CD&D National Editors

The lead story for this month's "Pharma" review is probably not too hard to predict.

The FDA last month approved Atryn, a therapeutic protein derived from goats (called a recombinant DNA or rDNA construct), genetically engineered to produce this human, an antithrombin, in their milk. The development is clearly in the "first-ever" category.

GTC Biotherapeutics (Framingham, Massachusetts), the manufacturer of ATryn, received approvals from two FDA centers: the Center for Biologics Evaluation and Research (CBER) approved the human biologic, based on its safety and efficacy, and the Center for Veterinary Medicine (CVM) for the rDNA construct in the goats that produce ATryn.
"This product offers an important new treatment option for patients with hereditary antithrombin deficiency, preventing life-threatening clots that otherwise frequently occur during high risk situations," said Jesse Goodman, MD, director of CBER.
The FDA granted aTryn an orphan drug designation because hereditary AT deficiency occurs in a small population (about one in 5,000 in the U.S.), the FDA granted ATryn an orphan drug designation. Hereditary AT deficiency generally is first recognized and diagnosed in teenagers or young adults when they develop clots in their blood vessels, particularly during pregnancy, surgery, or prolonged bed rest.
An advisory committee to CBER in January recommended approval of the drug, based on two studies that included 31 patients with hereditary antithrombin deficiency who received ATryn to prevent thromboemboli (TE) before, during or after surgery or childbirth. All but one patient had a prior history of at least one TE, which are likely to recur in high-risk situations if left untreated. Only one of the 31 patients treated with ATryn developed a TE.

The most common adverse reactions – occurring in about 5% of patients – were hemorrhage and reactions at the infusion site.

CVM assessed the safety of the rDNA construct to the animals, including a full review of the construct and its stability in the genome of the goats over seven generations. CVM specified that these goats cannot be used for food or feed and validated a method suitable for identifying the rDNA construct in both animals and their products, and it determined that the GE goats do not cause any significant environmental.
ATryn previously received approval from the European Medicines Agency for use in preventing clotting conditions during surgical procedures in patients with hereditary AT deficiency.

An alternative approach to heart failure

Most therapies targeting heart failure have focused, rather logically, on strengthening the weakened heart's ability to pump.

But in the Feb. 10 issue of the Proceedings of the National Academy of Sciences, researchers from Boston University, Tufts University, Universite Louis Pasteur (Strasbourg, France) and start-up firm NormOxys (Boston) report on trying another approach: increasing the ability of hemoglobin to give up oxygen and thus compensate for decreased pumping power. They did this by altering hemoglobin's oxygen-binding affinity and were able to increase the exercise capacity of both normal mice and animals genetically engineered to have heart failure.

"A normal red blood cell can give up 25% of the oxygen it has in the lungs" when it reaches tissues with lower oxygen concentration, PNAS co-author and NormOxys co-founder and Chief Scientific Officer Claude Nicolau said. "And under normal circumstances, that is certainly enough."

But when the heart's pumping capacity decreases in heart failure, less blood flows to tissues; and in order to make up for the reduced blood flow, the hemoglobin needs to part more generously with its oxygen.

In their PNAS paper, senior author Wilson Colucci and his colleagues showed that by treating mice with myo-inositol trispyrophosphate or ITPP, they were able to boost oxygen release by hemoglobin from 25% to 50%, improving oxygen delivery to the tissues of both normal mice and mice with severe heart failure.

Importantly, Nicolau noted, "this release is regulated" by tissue oxygen concentration. While the binding is essentially unchanged under conditions where oxygen is plentiful – in other words, in the lungs – ITPP makes hemoglobin more likely to release oxygen when oxygen concentration is low, such as in the oxygen-deprived tissues of an individual with heart failure.

ITPP was developed by another NormOxys co-founder, chemistry Nobel Laureate Jean-Marie Lehn. Earlier studies had shown that a related molecule named myo-inositol hexakisphosphate has the same effect on hemoglobin's oxygen binding. But due to its extreme negative charge, blood cells need to be treated ex vivo for it to be effective. In the experiments described in the current PNAS paper, ITPP was effective when it was given by injection, and even when it was added to the drinking water.

When animals were injected with a single dose of ITPP, hemoglobin binding to oxygen was affected for several days. The authors write in their paper that the change in binding was "was sustained for 48 [hours], had decreased by 50% in 5 days, and was no longer present after 12 days."

NormOxys holds the patents on the applications of ITPP and is developing the compound under the name Oxyren. The company was founded in 2004, had an $8 million Series A funding round in 2007, and is planning to file investigational new drug applications in two separate indications this quarter: a U.S. trial will explore the compound in the area of heart failure, while a separate trial, which Nicolau said will be conducted in Belgium and possibly China, will look at Oxyren's potential use as an anti-cancer agent.

Nicolau said that a peer-reviewed publication on Oxyren's use in cancer is forthcoming. In the meantime, it is known that increasing oxygen delivery to tumors can make them less likely to metastasize.

