SPP100 (Tekturna/Rasilez) Promising rezults in patients with heart failure

First potential Benefits of Renin inhibitor beyond blood pressure lowering

Basel, (PresseBox) - Speedel (SWX: SPPN) today welcomed the promising results of SPP100 (Tekturna/Rasilez[1]) in a Phase II clinical trial with heart failure patients which were announced by Novartis and presented on 2 September in a late-breaking session at the European Society of Cardiology Congress in Vienna, Austria by Professor John McMurray of the University of Glasgow, Scotland. The study results[2] show that SPP100, the first-in-class direct renin inhibitor, is generally well-tolerated and can potentially reduce the severity of heart failure, as indicated by significant reductions in brain naturietic peptide (BNP). Heart failure is a progressive condition which often occurs in patients with a history of high blood pressure[3]; it affects about 14 million patients around the world[4] and is a growing cause of hospitalization and death.

SPP100 was approved by the US Food and Drug Administration (FDA) in the US in March 2007 under the trade name Tekturna and by the European Union under the trade name Rasilez in August 2007 to treat hypertension both as monotherapy and in combination with other anti-hypertensives. Novartis announced in July 2007 that it was also approved in Switzerland. Speedel successfully developed SPP100 through Phase I and II clinical trials before Novartis exercised its license-back option in 2002.

Dr. Alice Huxley, CEO, said: "We are delighted with these encouraging results which demonstrate the potential of this novel class of therapy to provide patients with benefits over and beyond blood pressure lowering. A history of high blood pressure is found in 75% of heart failure patients[5] and it is clear that new therapies are required to treat this vulnerable patient population. It is particularly pleasing to note that the pioneering work done by Speedel in 2002 with SPP100 in heart failure patients has now been confirmed by our partner Novartis in a large clinical trial. These ALOFT results further strengthen Speedel's commitment to renin inhibition."

ALOFT study results
The ALOFT (ALiskiren Observation of Heart Failure Treatment) 12-week study treated 156 patients with SPP100 150mg once per day added to standard heart failure therapy of ACE[6] inhibitors or ARBs[7], compared to 146 patients receiving placebo once per day on top of standard therapy. Results showed that treatment with SPP100, when used on top of standard heart failure treatment, resulted in highly significant reductions in BNP nearly five times greater than those with standard therapy alone (-61 pg/mL versus -12 pg/mL, p= 0.016) BNP is a protein produced in the heart and brain that is an accepted indicator of heart failure severity.

Unlike some other blood pressure medicines, such as most calcium channel blockers and some beta blockers which can worsen heart failure[8] [9], SPP100 demonstrated good safety and a tolerability profile similar to placebo when used in this hard-to-treat patient population. When added to existing standard of care therapies, including ACE inhibitors and ARBs, as expected a slightly higher but non-significant number of patients receiving SPP100 than placebo experienced hyperkalemia. This was usually mild and did not lead to an adverse outcome[10].

SPP100 is not currently indicated for heart failure, and additional long-term Phase III studies are needed to assess its potential effects on heart failure.

The ALOFT study is the first of a series of trials in ASPIRE HIGHER, an extensive ongoing clinical programme by Novartis studying the 'beyond blood pressure' benefits of SPP100 due to direct renin inhibition. Further data in patients with heart failure (ALOFT) or kidney failure (AVOID) are expected to be presented later this year.

Speedel Phase IIa pioneering study in heart failure patients
In 2002 Speedel completed a pioneering Phase IIa study[11] comparing SPP100 with the ACE inhibitor ramipril on the safety and tolerability of 27 patients with congestive heart failure (CHF). The study evaluated different doses of SPP100 and ramipril once daily over 6 weeks. Results demonstrated that both SPP100 (n=13) and ramipril (n=14) were safe and well tolerated, and both drugs had a similar beneficial effect in patients, as evidenced by decreases in neurohormonal parameters such as BNP, Angiotensin II and aldosterone. The principal investigator of this study was also Professor John McMurray of the University of Glasgow.

