New data highlights potencial of SPP100 (Tekturna) as gold standard therapy in treatment of hypertension

Fixed dose combination with diuretic accepted for review by FDA

Basel, (PresseBox) - Speedel (SWX: SPPN) today welcomed the significant new results from clinical trials of SPP100 (aliskiren, Tekturna/Rasliez[1]) presented by investigators at the 22nd Annual Scientific Meeting and Exposition of the American Society of Hypertension (ASH) in Chicago, IL, USA. These results confirm the favourable safety and efficacy profile, as well as the potential advantages of this first-in-class once daily direct renin inhibitor for the treatment of hypertension. Tekturna was approved by the US Food and Drug Administration (FDA) and launched by Novartis in the US in March 2007 to treat hypertension both as monotherapy and in combination with other anti-hypertensives. In September 2006, SPP100 was also submitted by Novartis to the European Medicines Agency (EMEA) for review in the European Union. Speedel successfully developed SPP100 through Phase I and II clinical trials before Novartis exercised its license-back option in 2002.

Dr. J. Chris Jensen, Speedel Head of Scientific Affairs, commented: "The extensive data presented at this important scientific meeting highlights the potential of SPP100 as the next gold standard in the treatment of hypertension. It is particularly encouraging to note that SPP100 is the only anti-hypertensive therapy which lowers blood pressure and plasma renin activity, irrespective of the amount of renin circulating in the bloodstream."

Speedel also welcomes the announcement today by Novartis that the FDA has accepted for regulatory review the fixed dose combination of Tekturna with the diuretic HCTZ[2]. Single pill fixed dose combinations of different therapies, particularly a diuretic, are commonly used to help patients achieve their blood pressure goals and to improve patient compliance. The submission of Tekturna HCT[3] was based on data from seven clinical trials involving more than 6,200 patients[4], including the data presented at the ASH meeting. Submissions were made for four different dosage combinations of Tekturna and Hydrochlorothiazide: 150/12.5 mg tablets, 150/25 mg tablets, 300/12.5 mg tablets and 300/25 mg tablets.

Speedel was the first company to demonstrate the benefits of combining a renin inhibitor with a diuretic during its pilot clinical development programme of SPP100 between 2000-2002 [5].

Mr Ben Tan, Speedel Head of Business Development & Licensing commented "In the antihypertensive drug market, the most commonly prescribed fixed combinations contain a diuretic. It is rewarding to know that subject to FDA approval, patients may soon benefit from Tekturna HCT which will increase convenience and compliance, therefore resulting in better control of blood pressure".

Highlights of data presented at ASH

1. Patients treated for 6 months with SPP100 as monotherapy or in co-administration with a diuretic HCTZ showed sustained reductions in blood pressure (BP) and plasma renin activity (PRA), even though plasma renin concentration (PRC) remained elevated. These reductions in BP and PRA were greater than for those patients treated with ramipril (ACE-I[4]) who also showed elevated PRC (Poster P - 445).

2. Two weeks and four weeks after patients stopped receiving SPP100 based therapy, they still showed persistent reductions in BP and PRA respectively, compared to those patients who were taken off ramipril (ACE-I) therapy (Poster P- 445).

3. Patients treated for 12 months with SPP100 as monotherapy or in co-administration with amlodipine (CCB[5]) showed sustained reductions in blood pressure (BP) and plasma renin activity (PRA), while plasma renin concentration (PRC) was stable essentially at the same level after 12 months as it was after 6 months. In contrast, patients treated with a diuretic HCTZ showed increased PRA (Poster P- 421).

4. Patients treated for 8 weeks with a combination of the maximum dose 300mg of SPP100 and the maximum dose 320mg of Diovan [6] (ARB[7]) showed significant clinically relevant additional BP reductions of 4.2/3.2 mmHg and 4.4/2.5 mmHg compared to SPP100 and Diovan monotherapies respectively. This large study of 1,776 patients has produced a novel observation about the benefits of combining the maximum therapeutic doses of SPP100 and Diovan. There has only been one other small study combining the maximum recommended doses of an ACE-I and an ARB which also showed significant additional reductions in BP (Poster P - 418).

5. Patients treated with a combination of the maximum dose 300mg of SPP100 and the maximum dose 320mg of Diovan (ARB) showed significantly greater reductions in BP over an entire 24-hour period compared to SPP100 and Diovan monotherapies. This is particularly important during the night-time and early morning hours as many cardiovascular events occur between 2am and 6am. The results were consistent for both patients whose blood pressure naturally decreases at night (dippers) and for those whose blood pressure remains high at night (non-dippers) (Poster P - 452).

6. In a study of obese patients, who did not achieve BP control with the diuretic HCTZ alone, it was shown that patients treated for 8 weeks with a combination of SPP100 and HCTZ provided additional significant BP reductions. The combination also improved the number of patients achieving BP control compared to those receiving HCTZ alone. The combination of SPP100 and HCTZ also did not show the increased levels of fluid retention associated with the combination of amlodipine (CCB) and HCTZ (Poster P - 401)

The World Health Organization and the JNC-VII[8] estimate that 70% of hypertensive patients currently do not reach their blood pressure goals. As many patients with hypertension require more than one antihypertensive drug to control their elevated blood pressure, it is important that SPP100 leads to additional blood pressure lowering effects when combined with other antihypertensive drugs.

