Tekturna (aliskiren)

Tekturna is an orally active, nonpeptide, potent renin inhibitor. Renin is the enzyme at the beginning of the Renin Angiotensin System (RAS), one of the key regulators of blood pressure. Suppression of the RAS has been shown to treat hypertension and reduce cardiovascular events.

Tekturna is specifically indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. The use of Tekturna with maximal doses of ACE inhibitors has not been adequately studied.

Tekturna is supplied as a 150 mg or 300 mg tablet designed for oral administration. The recommended initial dose of the drug is 150 mg once daily. In patients who do not have adequately controlled blood pressure, the daily dose may be increased to 300 mg.

FDA Approval
FDA approval of Tekturna was based on the results of six clinical trials of aliskiren monotherapy, one trial of aliskiren alone and in combination with hydrochlorothiazide and one trial of aliskiren alone and in combination with valsartan. The six randomized, double-blind, placebo-controlled trials enrolled 2,730 subjects who received aliskiren in doses of 75-600 mg or placebo for eight weeks. Increase in response was observed for all doses studied, with reasonable effects seen at 150-300 mg, and no clear further increase at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment. Subjects in the placebo controlled trials continued in an open label trial for an additional year. A blood pressure lowering effect was demonstrated by a randomized withdrawal study, which showed a statistically significant difference between subjects kept on aliskiren and those randomized to placebo. When treatment ceased, blood pressure returned to baseline levels over a period of a couple of weeks.

Aliskiren and hydrochlorothiazide were studied alone and in combination with each-other. This randomized, double-blind, placebo-controlled, parallelgroup, 15-arm factorial study enrolled 2,776 subjects. Aliskiren was administered in doses of 75, 150, and 300 mg and hydrochlorothiazide in doses of 6.25, 12.5, and 25 mg, for eight weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies.

Aliskiren and valsartan were studied alone and in combination with each-other. This randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose escalation study enrolled 1,797 subjects. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies.

Ongoing Study Commitments

• Novartis has agreed to a deferred pediatric study under PREA for the treatment of hypertension in pediatric patients ages 6 to 16 years.
  Final Report Submission: March 5, 2009
• Novartis has agreed to submit the results of the cellular markers of proliferation and apoptosis from Study 2103 as soon as they are available, but no later than September 2007.
  Final Report Submission: 09/07
• Novartis has agreed to include intestinal procedures and neoplasms and angioedema as events of special interest in your proposed ALTITUDE trial as detailed in their special protocol assessment letters. You committed to providing safety information and periodic summaries during the ALTITUDE trial for the parameters of special interest. The data should be submitted when the final study report comes in. The periodic summaries will include: Monthly line listings of suspected/non suspected SAE and non serious AE (reported in the previous month) and Aggregate summaries (cumulative) of suspected/non suspected SAE and non serious AE in PSUR semi-annually for the first 2 years post-launch and annually thereafter.
  Protocol Submission: 09/07
  Study Completion: 09/11
  Final Report Submission: 03/12
• Novartis has agreed to incorporate a colonoscopy substudy into their proposed long-term outcome study. The colonoscopy substudy should include colonoscopies performed at baseline and after drug treatment for 12 months or longer. This study should be powered to rule out a doubling in the rate of cancerous or precancerous lesions. They should discuss this substudy with the Agency.
  Protocol Submission: 09/07
  Study Completion Date: 02/09
  Final Report Submission: 05/09
• Novartis has agreed to provide evidence that it is not likely to be clinically useful to give aliskiren in a twice-daily dosing regimen to patients whose blood pressure is not controlled on the highest recommended dose given once daily. These data could come from a study comparing once- and twice-daily dosing, but the Division would consider alternative strategies to address this issue.
  Protocol Submission: 06/07
  Final Report Submission: 02/09

Adverse events associated with the use of Tekturna may include, but are not limited to, the following

• Hand, face and/or body edema
• Diarrhea
• Abdominal pain
• Dyspepsia
• Gastroesophageal reflux
• Rash
• Elevated uric acid
• Gout
• Renal stones

Tekturna is a renin inhibitor. Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen, a peptide in the blood that causes vasoconstriction and increased blood pressure, to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption, which increases blood pressure and it inhibits renin release, providing a negative feedback to the system. This cycle is known as the renin-angiotensin-aldosterone system (RAAS). Thus, as a direct renin inhibitor, Tekturna disrupts the RAAS process by decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I.

Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, Chiang Y, Satlin A Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. American journal of hypertension : journal of the American Society of Hypertension 2007 Jan;20(1):11-20

Villamil A, Chrysant SG, Calhoun D, Schober B, Hsu H, Matrisciano-Dimichino L, Zhang J Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. American journal of hypertension : journal of the American Society of Hypertension 2007 Jan;25(1):217-26

Vaidyanathan S, Valencia J, Kemp C, Zhao C, Yeh CM, Bizot MN, Denouel J, Dieterich HA, Dole WP Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. International journal of clinical practice 2006 Nov;60(11):1343-56.

Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Gratze P, Meiners S, Feldman DL, Webb RL, Garrelds IM, Jan Danser AH, Luft FC, Muller DN. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005 Sep;46(3):569-76. Epub 2005 Aug 15.

Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005 Mar 1;111(8):1012-8. Epub 2005 Feb 21.

Stanton A Therapeutic potential of renin inhibitors in the management of cardiovascular disorders. American journal of cardiovascular drugs : drugs, devices, and other interventions 2003;3(6):389-94.

For additional information regarding Tekturna or hypertension, please visit the Tekturna web page.