Karo Bio Moves Eprotirome to Pivotal HeFH Trial; MAA in 2014?
BioWorld International Correspondent
Next month, Karo Bio AB will begin recruitment in a pivotal Phase III trial of eprotirome in patients with heterozygous familial hypercholesterolemia (HeFH), having received a green light from regulatory authorities in Europe.
A regulatory filing could happen as early as 2014. "The full study is two years, but we are going to get interim data in autumn 2013. We're going to submit those data to the regulatory authorities," acting president Per Bengtsson told BioWorld International.
The Huddinge, Sweden-based company will receive its first indication of the trial's progress before then. In April 2012, an independent safety monitoring committee will recommend continuation or discontinuation of the study, based on an analysis of initial safety and efficacy data.
The upcoming study will test the ability of eprotirome, a liver-selective thyroid hormone receptor agonist, to lower levels of low-density lipoprotein cholesterol (LDL-C) to clinically meaningful levels in patients who are generally on statin therapy already.
"We're looking for something similar to the Phase II study, in which the reduction was over 20 percent," Bengtsson said. "Anything above 10 percent is approvable, but that will not be accepted by physicians."
The study will recruit 630 patients through 70 treatment centers located in 12 countries. John Kastelein, of the Academic Medical Center of the University of Amsterdam in the Netherlands, is principal investigator.
Patients will be randomized to a placebo arm or one of two treatment arms, in which they will receive a single daily dose of either 50 mcg or 100 mcg of eprotirome, on top of background therapy.
A variety of genetic causes can give rise to HeFH, although mutations in the gene encoding the LDL receptor are the most common. The condition is associated with early onset heart disease, and reducing the risk of cardiovascular events is a major therapeutic goal.
"We've had a dialogue with the authorities. In order to get approval we believe we need to treat a certain number of patients with coronary arterial disease long term," Bengtsson said.
Karo Bio is targeting HeFH initially, partly because it has been unable to find a Western pharmaceutical partner for a larger indication, owing to regulatory uncertainties in the area of managing dyslipidemia. "If the results are good and the safety is acceptable, it's a natural step to take this into a broader population and other types of disease," Bengtsson said.
An alliance with Alkem Laboratories Ltd., of Mumbai, India, offers an early opportunity to explore eprotirome's potential in a broader patient population. That firm also is embarking on a clinical development program, which will form part of Karo Bio's regulatory submission in Europe. (See BioWorld International, Apr. 27, 2011.)
Its most immediate competitor is the antisense drug mipomersen, developed by Isis Pharmaceuticals Inc., of Carlsbad, Calif. Isis partner Genzyme Corp., now owned by Paris-based Sanofi Group, filed for approval in homozygous and severe heterozygous familial hypercholesterolemia in Europe in July and is on track to complete an FDA filing later this year.
In a Phase III trial, mipomersen, which targets synthesis of apolipoprotein B (ApoB), reduced LDL-C levels by 36 percent in HeFH patients vs. a 13 percent reduction for placebo. The drug was associated with higher levels of treatment discontinuation than was the placebo.
"It's a totally different mechanism of action," Bengtsson said of eprotirome. Thyroid hormone – and analogues thereof – have long been associated with a cholesterol-lowering effect, but they also cause cardiovascular and bone problems. Karo Bio aims to differentiate eprotirome on the basis of its liver selectivity and, so far, it has not detected the safety problems commonly associated with the wider class.
News of the drug's progress failed to raise investor enthusiasm when it was disclosed Monday, however. The stock (STOCKHOLM:KARO) edged down almost 3 percent to close at SEK0.99 (US$0.15), and it's off by 50 percent since the beginning of the year.
Sentiment has not been helped by apparent upheaval at the firm. Karo Bio parted company with former CEO Fredrik Lindgren at the start of the summer, following a disagreement with the board. Its chief medical officer, Jens Kristensen, left in August.
Bengtsson declined to comment on those issues, although he said the board will shortly update investors on the search for a permanent CEO.
Published: September 21, 2011
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