Summary of posters presented by investigators 19-22 May 2007 at the 22nd Annual Scientific Meeting and Exposition of the American Society of Hypertension (ASH) in Chicago, IL, USA

Aliskiren-based therapy provides long-term suppression of plasma renin activity that persists after stopping therapy in patients with hypertension
Myron H Weinberger, Karl Andersen, Christian M Constance, Mohammed A Ali, James Jin, Margaret F Prescott; Poster P-445

- Aliskiren-based therapy produced effective control of blood pressure and plasma renin activity over 6 months.
- Significant reductions of plasma renin activity persisted 4 weeks after stopping aliskiren treatment in parallel with sustained blood pressure reductions, suggesting that aliskiren has continued inhibitory effects on the renin system beyond its plasma elimination half-life.

Aliskiren-based therapy provides long-term renin system suppression in patients with hypertension in a 52-wk comparator trial with hydrochlorothiazide-based therapy
T Philipp, RE Schmieder, J Guerediaga, M Gorostidi, B Smith, M Maboudian, J Botha, MF Prescott; Poster P-421

- Aliskiren-based therapy provided reductions of plasma renin activity that were maintained during long-term (12 months) treatment in patients with mild-to moderate essential hypertension.

The direct renin inhibitor aliskiren in combination with valsartan provides additional blood pressure-lowering effects compared with either agent alone in patients with hypertension
S Oparil, SA Yarows, S Patel, H Fang, J Zhang, A Satlin; Poster P-418

- Dual renin system intervention with the combination of aliskiren and valsartan provides clinically significant additional blood pressure reductions and improved blood pressure control, with tolerability similar to that of the individual monotherapies.

Aliskiren in combination with valsartan provides superior 24-hour ambulatory blood pressure reductions compared with either agent alone in patients with hypertension
SA Yarows, S Oparil, S Patel, H Fang, J Zhang, A Satlin; Poster P-452

- The additional blood pressure reductions provided by an aliskiren/valsartan combination over each antihypertensive agent alone are sustained over the entire 24-h dosing interval in both dippers and non-dippers and exhibit less variability.

Direct renin inhibition with aliskiren improves blood pressure control in obese patients with hypertension who do not respond to first-line hydrochlorothiazide treatment
J Jordan, SW Boye, S Le Breton, DL Keefe; Poster 401

- The combination of aliskiren with hydrochlorothiazide provided significant additional blood pressure reductions and significantly improved blood pressure control rates in obese patients with hypertension, without the increased rate of edema associated with amlodipine/hydrochlorothiazide.

Aliskiren, a direct renin inhibitor, provides antihypertensive efficacy and excellent tolerability independent of age or gender in patients with hypertension
B Dahlöf, DR Anderson, V Arora, C Bush, DL Keefe; Poster P-376

- This pooled analysis of randomized clinical trials in a total of 8481 patients showed that once-daily treatment with the direct renin inhibitor aliskiren at doses of 150 and 300 mg provided effective, dose dependent blood pressure-lowering independent of age or gender in patients with mild-to-moderate hypertension.

- Aliskiren treatment provided numerically greater placebo-subtracted reductions in mean systolic blood pressure in patients aged over 65 years compared with younger patients. This may be clinically useful because the prevalence of isolated systolic hypertension is increased in elderly patients, and elevated systolic blood pressure is difficult to control.

- Aliskiren 150 and 300 mg monotherapy was equally well tolerated in elderly and younger patients, and in men and women with hypertension, and exhibited a tolerability profile similar to that of placebo in all subgroups.

Long-term safety and efficacy of aliskiren, an oral direct renin inhibitor, in Japanese patients with hypertension
T Kushiro, H Itakura, Y Abo, H Gotou, S Terao, DL Keefe; Poster P-406

- Long-term therapy with aliskiren alone or in combination with a diuretic and/or calcium channel blocker in Japanese patients with hypertension is well tolerated and provides effective blood pressure reductions that are maintained over 52 weeks of treatment.

Aliskiren in combination with hydrochlorothiazide is effective and well tolerated during long-term treatment of hypertension
AH Gradman, RE Kolloch, M Meyers, J Cai, J Zhang; Poster P-384

- Aliskiren, as monotherapy and in combination with hydrochlorothiazide, provides an effective and well-tolerated long-term treatment for hypertension. Furthermore, the high-dose combination of aliskiren/hydrochlorothiazide (300 mg/25 mg) shows good tolerability and durable blood pressure-lowering efficacy over 12 months of treatment.

Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in patients with hypertension
RE Schmieder, T Philipp, J Guerediaga, M Gorostidi, B Smith, N Weissbach, A Krebs-Brown, H van Ingen; Poster P-436

- Long-term aliskiren-based therapy was well tolerated and provided significantly greater blood pressure reductions than hydrochlorothiazide-based therapy in patients with mild-to-moderate hypertension.

- Aliskiren 300 mg monotherapy was superior to hydrochlorothiazide 25 mg monotherapy in lowering blood pressure.

About SPP100 (aliskiren, Tekturna/Rasilez[9])
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 key 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 is believed to be very important in end-organ protection (e.g. heart and kidney). PRA is an independent and direct surrogate marker for several cardio-renal diseases, such as myocardial infarction and chronic renal disease. 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 Novartis subsequently 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 a regulatory submission was made by Novartis in the EU during Q3 2006.
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 Tekturna 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).

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