Editor

Recalling biotechnology battles is almost like re-living boxing matches from the past.

Who could forget when Genzyme Corp. faced off against Transkaryotic Therapies Inc. to get first approval for a Fabry's disease therapy? In a hard-fought showdown, Genzyme had Fabrazyme (agalsidase beta) pitted against TKT's Replagal (agalsidase alfa). At the final bell, the loser was TKT, which gave up efforts to win FDA approval after gaining market clearance in 27 countries, and the FDA gave its nod to Genzyme's drug. Lights out.

Shaping up as a somewhat similar situation is the double-team war that runs Tercica Inc. and licensor Genentech Inc. against Insmed Inc. and its acquired firm Celtrix Inc. over their drugs for idiopathic short stature. Tercica/Genentech's drug awaiting FDA approval is Increlex (recombinant human insulin-like growth factor-1) and Insmed has SomatoKine, composed of recombinant human IGF-I and IGF-binding protein-3.

Their legal conflict first made news about seven months ago, shortly before Insmed submitted its new drug application for SomatoKine. At that point, Tercica had reported positive Phase III data with Increlex, and the company since has filed its NDA. The situation has only heated up since. Both drugs have been granted orphan status by the FDA, giving the first one approved seven years of market exclusivity.

This summer, Tercica/Genentech filed a motion for a preliminary injunction against Insmed, reiterating the patent-infringement claims and trying to block the latter from making, using, offering to sell, or selling SomatoKine. Also, the motion wanted the court to compel Insmed to grant Tercica/Genentech joint exclusivity in any orphan drug marketing right if SomatoKine were approved before Increlex.

In less than a month, though, Tercica/Genentech had withdrawn the motion, backing into its corner because the FDA had extended SomatoKine's PDUFA date to Oct. 3, which comes after Increlex's fast-approaching PDUFA date of Aug. 31. But then, last week, another punch was thrown when Insmed filed a citizen petition asking that the FDA immediately deny approval of Increlex.

A citizen petition lets private citizens or corporations outline a problem they think the agency should fix, explain why, and propose a way to do it. Insmed's document did not become public until three days after it was filed, when John Scarlett, president and CEO of Tercica, said there was nothing new in the document - although "there were a lot of points," he told BioWorld Financial Watch.

Insmed's safety concerns about Increlex relate to hypoglycemia. Further, the petition says Tercica is asking for approval of Increlex for severe primary IGF deficiency with data generated in a different patient population, i.e., growth-hormone insensitivity syndrome.

Raymond noted that no patients dropped out of Tercica's trial program as a result of the well-known hypoglycemia side effect, which was fixed by giving Increlex before a meal. As for the other matter, he pointed out that "patients treated by Increlex were actually IGF-I deficient."

Under the agency's rules, it must respond (or explain why it hasn't responded) to a citizen petition within 180 days. The eleventh-hour bid by Insmed seemed like it might work, to one degree or another. At the very least, the FDA might push back Increlex's approval date to a point nearer SomatoKine's fall PDUFA date - or even beyond that date, assuming the agency takes the full 180 days.

Insmed took a risk. As Christopher Raymond, analyst with Robert Baird & Co., pointed out, FDA leader Lester Crawford has remarked upon abuses of the citizen-petition process, and Raymond said Insmed's move looks like a "transparent use" of that route for the company's gain. The agency might not take it well.

Scarlett said the citizen-petition arena has "become, unfortunately, a pretty common battleground for generics vs. pioneer companies," though it's less usual for two such as Tercica and Insmed to square off.

One of two scenarios seems likely in the skirmish, Raymond wrote in a research note. The FDA could either push back the Increlex PDUFA date as it takes time in responding to the Insmed petition, or it could handle Increlex's approval separately from the petition - approving Increlex and then making a decision on the petition later.

"We continue to point to Increlex's more robust clinical data and more rigorous manufacturing validation process as positives for its regulatory prospects," Raymond wrote. "While [Tercica] shares may be choppy in coming weeks, we remain confident in an early 2006 Increlex launch."

Scarlett said the FDA has much flexibility in responding. The agency could do so without deciding anything immediately. Historically, he said, the first response sometimes has been "that they don't have time or necessary resources to address it."

Other companies have run into trouble with citizen petitions, among them Andrx Corp., albeit in an indirect way.

In May, Andrx entered a deal with Amphastar Pharmaceuticals Inc. for marketing rights to a proposed generic version of Aventis Pharmaceuticals Inc.'s anti-thrombotic drug Lovenox (enoxaparin sodium). In June, the U.S. District Court for the Central District of California granted summary judgment in Amphastar's favor in the patent infringement lawsuit filed by Aventis - but Amphastar's abbreviated new drug application is being delayed by an Aventis citizen petition, to which Amphastar responded in mid-July.

One Lovenox patent expired last year, but another was at the center of the dispute with Amphastar (as well as with Teva Pharmaceuticals Industries Ltd., which has filed an ANDA for its version).

Also the target of a citizen petition has been mifepristone, known in its generic form as RU486, the French abortion pill approved in the U.S. in September 2000 as a way of ending pregnancy. In 2004, the drug's label was changed to include a "black box" warning about bacterial infections, sepsis and death. Pro-life groups are especially opposed to mifepristone, and last month the FDA said it was still reviewing a citizen petition.

Interestingly, a biotechnology firm is working with the same compound. Corcept Therapeutics Inc. in May started its third Phase III trial designed to evaluate its version of mifepristone, called Corlux, for psychotic features of major depression. Against that indication, the compound works by a different mechanism of action, selectively blocking the binding of cortisol to one of its two known receptors. (In an abortion, it blocks the effects of progesterone, shutting off nutrition to the placenta and fetus.)

But for now, more eyes are watching the citizen-petition case between Tercica/Genentech and Insmed. Scarlett stood behind Increlex and, though he would not predict what regulators might do, he said he felt sure it would be the right thing.

"We have a lot of faith in the FDA," he said.

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