Speedel puts its eggs in renin inhibitor basket
award-winning new class of drugs has generally been well-received.
However, some have raised questions about their safety and
effectiveness. DrugResearcher.com went to find out more.
Speedel began the development of the only currently available renin inhibitor on the market, called Rasilez or Tekturna (aliskiren), before licensing the drug to Novartis for Phase III trials and marketing. Speedel also has several other drugs in development in the same class: SPP1148 is in Phase I trials; SPP635 in Phase II; and last week the company announced SPP676 had entered the clinic. The company's pipeline is almost exclusively stocked with this class of drugs (there is one direct thrombin inhibitor in Phase II trials too), and so their success is directly linked to that of the company. Interestingly, the renin programme that led to Tekturna was originally in-licensed from Novartis in 1999 and then licensed back in 2002 for further development. It was passed by regulators in both the US (in March) and Europe (in August) this year. However, signs that something might be wrong emerged in May, when an article in the American Journal of Hypertension claimed that because the body secretes more renin in response to the drug, its efficacy is limited. The authors of that paper found that, in trials involving over 5000 hypertensive patients, Tekturna was no more effective than other classes of drugs that block the same renin-angiotensin system - namely (angiotensin) converting enzyme inhibitors (ACE inhibitors or CEIs), angiotensin receptor blockers (ARB) or diuretics. The reason for these "very disappointing" results for the drug, the authors claimed, was its "unexpectedly strong stimulation of kidney renin secretion". The drug blocks around 90 to 95 per cent of plasma renin. However, the causes a reactive rise in the remaining plasma renin and could actually increase blood pressure, according to the paper. However, when DrugResearcher.com spoke to Dr Chris Jensen, director of scientific affairs at Speedel, he pointed out any perturbation of the renin-angiotensin system causes a reactive rise in the amount of renin. "You get a 50-fold increase [in renin] with ARBs or ACE inhibitors. But direct renin inhibitors are the only drugs that block that rise in renin," he said. Although there is a rise in renin levels with Tekturna, plasma renin activity (PRA) is actually decreased, he pointed out. "That paper has a theoretical, 'What if?' basis, and [whether the drug blocks reactive increases in renin and continues to do so] was one of the first questions we asked ourselves." With ACE inhibitors, angiotensin activity can creep back up over time, so the question is a valid one for a drug that works on the same pathway. In Novartis' and Speedel's research, they have found that Tekturna does indeed block renin at levels above 90 per cent at any given time and, crucially, 24 hours after the first dose of Tekturna, PRA is decreased "by 80 to 90 per cent", Jensen added. This effect continues for up to a year of treatment - renin levels don't increase up and up: they get to a higher level but then remain steady and, crucially, renin activity continues to be blocked. There has also been more recent concerns that the drug raises potassium levels in the body, which could cause potentially life-threatening side effects. However, Jensen said that the drug regulators have seen registration documents relating to treatment in over 8000 patients and that clinicians haven't reported a single serious adverse effect related to this. "With Tekturna, 4.2 per cent of patients had increased levels of potassium compared with 2.7 per cent on placebo," he explained. These increased amounts were above 5.5mmol and "a few" reached 6mmol at the most. Jensen said that levels have to get to 7 to 7.5mmol before they were dangerous. He went on to point out that, in over forty years of research, scientists haven't found that renin does anything, good or bad, other than convert angiotensin. But this is the first drug to directly inhibit renin and so he can't totally rule out that scientists may find a new use for the protein. The rest of the renin inhibitor pipeline Speedel has four distinct classes of compound that are all renin inhibitors, the 100 series that Tekturna is part of, and the 600, 800 and 1100 series. Each class is structurally different and so shouldn't be considered as "sons of Tekturna", according to Jensen. The 600 series is slightly unusual in that is based on knowledge gained from the 100 series and also from an in-license deal with Roche. As part of this, should a compound in this series ever be available for licensing, Speedel are obliged to give Roche "right of first offer", although they don't have to accept it. The 800 series, the least advanced programme, was developed utilising Locus Pharmaceuticals computational chemistry expertise and should a compound enter the clinic, or indeed over be marketed, Locus would receive a "small" royalty fee. The 1100 series is a brand new series of compound, which belongs to Speedel entirely. As well as structurally, some of the classes vary mechanistically. All of the compounds are transition inhibitors, which interfere with a flap in the renin proteins and its ability to open and close. This in turn, prevents the protein from converting angiotensin to angiotensin I, whether it is bound to its receptor or in circulation. Tekturna binds to renin when the flap is closed, whereas the 600 series of compounds bind when it is open, inducing a larger and more open binding site.