Dimera has developed a transdermal progesterone cream called DP9 to treat angina pectoris in women. Over 500,000 women die annually from cardiovascular disease, yet current drugs do not effectively treat the symptoms experienced by many menopausal women. DP9 aims to downregulate thromboxane receptor expression at the gene level to prevent abnormal vasoconstriction. Clinical trials show DP9 significantly reduces angina events and duration of symptoms. With over 3 million women suffering from treatment-resistant angina, DP9 has the potential to become a blockbuster drug as the first FDA-approved treatment tailored to women's heart health needs.

1. The 1st heart drug
for women
Gentle transdermal Rx
progesterone cream
to treat angina
pectoris in millions of
women

2. Unmet Need:
Angina Pectoris in Women
 In the US, ~500,000 women die annually from
cardiovascular (CV) disease
 7.2 million have coronary disease
Deaths from
 4.6 million suffer from angina pectoris (AP), a cardiovascular
symptom of coronary ischemia disease are twice the
number from
(source: CDC and AHA data) all kinds of cancer
combined
 3.2 million (70% of the 4.6 M women) treated for
angina pectoris find no relief
 Current drugs do not provide effective treatment for
menopausal women
 Their symptoms persist, despite all available
anti-anginal treatments, even if used
simultaneously
(source: NIH WISE data)

3. Key question—how does heart disease in women
differ from heart disease in men?
 Portion of AP women treated with non-obstructive coronary
disease (from cath lab) is 70% (WISE data)
 Portion predicted with coronary hyperreactivity (CH) and
progesterone deficit may be 70% (Dimera discoveries
published in 1997, 1998, 2001, 2004, and 2008)
 Randomized Clinical Trials will investigate this as the 1st
CV human study of progesterone therapy ever performed

4. Dimera’s 1st discovery – the link between
angina pectoris and coronary hyperreactivity
 In women, persistent constriction of
arteries leads to myocardial ischemia and
resulting angina pectoris
 Causing ischemia in the absence of “structural”
causes, such as atherosclerosis (plaques & clots)
 Coronary hyperreactivity (CH) is a new
target for anti-anginal drug development—a
new medical insight
 Primate model developed by Dimera
established CH as a cause of ischemia
 Q: Why does incidence of angina
increase so dramatically in menopausal
women?

5. Dimera's 2nd discovery—
Progesterone (DP9) controls the thromboxane receptor
 Thromboxane is a natural constrictor
inflammatory substance continuously -DP9 +DP9 -DP9 +DP9
released (with serotonin) from blood
platelets that can trigger myocardial TP
ischemia and angina pectoris receptor
 Deficiency in progesterone causes over- ERK
1/2
expression of thromboxane-prostanoid in vivo in vitro
(TP) receptors in coronary vascular
muscle cells
 A: Inadequate progesterone level Proof of vascular muscle mechanism
 14-day transdermal in vivo and
allows increased expression of TP  3-day single cell exposure in vitro
 P levels are < 1/8 of luteal peak
receptors—which appears to increase
risk of anginal ischemia in menopausal
women
DP9 progesterone restores transcriptional suppression of TP receptor at
the gene level, thereby preventing abnormally prolonged vasoconstriction
(the source of microvascular angina)

6. Efficacy Evidence in Women
DP9 Extended-Crossover RCT Results
Angina pectoris Angina duration
Endpoints
events /28 days in minutes
Women Control +DP9 Control +DP9
Subject 1 49 11 10760 660
Subject 2 17 1 2370 1
Subject 3 21 14 248 241
Four weeks of treatment alternating following 4 week washouts
DP9 at 1-4 ng/ml plasma improved clinical outcomes over
key angina parameters, notably without consistent TET
benefits (present diagnostic criteria)

7. Solution to the unmet need—DP9
 DP9 is the 1st heart drug for women—who
predominantly experience atypical, non-exercise
(microvascular) angina; DP9 is unlike synthetics
 DP9 modulates (down regulates) expression of TP
receptors—a new epigenetic (DNA level) treatment
modality aimed at the cause
 DP9 is a proprietary low-dose, slow-release (>8 hr)
topical 2% progesterone cream optimized to treat and
prevent AP and CV maladies in women
 DP9 is effectively administered as a unit-dose
vanishing cream—or a patch (prescription medication
forms well accepted by women)
 Progesterone has a long history of safety—and is the
only endogenous steroid studied that is not
associated with cancer (Missmer 2004)

8. Markets for transdermal progesterone Rx
Hyperreactivity pathophysiology treated at the gene level
is the drug platform, which is being developed for:
 Angina Pectoris
 Symptom of coronary ischemia
 3.2 M at $400-800 each annual cost
 Intermittent Claudication
 Symptom of Peripheral Vascular
Disease (PVD)
 8 M at $400-800 each annual cost

9. Regulatory and Scientific Advisors
Raymond J. Lipicky, MD Robert J. Wolters, PhD
Regulatory/Clinical Trial Chemical Mfg & Controls/QA
 Former Director, Division of Cardio-  Former CMC expert at FDA with
Renal Drug Products at FDA (1984- 26 years experience
2002)
 Senior consultant, Mediquest
 Academic medicine for 13 years (Prof Associates Inc
of Medicine & Pharmacology at Univ
of Cincinnati)  Experierienced FDA auditor
 Dimera board member
Elizabeth Barrett-Connor, MD Gerald M Pohost, MD
Epidemiologist/Clinical Trial Mag Res Pioneer/Clinical Trial
 Prof Family and Prev Med, UCSD  Prof USC, Loma Linda, UCLA
 HERS and PEPI Principal Investigator  Editorial Bd, J CV Magnetic Res
 Salick Center Medical Director

10. Current Status (15/16 accomplished)
Preclinical (12 major papers) Clinical
•Efficacy : rhesus •Safety: 505(b)(2)
•Toxicology: rats •Plasma 1-4 ng/ml
•Pharmacology
Manufacturing: 2 batches •Active >8 hrs
•Peak/valley <2
•Scalable, attractive cost
•Stability beyond 4 yrs Efficacy
•Pilot consistently positive
Regulatory •Major AP reductions
•Active IND 60,595 •Sleep greatly improved
•End of Phase II
•SPA concurrence
•Demonstration in women

11. Dimera DP9 Value Highlights
 Novel therapeutic approach  Large market with unmet needs
 First heart drug for women—treats  Large and growing menopausal and
cause, not just symptoms peri-menopausal population
 Unique angina treatment with a  Current angina drugs largely
progesterone cream; high profit ineffective in this population
 Low-risk profile—simple, safe  Current angina drugs have significant
adverse side-effects
 No DSMB required
 Prevalence of 3.2 M women means
 Progesterone is not associated with blockbuster potential
cancer
 First to market
 Clear FDA approval path
 No other FDA-approved topical
 505(b)(2) type of NDA progesterone with CV claims
 SPA has been defined  Platform for drug development
FTC action eliminating the non-Rx  Epigenetic approach
marketing of progesterone

12. Dimera Incorporated
PO Box 56600
Portland OR 97238
www.dimera.net
503 295 2775 desk
503 295 2757 FAX