Vellus Hair Counts – 12 Weeks • Statistically significant increase in terminal hair count,

Statistically significant increase in terminal hair count, a primary efficacy measure

An increase in vellus hair count was also seen, supporting the hypothesis that HSC rescues dying follicles, in addition to converting vellus to terminal hairs and increasing the number of hairs per follicle.

28 ** 23 18 * 13 8 3 -2 Vellus Hair Count Terminal Hair Count
28
**
23
18
*
13
8
3
-2
Vellus Hair Count
Terminal Hair Count
p=0.033
p=0.0135
% Change

Hair Thickness – 12 Weeks

Hair Thickness – 12 Weeks An increase in hair thickness density is a result of: 1)

An increase in hair thickness density is a result of: 1) An increase in hair count, 2) An increase in the number of terminal hairs and 3) An increase in hair shaft diameter, all of which are important to cosmetic impact.

8.80 * 8.60 8.40 8.20 8.00 7.80 7.60 7.40 7.20 Baseline 12 Weeks p=0.026 Cm
8.80
*
8.60
8.40
8.20
8.00
7.80
7.60
7.40
7.20
Baseline
12 Weeks
p=0.026
Cm Thickness Density (mm/cm 2 )

Clinical Chemistry

Clinical Chemistry No indication of toxicity or blood/urine abnormalities in the patient population following both sets
Clinical Chemistry No indication of toxicity or blood/urine abnormalities in the patient population following both sets
Clinical Chemistry No indication of toxicity or blood/urine abnormalities in the patient population following both sets
Clinical Chemistry No indication of toxicity or blood/urine abnormalities in the patient population following both sets
Clinical Chemistry No indication of toxicity or blood/urine abnormalities in the patient population following both sets

No indication of toxicity or blood/urine abnormalities in the patient population following both sets of HSC injection. Clinical evaluation of blood serum chemistry, hematology and urinalysis showed no changes from baseline over the course of the treatment. No evidence of toxicity is observed in any of the clinical indicators.

Trend Analysis 35% 30% 25% Following the trend, a 25% increase is forecasted for the
Trend Analysis
35%
30%
25%
Following the trend,
a 25% increase is
forecasted for the 48
week timepoint.
20%
15%
10%
Philippines
Honduras
5%
0%
12wk
24wk
48wk

HSC injections result in the stimulation of bulge stem cells and the conversion of vellus to terminal hairs follicles from late telogen to anagen.to result in increased terminal and vellus hairs at the 12 week time point.

HSC injections are compressing the anagen phase and accelerating the catagen and telogen cycles which explains the decline in terminal and increase in vellus at 24 weeks and subsequent increase in

total, terminal, and vellus hairs at week 48.

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Philippines Phase I/II Regional Data

Philippines Phase I/II Regional Data Mid-Scalp Treatment Locations 30 25 20 15 10 5 0 12

Mid-Scalp Treatment Locations

30 25 20 15 10 5 0 12 Weeks 24 Weeks 36 Weeks % Change
30
25
20
15
10
5
0
12 Weeks
24 Weeks
36 Weeks
%
Change from Baseline

Vertex Treatment Zones

30 Total Hair Count 25 Terminal Density 20 Vellus Density 15 10 5 0 12
30
Total Hair Count
25
Terminal Density
20
Vellus Density
15
10
5
0
12 Weeks
24 Weeks
36 Weeks
%
Change from Baseline

• Graphs show the % Change in Total, Terminal and Vellus Densities at each time point.

• Mid-Scalp and Vertex treatment regions show similar growth trends and are consistent with the trends shown to date

Philippines Phase I/II Regional Data

• % Change each time point for treatment zones in the Temporal Recession shown below

• Unlike currently available treatments, HSC produced visible growth in subjects treated in TR region.

30

25

20

15

10

5

0

-5

-10

Temporal Recession

12 Weeks 24 Weeks 36 Weeks
12 Weeks
24 Weeks
36 Weeks

Total Hair Count10 5 0 -5 -10 Temporal Recession 12 Weeks 24 Weeks 36 Weeks Terminal Density Vellus

Terminal Density10 5 0 -5 -10 Temporal Recession 12 Weeks 24 Weeks 36 Weeks Total Hair Count

Vellus Density10 5 0 -5 -10 Temporal Recession 12 Weeks 24 Weeks 36 Weeks Total Hair Count

Recession 12 Weeks 24 Weeks 36 Weeks Total Hair Count Terminal Density Vellus Density S2005 Baseline

S2005

Recession 12 Weeks 24 Weeks 36 Weeks Total Hair Count Terminal Density Vellus Density S2005 Baseline

Baseline

Recession 12 Weeks 24 Weeks 36 Weeks Total Hair Count Terminal Density Vellus Density S2005 Baseline

36 Weeks

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Age Analysis

Age Analysis Unlike current non-surgical treatments, with efficacy limited to younger patients or earlier stages of

Unlike current non-surgical treatments, with efficacy limited to younger patients or earlier stages of hair loss, HSC has the potential to expand the hair restoration market by offering a successful option to older patients.

