From rxpgnews.com
Next Generation Renin Inhibitors Successfully Complete Human Micro-Dosing Studies
By Akanksha, Pharmacology Correspondent
Feb 4, 2005, 08:47
Speedel announced today that it has successfully completed the first human micro-dosing studies of its new renin inhibitors, SPP630 and SPP635, for the treatment of hypertension and for protecting end-organs such as the heart and kidneys.
Speedel has made rapid progress with the development of its SPP600 series by using rational drug design, state-of-the-art preclinical models, and human microdosing to obtain early ADME information, allowing it to �screen-in� the most promising candidates for clinical development.
Such selections are usually made in the absence of human data, but Speedel�s adoption of microdosing has allowed the company to reach this stage in less than 9 months from first synthesis of a compound to human testing.
Dr. Alice Huxley, CEO, commented: "This significant milestone further strengthens Speedel's leadership in renin inhibition and demonstrates our ability to generate our own drug candidates. Our innovative approach with the use of human microdosing has allowed us to fast-track these compounds to a stage where we expect to select the best candidate(s) to continue classical Phase I studies in Q3 2005.�
SPP630 and SPP635, compounds with low nanomolar potency, have now been successfully tested in microdosing studies with human volunteers and in preclinical studies with transgenic rats that express the human genes for renin and angiotensinogen. These studies show that this next generation of renin inhibitors offer potential improvements over currently available therapies, and specifically show that both compounds:
. demonstrate bioavailability in humans of upto 30% and in rats of 70-90%; figures far greater than have been obtained with any previous renin inhibitor;
. have a half-life of more than 30 hours in man, making them suitable for once-a-day dosing;
. show larger tissue distribution than previous renin inhibitors, indicating their incremental potential for end-organ protection; and
. not only reduce blood pressure in transgenic rats over 24 hours, but also slow down the progression of renal damage after oral treatment.
Dr. Chris Jensen, Director of Pharmacology, added: �New therapies for the treatment of cardiovascular diseases will not only reduce blood pressure but will have to provide end-organ protection to the heart and kidneys.These microdosing results in man � in conjunction with the favourable results in the transgenic rat model of renal disease�provide us with great optimism in continuing our development programmes for the SPP600 series and other renin inhibitors.�
The microdosing studies were performed in collaboration with Xceleron Ltd. Both SPP630 and SPP635, together with other compounds from the SPP600 series, will be evaluated in toxicology studies before a decision is made about which compound(s) will continue in classical Phase I studies with single ascending and multiple ascending doses.
Renin inhibitors are a new class of compounds under development for the treatment of hypertension,chronic renal disease and congestive heart failure.Experts estimate that more than 50% of all patients with high blood pressure are not adequately controlled with current drugs and therefore physicians need additional therapeutic options.Global antihypertensive drugs sales are forecasted by Datamonitor to grow from USD 40 billion in 2003 to USD 50 billion by 2009.
Hypertension is a common disorder in which blood pressure is abnormally high,placing undue stress on the heart,blood vessels and other organs such as the kidney and the brain. Blood pressure is determined in two phases as the heart contracts and relaxes.Systolic blood pressure represents the force that blood exerts on the walls of arteries as the heart contracts to pump out blood.Diastolic blood pressure represents the force as the heart relaxes to allow the blood to flow into the heart.
Due to its wide prevalence and impact on cardiovascular health, hypertension is a major cause of disease and death in Europe and North America.More than one in three Europeans and North Americans over the age of 35 suffers from hypertension�but for the vast majority of patients who undergo hypertension treatment, the causes of high blood pressure are unknown.
The latest potential therapeutic agents for hypertension are renin inhibitors.Renin is an enzyme produced in the kidneys in response to reduced renal perfusion.Through a cascade of biological events,renin acts to bring about sodium retention, an increase in blood pressure, and restoration of renal perfusion, which shuts off the signal for renin release.
For hypertensive individuals, renin inhibitors are currently being investigated as a therapy that may provide benefits over current therapies to reduce blood pressure, decrease salt retention and may protect end organs such as the kidney, heart and brain.
Inhibition of renin,articulated as Plasma Renin Activity (PRA),is believed to be very important in end-organ protection (e.g. heart and kidney).PRA is an independent and surrogate marker for several cardio-renal diseases, such as myocardial infarction and chronic renal disease. Only Renin Inhibitors lower PRA efficiently, whereas current antihypertensive therapies increase PRA levels.
Human microdosing is a new concept pioneered by Xceleron Ltd in the United Kingdom. Microdosing relies on the ultrasensitivity of Accelerator Mass Spectrometry (AMS), one of the most sensitive measuring devices ever invented. Using AMS it is possible to conduct a full human metabolism study after administration of as little as 0.1 milligram of drug substance, measuring drug concentrations in biological fluids up to 1000 times less than the levels one would observe in a classical Phase I clinical study.
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