| Renin Inhibitors Show Promise for Treating Hypertension
Valued at over $30 billion, the world antihypertensive market is still crying out for therapies that can effectively control blood pressure over a sustained period of time. Renin inhibitors—some of the latest and most promising entrants in this market--just might deliver. These drugs act by blocking the initial, rate-limiting step of the renin-angiotensin system (RAS), which may be more effective while producing fewer side effects than current treatments that act further downstream in the RAS pathway. Early studies hint that renin inhibitors can be used alone or in combination with existing therapies. Major companies, including Merck and GlaxoSmithKline, are backing development efforts in this emerging market. The clear leader, however, is Novartis--the first company to file for marketing approval for a renin inhibitor amidst projections that peak sales for its candidate could reach nearly $4 billion.
According to the American Heart Association (AHA), approximately 65 million Americans over age 20 have high blood pressure. The AHA also reports that, of all people with high blood pressure, 63.4% are aware of it and nearly half are currently being treated for it, but only 29.3% have their high blood pressure under control. Hypertensive individuals are at increased risk for a host of other serious conditions, including coronary heart disease (e.g., heart attacks or congestive heart failure), stroke, and kidney disease.
Currently available drugs for treatment of hypertension include diuretics, vasodilators, beta-blockers, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II-receptor blockers (ARBs). Although these drugs can help control hypertension, they may also cause side effects.
How RAS Modulators Treat Hypertension
Renin is an attractive target for modulating the RAS, which plays an important role in regulating blood pressure. Renin is an enzyme (an aspartyl protease) that is produced in the kidneys and released into the plasma, where it catalyzes conversion of the protein angiotensinogen into angiotensin I. Angiotensin I is an inactive protein that is converted to the active vasopressor peptide angiotensin II by the enzyme ACE. Angiotensin II interacts with cellular receptors to induce vasoconstriction, thereby raising blood pressure.
Renin is specific for its substrate (angiotensinogen), and so blocking renin activity may lower the risk of side effects compared with other drugs that target the RAS, such as ACE inhibitors and ARBs. ACE inhibitors block the conversion of angiotensin I to angiotensin II. However, blockage of the RAS with ACE inhibitors is not complete: Treatment with ACE inhibitors increases the level of angiotensin I, which can still be converted to angiotensin II via alternative pathways.
ARBs block interaction of angiotensin II with its cellular receptors, but treatment with ARBs therefore results in increased levels of angiotensin II. Treatment with renin inhibitors, on the other hand, reduces levels of both angiotensin I and angiotensin II. In addition, the RAS has a negative feedback loop, and so blockage of the RAS by ACE inhibitors or ARBs results in an increase in plasma renin activity (PRA), thus activating the RAS and increasing levels of the angiotensin peptides. It is believed that reducing PRA may help limit damage to organs that occurs as the result of high blood pressure.
Renin Inhibitors in Development
Pharmaceutical companies have been working to develop renin inhibitors for over 20 years, but have encountered problems that led some to abandon their programs. Such challenges included poor oral bioavailability of molecules that inhibit renin, low potency, short duration of action, and synthesis issues. To counter these issues, researchers from the Novartis Institutes for BioMedical Research used a combination of molecular modeling and crystallographic structure analysis to design structurally different renin inhibitors (including aliskiren), which lack the peptide backbone of the earlier generations. As a result, aliskiren is orally active, highly specific, and one of the most potent renin inhibitors yet identified.
In 1999, Speedel licensed aliskiren (SPP100) from Novartis. Speedel designed a new synthetic route for production of SPP100 (which addressed cost issues associated with this compound), and conducted 18 Phase I and II clinical trials in approximately 500 healthy volunteers and patients. In 2002, Novartis exercised a call-back option restoring its
worldwide rights to develop and commercialize aliskiren.
Novartis is seeking approval of Rasilez for treatment of hypertension as a monotherapy and also in combination with other hypertension drugs. A new drug application was submitted to the FDA during the first quarter of 2006, including data from 34 clinical trials and more than 6,000 patients. If approved, Rasilez would be the first renin inhibitor to reach the market. In addition, it would be the market’s first hypertension drug with a novel mechanism of action in more than a decade. Novartis plans to file for European approval by the end of 2006.
The results of several Phase III trials with aliskiren have been made available by Novartis, in which monotherapy and additive effects were shown. As a monotherapy, once-daily administration of aliskiren significantly lowers blood pressure for a sustained period of over 24 hours. That is an important benefit, because some current hypertension medicines do not control blood pressure for that long. Novartis also reports that when aliskiren was used as a monotherapy, it showed placebo-like tolerability. When used with other hypertension drugs (i.e., ACE inhibitors, calcium-channel blockers, or a diuretic), blood pressure was reduced even further, suggesting an additive effect. Going even further, aliskiren could also potentially improve end-organ protection compared with alternative therapies. According to Speedel, Novartis is conducting Phase II trials examining the effect of aliskiren on surrogate markers for serious and fatal diseases of vital organs. These indications include diabetic kidney disease, heart failure, and left ventricular hypertension.
For all of the above-stated reasons, analysts claim Rasilez has blockbuster potential: According to analysis done as part of its coverage of Speedel, Vontobel Research estimates five-year sales potential of $1,090 million and peak sales potential at around $3,950 million.
Speedel remains an active player in this arena, with multiple renin inhibitors in development. In December 2001, Speedel acquired exclusive, worldwide rights to Roche’s renin inhibitor program, which has become the SPP600 series of renin inhibitors at Speedel. The most advanced of these compounds is SPP635, which started Phase I trials in October 2005. Speedel reports that these second-generation renin inhibitors have improved bioavailability and tissue distribution.
In addition to the renin inhibitor activities underway at Novartis and Speedel, there are at least three early-stage renin inhibitor programs (see Table). The most advanced is a renin inhibitor being developed by Actelion and Merck, which began Phase I clinical development in July 2006.
Although aliskiren would face significant competition from currently available hypertension therapies (several of which are available as generics), its benefits and likely use in combination with other hypertension drugs suggest it is likely to be well accepted. If approved, aliskiren would not face competition from other renin inhibitors for several years. According to Speedel, aliskiren has patent protection worldwide until 2015, with prolongation of this protection until 2020 possible in some countries. Aliskiren therefore appears to be giving Novartis a significant leg up on the emerging class of renin inhibitors.
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