Subjects Age 40+ % Change from Baseline Total Terminal Vellus 12wk 19.35 39.11 15.67 24wk
Subjects Age 40+
% Change from Baseline
Total
Terminal
Vellus
12wk
19.35
39.11
15.67
24wk
13.39
16.96
17.26

Cosmetically significant results seen in subjects 40-59 years of age in both trials.

Pilot Trial -Subjects Age 40+ % Change from Baseline Total Terminal Vellus 12wk 8.52 21.94
Pilot Trial -Subjects Age 40+
% Change from Baseline
Total
Terminal
Vellus
12wk
8.52
21.94
5.09
24wk
5.42
12.88
-0.05
48wk
18.30
37.17
18.34

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Dr. Ziering - Phase I U.S.   IRB approved Original Design: Treatment: • Open Label,
Dr. Ziering - Phase I U.S.   IRB approved Original Design: Treatment: • Open Label,

Dr. Ziering - Phase I U.S.

 

IRB approved Original Design:

Treatment:

Open Label, safety study

Up to 20 0.1mL injections of HSC in two treatment areas at baseline with an additional 20 0.1mL intradermal injections at Week 6.

• 10 Subjects (5 Female and 5 Male)

• Baseline, 6 Week repeat dose

Amended Design:

 

Patient consent obtained

• Up to 40 intradermal injections (0.1mL each) of HSC in broader treatment area (at the 12 week time point and

 

again at 18 week time point)

Subjects who have completed amended design will have a total of 120 injections throughout study

Enrollment:

 
 

Safety Update:

• No SAEs

100% Enrollment 100% of Subjects have completed 6 week Repeat dose

100% of Subjects have re-consented and have had increased volume

• All injections well- tolerated

 

40

x 0.1cc injections in the same areas and surrounding areas

~97% of the injectate is retained in the tissue

 

U.S. Physician-sponsored Trial- Dr. Craig Ziering

Re-consented female subject received an additional 20 injections of 0.1 cc HSC with a repeat dose at 6 weeks.

20 injections of 0.1 cc HSC with a repeat dose at 6 weeks. Baseline . *Photo

Baseline

.
.

*Photo reflects total of 30 injections

19 Weeks

U.S. Physician-sponsored Trial- Dr. Craig Ziering

Female Subject received 20 injections of 0.1cc HSC in area of thinning, with a repeat of this dose at 6 weeks.

received 20 injections of 0.1cc HSC in area of thinning, with a repeat of this dose

Baseline

received 20 injections of 0.1cc HSC in area of thinning, with a repeat of this dose

19 Weeks

U.S. Physician-sponsored Trial- Dr. Craig Ziering

Re-consented female subject received an additional 20 injections of 0.1 cc HSC in new treatment location- frontal thinning, with a repeat dose at 6 weeks

injections of 0.1 cc HSC in new treatment location- frontal thinning, with a repeat dose at

Baseline

injections of 0.1 cc HSC in new treatment location- frontal thinning, with a repeat dose at

12 Weeks

U.S. Physician-sponsored Trial- Dr. Craig Ziering

Reconsented male subject received an additional 40 injections of 0.1 cc HSC in the same regions- broadening the treatment area, with a repeat dose at 6 weeks .

of 0.1 cc HSC in the same regions- broadening the treatment area, with a repeat dose

Baseline

of 0.1 cc HSC in the same regions- broadening the treatment area, with a repeat dose

24 Weeks

Local Tolerance

Local Tolerance Subject Self Assessment on Local Tolerance 7 6 5 4 3 2 1 0

Subject Self Assessment on Local Tolerance

7 6 5 4 3 2 1 0 No Mild Slightly Moderately Extremely Discomfort Discomfort
7
6
5
4
3
2
1
0
No
Mild
Slightly
Moderately
Extremely
Discomfort
Discomfort
Painful
Painful
Painful
Number of Responses

Subject self assessments (SSA) from IND trial reflect an excellent tolerance for the procedure, with the majority of subjects reporting no discomfort. These results are consistent with those reported in other trials.