Growing global health risks of high blood pressure
The Lancet published an editorial on 17 August which stated that: "The risk of becoming hypertensive during lifetime exceeds a staggering 90% for a person in a developed country." The editorial also observed that: "The increasingly common combination and interaction of obesity, diabetes, hyperlipidaemia and high blood pressure, if left untreated for too long, leads to cardiovascular disease, stroke, renal failure, dementia, and ultimately death. Worldwide, the estimated number of adults with hypertension was 972 million in 2000; 639 million live in developing countries. By 2025, the total number is expected to increase to 1.56 billion."[12]

About SPP100 (aliskiren, Tekturna/Rasilez[13])
SPP100 (aliskiren, Tekturna/Rasilez) is the first-in-class oral direct renin inhibitor. The development of SPP100 is the result of over 20 years of research on renin. Renin is the rate-limiting enzyme at the top of the Renin Angiotensin System (RAS), one of the key regulators of blood pressure. The RAS is a cascade, starting with renin, leading to angiotensin I and finally to angiotensin II. Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor antagonists (ARBs) have been developed to block this system "down stream" and have shown clinical efficacy in patients with hypertension and other cardiovascular diseases.

By inhibiting renin at the top of the RAS, SPP100 decreases the system's activity, as measured by plasma renin activity (PRA). Lowering PRA is believed to be very important in end-organ protection (e.g. heart and kidney). PRA is an independent risk factor and direct surrogate marker for several cardio-renal diseases, such as myocardial infarction and chronic renal disease. Direct renin inhibitors lower PRA whereas most current leading anti-hypertensive drug classes such as ACE-Is and ARBs increase PRA levels.

Speedel in-licensed SPP100 from Novartis in 1999 and successfully completed 18 clinical trials, through Phase I and II in about 500 patients and healthy volunteers. Based on the results generated during this programme, Novartis exercised a license-back option in 2002, and subsequently Novartis started trials with SPP100 in Phase III as monotherapy for hypertension and in Phase IIb as combination therapy. Regulatory approval was given by the US FDA in March 2007 and by the EU in August 2007.

Speedel believes that it is the first company to establish successfully a clinical proof of concept in Phase II and to have developed and filed for patent protection a commercially viable manufacturing process for a renin inhibitor, an area of industry research for over 20 years. In a Phase II study of 200 patients conducted by Speedel, it was demonstrated that SPP100 achieves dose-dependent blood pressure reduction. The study also showed that 150mg and 300mg SPP100 once daily were comparable to Losartan 100mg, which is double the usual starting dose of this ARB (Stanton, Jensen, Nussberger, O'Brien, Hypertension.2003; 42: 1137-1143).

[1] Tekturna/Rasilez® are Novartis trademarks
[2] McMurray J et al. ALOFT - a 12 week safety evaluation of aliskiren 150 mg vs. placebo when added to standard therapy for stable heart failure. Oral presentation in Hotline I session at European Society of Cardiology Congress 2007
[3] Mosterd A, Hoes A. Clinical epidemiology of heart failure. Heart Online 2007;93:1137-46
[4] Remme WJ, McMurray JJV, Rauch B, et al. Public awareness of heart failure in Europe: first results from SHAPE. European Heart Journal 2005;26:2413-2421
[5] Heart Disease and Stroke Statistics - 2007 update. American Heart Association
[6] Angiotensin-converting enzyme inhibitors
[7] Angiotensin II receptor antagonists
[8] Packer M. Calcium Channel Blockers in Chronic Heart Failure. The Risks of "Physiologically Rational" Therapy. Circulation 1990; 82;2254-2257
[9] Swedberg K, Cleland J, Gargie H, Drexler H, Follath F, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). European Society of Cardiology (Accessed 2007 August 14, cited 2005.) Available at: http://www.escardio.org/NR/rdonlyres/
A13E135D-5C0C-4A51-B632-03F36AF92010/0/guidelines_CHF_ES_2005.pdf
[10] McMurray J et al. ALOFT - a 12 week safety evaluation of aliskiren 150 mg vs. placebo when added to standard therapy for stable heart failure. Oral presentation in Hotline I session at European Society of Cardiology Congress 2007
[11] Speedel study SPP100CHF06 on file
[12] The Lancet: 2007; 370:539
[13] Tekturna/Rasilez® are Novartis trademarks
[14] Tekturna/Rasilez® are Novartis trademarks


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