Dimera approached the question of coronary heart disease that is typical in women by asking innovative questions such as why women who are generally at lower risk for heart disease before ovarian function decline (that normally begins after age 40 in peri-menopause) is lost. As ovarian function is lost, progesterone declines profoundly (and to below threshold daily exposure levels in a large fraction of women). Dimera explored differentially the effects of ovarian steroids and prescription medicines used to treat the consequent endocrine deficiencies from the standpoint of blood vessels. The novel approaches taken by Dimera include the following.
- Explore the causes of ischemic heart disease in women
- Dynamically determine coronary ischemic event triggers during cardiac cath studies
- Investigate underlying molecular mechanisms for ischemia
- Find a drug formulation to normalize coronary artery function at the genomic level
- Invent and optimize a novel continuous method for release of the drug for genomic action
- Determine the continuous release threshold for DP9 treatment of angina pectoris
- Explore the threshold and duration of treatment for DP9 prevention of angina pectoris
- Provide a complementary diagnostic test to guide individualized medical management
- Offer an effective, minimized side-effect option that will be readily accepted by women
Discoveries by Dimera that 1) coronary hyperreactivity (excessive prolonged vasoconstriction) occurs unless there is continuous (at least 8 hour) exposure to progesterone each day, and 2) overexpression of the blood vessel thromboxane-prostanoid (TP) receptor results from below threshold continuous exposure to progesterone allowed this development of this novel drug. A key element in the DP9 design is the advanced pharmacokinetics that distinguish the continuous transdermal drug route of administration from other progesterone drug products. Both the coronary hyperreactivity responses observed in the catheterization laboratory and the molecular mechanism determined in TP receptor expression in coronary blood vessels require the continuous supply of progesterone for at least 8 hours of each day, which is the normal pre-menopausal condition.
The continuous release of progesterone is important because progesterone is rapidly metabolized by the liver, resulting in a half-life of only minutes. Progesterone must be continuously provided to blood vessels at the blood vessel threshold or greater for at least 8 hours based on steady supply as is ideally provided by transdermal routes. Progesterone taken orally fails, instead supplying only a large peak that falls to below threshold in only 2 hours. DP9 provides transdermal skin cream progesterone in unit-dose packages that allow reliable achievement of effective exposure levels with optimized pharmacokinetics.
Progesterone is presently approved for use and known to be safe for treatment of infertility and secondary amenorrhea in products such as Prometrium (oral capsules) and Prochieve (vaginal gel). Much higher concentrations of progesterone are the result of treatment with Prometrium capsules than with DP9. Concentrations of progesterone as much as 400 times the levels provided by DP9 are experienced by the human fetus in utero, providing compelling evidence for the safety of low dose progesterone released continuously from the skin. Lower dose transdermal progesterone has the virtue of minimizing or eliminating side-effects. When the essential role of progesterone for normal blood vessel function is recognized, major insight beyond the well-known role of progesterone for pregnancy can be appreciated.
DP9 thus represents a novel drug platform possible because of advanced knowledge of blood vessel wall molecular biology that allows the desired end-point to be normalization of TP receptor expression, and thus coronary reactivity, at the source. Rather than using block of receptors or inhibition of enzymes as the drug platform, with unwanted side-effects, action directly at the heart of the problem allows for extension of normal physiology by correcting a deficit. Dimera has furthermore defined the threshold for progesterone providing diagnostic measures that allow for individualized medical management. DP9 exemplifies the first drug platforms to aim for targeted gene regulation and individualized medicine, which are important therapeutic advances.
When left unchecked, as in the absence of sufficient levels of progesterone, the TP receptor increases the risk and the severity of episodes of excessively prolonged vasoconstriction, especially microvessel constriction. DP9 prevents abnormally prolonged microvascular ischemic episodes which appear to be the primary source of chronic angina pectoris in women, and/or possibly acute coronary syndromes (ACS) which occur even in the absence of anatomical obstructions.
DP9 has been found to be effective in treating and preventing angina pectoris (as a symptom of coronary disease) in small pilot randomized controlled clinical trials, and has completed the FDA Phase II requirements. When Phase III studies planned are completed, the last steps for approval of DP9 will be possible and this new drug may be available in coming years. Dimera is presently pursuing possible sources of capital to allow the Phase III clinical trials and submission of the FDA form 21CFR505(b)2 New Drug Application. Interested parties are invited to contact us at Dimera.