Visual examination for redness, inflammation, swelling or edema continues to show overall excellent safety profile for HSC in all subjects

Clinical Experience Summary

Proof of Concept Clinical Trial

SAFETY (primary objective) 2 year follow-up

Clinical Trial SAFETY (primary objective) 2 year follow-up • No adverse reactions, hamartomas, toxicity; normal

No adverse reactions, hamartomas, toxicity; normal histology

EFFECTIVENESS (secondary objective)

• 12 Weeks: HSC injection resulted in significant increase in terminal hairs and thickness density

Cumulative thickness density (mm/cm 2 ) p=0.0249

Terminal hair density

p=0.029

• 1 Year: HSC injection resulted in continued significant hair growth

Total hair count

p=0.032

Phase I/II Clinical Trial – 56 Subjects

PRIMARY SAFETY 12 weeks

Clinical chemistry showed no indication of toxicity or blood/urine abnormalities PRIMARY EFFICACY 12 weeks

• 10.45% increase in mean total hair count over baseline

• 19.5% increase in mean terminal hair count over baseline p=0.0135

• Statistical significance in all efficacy measurements

• No indication of toxicity or blood/urine abnormalities following both treatment timepoints

p=0.0013

Clinical Experience Summary (cont)

U.S. Physician sponsored IND- 10 Subjects

5 men, 5 women

U.S. Physician sponsored IND- 10 Subjects 5 men, 5 women • All patients have shown new

• All patients have shown new hair growth by 6 weeks

• 9/10 subjects have had 20 injections at baseline and 6 weeks, and achieved safe passage to 40 injections at 12 and 18 weeks.

• 4/10 subjects have completed the study

• 4/4 of the subjects that have completed the study all answered that they would participate in future clinical studies

Responder rate:

84.6% in Proof of Concept Trial at 24 weeks

• 86% in Phase I/II at 24 weeks

• 100% in Physician IND trial

Clinical Update Summary

Clinical Update Summary Further analysis of the data suggests a tremendous marketing advantage over other approved

Further analysis of the data suggests a tremendous marketing advantage over other approved treatments, offering a treatment option to those patients that currently have none:

• Regional analysis shows that HSC grows new hair in all regions of the scalp – temporal recession, mid scalp and vertex. (Minoxidil and Propecia do not have positive results in hard-to-treat temporal regions)

• Data shows that men over 40 respond extremely well to HSC, as shown in both Honduras and Philippine trials (current products are most effective in men in their 20s and 30s, in the early stages of hair loss)

• Furthermore, investigator-initiated trial shows great efficacy results in women

• HSC continues to have a very strong safety profile, even at 36 weeks

Questions?

Gail K. Naughton, Ph.D. CEO & Chairman of the Board Histogen, Inc. www.histogen.com

Questions? Gail K. Naughton, Ph.D. CEO & Chairman of the Board Histogen, Inc. www.histogen.com 24

Business Model

Business Model Histogen’s focus is on the development and manufacturing of products from its novel core

Histogen’s focus is on the development and manufacturing of products from its novel core technology process.

As such, Histogen will achieve profitability through research partnerships, upfront licensing payments and post-commercialization royalty streams attached to each of its product applications.

Research Partnerships

Example: use of Histogen’s extracellular matrix (hECM) as a coating to improve biocompatibility of existing medical devices.

Licensing Deals

Example: license for specific product applications, such as the ReGenica skincare products, hECM for wound healing or soft tissue augmentation, or the HSC injectable for hair growth.

Biomaterial Supplier

Example: supplying of Histogen’s soluble extracellular matrix as a raw material for product formulations such as a private label skin or hair care line.

Attachment to material presented on October 19, 2012

Current Private Placement Financing

Current Private Placement Financing The Company is currently looking to sell 23 million shares of Series

The Company is currently looking to sell 23 million shares of Series B Preferred

Stock at $1 per share to accredited investors (i.e., investors whose net worth, including the fmv of their home, exceeds $1 million and whose annual income exceeds $200,000).

To date, $3.3 million is committed.

The proceeds from the financing will be used to:

Complete large animal and clinical serum (ADA) testing required

before starting the next HSC clinical trial

Complete Scale-up of GMP Manufacturing

Complete two preclinical studies with oncology product

Prepare and submit IND for Phase I pancreatic cancer trial

Support worldwide development of patent portfolio

cancer trial  Support worldwide development of patent portfolio Attachment to material presented on October 19,

Attachment to material presented on October 19, 2012