ATHENA backs Multaq for AF, AFL

Data from the ATHENA trial has shown that that Multaq (dronedarone), made by Sanofi Aventis (Paris), in combination with standard therapy, significantly reduced the risk of first cardiovascular hospitalization or death by 24% (31.9% vs. 39.4%, p<0.001) in patients with atrial fibrillation (AF)/atrial flutter (AFL) or a recent history of these conditions.

The findings, reported in the New England Journal of Medicine, showed a significant decrease in the risk of cardiovascular death by 29% in patients with AF. Multaq significantly decreased the risk of arrhythmic death by 45% and there were fewer deaths (16%) from any cause in the dronedarone group compared to placebo. First cardiovascular hospitalization was reduced by 26% in the dronedarone group.

"The ATHENA trial is the first trial to show a reduction in the incidence of cardiovascular hospitalization or death in patients taking an anti-arrhythmic drug for atrial fibrillation," said Stefan Hohnloser, of the division of clinical electrophysiology at Goethe University (Frankfurt, Germany) and principal investigator of the study.

The landmark ATHENA study is the only double-blind, antiarrhythmic study in patients with AF that assesses morbidity-mortality. The study was conducted at more than 550 sites in 37 countries and enrolled a total of 4,628 patients.

Patients enrolled in ATHENA were 75 years old or older (with or without cardiovascular risk factors) or below 75 years of age with at least one additional cardiovascular risk factor. Patients with recently decompensated heart failure or in New York Heart Association class IV were excluded. Patients were randomized to receive dronedarone 400 mg BID or placebo, with a mean follow-up of 21 months.

The ATHENA study objectives were designed to analyze a potential benefit of dronedarone on the composite endpoint of all-cause mortality combined with cardiovascular hospitalization compared with placebo. Secondary endpoints were death from any cause, cardiovascular death and hospitalization for cardiovascular reasons. The safety endpoint was the incidence of treatment-emergent adverse events.
Significant adverse events in the Multaq arm included diarrhea (9.7% vs. 6.2% in control), nausea (5.3% vs. 3.1%), bradycardia (3.5% vs. 1.2%), QT-interval prolongation (1.7% vs. 0.6%); skin disorders (10.3% vs. 7.6%) mainly rash, and an increase in blood creatinine (4.7% vs. 1.3%).

Multaq (dronedarone) is an investigational treatment and the only antiarrhythmic drug to have shown a significant reduction in cardiovascular hospitalization or death in patients with AF/AFL. Multaq, discovered and developed by sanofi-aventis, has been studied in a clinical development program including more than 6,200 patients. Multaq is one of the major therapeutic innovations in atrial fibrillation for the last twenty years. Multaq has been granted a priority review by the FDA and a registration dossier is also under regulatory review by the European Medicines Agency.

New Atacand dose strengths approved

AstraZeneca (London) reported receiving approval for two new dose strengths of Atacand Plus, aimed at hypertensive patients who are not optimally controlled by monotherapy alone. The decentralized procedure – including 11 EU member states and Iceland, and with Sweden as reference member state – ended positively, and national approvals will follow, the company said.

The approval is for new dose strengths of the fixed dose combination Atacand Plus, an angiotensin receptor blocker (candesartan cilexetil) 32 mg, combined with a diuretic (hydrochlorothiazide - HCT), in doses of either 12.5mg or 25mg. Research shows that in more than two-thirds of hypertensive individuals, blood pressure is not controlled on one drug and will require two or more antihypertensive agents selected from different drug classes. In Europe, Atacand Plus has until now only been available in doses up to 16 mg of candesartan cilexetil in combination with HCT.

Atacand acts on the renin-angiotensin system (RAS), which plays an important role in regulating blood pressure. Angiotensin II, the main effector hormone in the RAS, mediates a wide range of responses such as vasoconstriction, sodium and fluid retention, cell growth, and sympathetic activation. Atacand binds to the AT1-receptor, thereby blocking its interaction with angiotensin II. This blockade leads to vasodilatation and a decrease in blood pressure.

Atacand was first launched for hypertension in 1997 and is currently approved and marketed in over 110 countries around the world. In 2004 Atacand received the first approval for the treatment of CHF in patients with left ventricular systolic dysfunction.
Atacand Plus is a fixed dose combination of candesartan cilexetil and hydrochlorothiazide in doses of 8/12.5 mg, 16/12.5mg, 32/12.5 and 32/25mg. Atacand Plus is indicated for the treatment of essential hypertension in patients who are not optimally controlled by monotherapy alone.

In brief ....

Osiris Therapeutics (Columbia, Maryland) reported final two-year results from its Phase I trial evaluating Prochymal for the treatment of acute myocardial infarction (MI) found heart attack patients receiving the intravenous therapy had lower rates of adverse events and significantly improved heart function.

The trial met its primary endpoint demonstrating safety of Prochymal in the acute MI setting. Data showed 47.4% of placebo patients experiencing cardiac arrhythmia, compared to only 11.8% of Prochymal patients.

Data also showed Prochymal patients had fewer adverse events compared to placebo, and a lower percentage of patients treated with Prochymal required repeat hospitalization. Also, patients receiving Prochymal had a significant and durable improvement in cardiac function.

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