EU's CHMP Warns About Boceprevir In HIV, Aliskiren In Diabetes, But Clears Orlistat And Reinstates Trasylol

The EU's scientific advisory panel, the CHMP, recommends prescribing information changes for drug/drug interactions with Merck's Victrelis and adverse events with Novartis' aliskiren, but clears obesity therapy orlistat of causing liver injury and reverses its 2007 negative opinion on Bayer's Trasylol.

Not only is it lagging behind its close competitor, but Merck & Co. Inc.'s hepatitis C therapy Victrelis (boceprevir) was dealt a further blow Feb. 17 when the European Medicines Agency recommended adding a warning to its prescribing information about potential interactions with ritonavir-boosted HIV protease inhibitors.

Victrelis and Vertex Pharmaceuticals Inc.'s hepatitis C protease inhibitor Incivek (telaprevir) were both launched last year, but Incivek has been more successful in the marketplace, with 2011 sales of $951 million compared with $140 million for Victrelis (Also see "Early Success For Kalydeco Is Just The Beginning For Vertex’s CF Drug" - Pink Sheet, 6 Feb, 2012.). Neither drug is recommended for treating HIV patients co-infected with hepatitis C, but companies – and regulators - recognize that they might be used in that setting.

Following a review by the EU's scientific advisory panel, the Committee for Medicinal Products for Human Use (CHMP), EMA is now recommending updating Victrelis' prescribing information on drug interactions, and recommending increased clinical and laboratory monitoring of co-infected patients treated with the medicine.

Victrelis should not be co-administered with ritonavir (Abbott Laboratories Inc.'s Norvir)-boosted darunavir (Johnson & Johnson's Prezista) or lopinavir (Abbott's Kaletra) in HIV and hepatitis C co-infected patients, the committee says. But Victrelis and ritonavir-boosted atazanavir (Bristol-Myers Squibb Co.'s Reyataz) may be co-administered on a case-by-case basis, if necessary in patients with a suppressed HIV viral load and with an HIV strain with no suspected resistance to the HIV regimen used.

The changes follow the results of a drug interaction study in healthy volunteers performed by Merck that found blood levels of darunavir, lopinavir and atazanavir were markedly lower when they were administered with Victrelis. Also, blood levels of Victrelis were markedly lower when given with ritonavir-boosted darunavir or lopinavir, but not with ritonavir-boosted atazanavir.

Preliminary results of the study were released by Merck Feb. 8, when the company also said it was discussing the results with regulators and with investigators conducting clinical trials in hepatitis C/HIV co-infected patients. Victrelis is not indicated for the treatment of chronic hepatitis C in HIV patients, but Merck noted some physicians have treated, or may be considering treating, such patients. The CHMP acknowledged data was still needed from ongoing clinical trials to assess the actual clinical impact of the drug interaction.

Aliskiren Contraindicated In Certain Combinations

Novartis AG is already facing U.S. patent expiry this year on its blockbuster antihypertensive Diovan (valsartan), and CHMP recommended Feb. 17 that contraindications and restrictions should be added to the prescribing information for its newer antihypertensive, the renin inhibitor Rasilez/Tekturna (aliskiren), following adverse events seen in an interim analysis of the ALTITUDE clinical trial.

In ALTITUDE, there was a higher incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension associated with aliskiren, in patients with type 2 diabetes and renal impairment, with or without cardiovascular disease, also being treated with either an angiotensin converting enzyme (ACE)-inhibitor or an angiotensin receptor blocker (ARB). Novartis halted the study and informed regulators in December 2011.

Since then the CHMP has reviewed the ALTITUDE study results along with data from other studies, and has confirmed that there is a risk of those adverse events with combination therapy. It recommends contraindicating the use of all aliskiren-containing medicines in patients with diabetes or moderate to severe renal impairment who take ACE-inhibitors or ARBs. It also wants a warning, for all patients, that a combination of aliskiren and an ACE-inhibitor or ARB is not recommended because adverse outcomes cannot be excluded.

Novartis markets aliskiren alone and in combination with other antihypertensive agents like the calcium channel blocker amlodipine (Resilamlo) and the diuretic hydrochlorothiazide (Rasilez HCT), but the products are now unlikely to figure prominently at Novartis in the future (Also see "With Its Hypertension Franchise in Crisis, Novartis Restructures" - Pink Sheet, 13 Jan, 2012.). Novartis' sales of aliskiren declined by 19% to $108 million in the fourth quarter, and the company included the episode as one of several mishaps for which it took a $1.7 billion charge in the quarter (Also see "For Novartis, 2012 Is Set To Be A Bumpy Ride" - Pink Sheet, 25 Jan, 2012.). Until that point, sales of aliskiren had been growing and totaled $557 million in 2011.

Health technology assessment groups have also been unhappy with aliskiren, for what they perceive as its lack of additional benefits over other antihypertensive therapies. The German HTA body, IQWiG, rejected aliskiren's use in Germany on Feb. 15 (Also see "Germany’s IQWiG Downs Two Drugs In One Day" - Pink Sheet, 15 Feb, 2012.). And the U.K.'s NICE didn't think it required an appraisal, saying only that it would include it in any updated hypertension treatment guidelines.

Orlistat Doesn't Cause Severe Liver Injury

But there was good news for the obesity therapy orlistat following the CHMP meeting on Feb. 13-17. The committee concluded there was no strong evidence that orlistat increased the risk of severe liver injury, after conducting an extensive review of all the available data on such risks.

Orlistat, which is marketed as the prescription product Xenical by Roche and as the over-the-counter product Alli by GlaxoSmithKline Consumer Healthcare LP, as well as by generic companies, was found to be associated with a rate of severe liver reaction reports below that expected in non-treated patients.

The committee concluded there was no strong evidence that orlistat increased the risk of severe liver injury and no known mechanism by which it could cause liver disorders. However, it recommended the product information on possible very rare liver-related side effects should be included in the prescribing information and should be the same for all orlistat-containing medicines.

Opinion Reversed On Trasylol

The CHMP has reversed its opinion on the use of the antifibrinolytic aprotinin (Bayer AG's Trasylol), which it suspended in 2007 because of preliminary results from the BART study, which apparently showed it was associated with increased mortality in patients undergoing heart surgery. Bayer withdrew Trasylol from the market in 2007 because of the concerns (Also see "BART Sends Bayer’s Trasylol Off The Market" - Pink Sheet, 5 Nov, 2007.).

After the final results of the BART study became available, and after an extensive review of other evidence, the CHMP has concluded the BART study results were not replicated in other studies and there were problems with the BART analysis, such as imbalances in the way heparin was used, that were not taken into account.

It is now recommending that aprotonin's suspension should be lifted in a narrowly defined group of patients where its benefits outweigh its risks, that is in patients undergoing isolated heart bypass surgery who are at high risk of major blood loss.