Poised to wade into a crowded field of drugs for hereditary angioedema (HAE), Santarus Inc. and partner Pharming Group NV said the pivotal Phase III study with the C1 esterase inhibitor Ruconest for acute HAE attacks met the primary endpoint of time to beginning of symptom relief.

Two already marketed products – Berinert, from King of Prussia, Pa.-based CSL Behring LLC, and Cinryze, from ViroPharma Inc., of Exton, Pa. – are also C1 esterase inhibitors, though the latter is used as an HAE prophylactic rather than for acute attacks. Both, like Ruconest, are intravenous (I.V.).

But Ruconest's key difference is that it's recombinant; the others are plasma-derived. Just as with blood products, the trend is away from the latter.

"We have yet to see any of the side effects that plague the plasma-derived [products], which are thromboembolic," said Wendell Wierenga, vice president of research and development of San Diego-based Santarus. "There's good preclinical data to support why that's the case. [Ruconest] is not treated, frankly, as foreign, so it's not bringing any new issues to the table." No neutralizing antibodies were raised, either, in single or multiple treatments with Ruconest, he said.

Other HAE drugs approved by the FDA include subcutaneous Kalbitor (ecallantide), a kallikrein inhibitor from Burlington, Mass.-based Dyax Corp., for acute attacks in patients 16 years of age and older, and Dublin, Ireland-based Shire plc's bradykinin receptor antagonist Firazyr (icatabant), also subcutaneous, for acute attacks in those 18 and older.

"As we see I.V. becoming more and more comfortable [for patients] in the on-demand, self-administration mode, I would question whether subcutaneous delivery would be as competitive," since I.V. gets immediate distribution of the protein to blood volume, Wierenga noted.

HAE 'Stepping Stone'

In the Phase III trial, which enrolled 75 patients who were randomized 3-to-2 to receive either Ruconest or saline, a statistically significant difference in the time to beginning of symptom relief was observed in the intent-to-treat population (n=75) between drug and placebo (p=0.031, log-rank test); the median time to beginning of symptom relief was 90 minutes for Ruconest patients (n=44) and 152 minutes for placebo patients (n=31).

The time to beginning of symptom relief was defined as the time from the beginning of infusion of study medication (Ruconest or placebo) until the beginning of a persistent beneficial effect, based on the patient's responses to a Treatment Effect Questionnaire for the primary attack location.

The drug was generally well tolerated and the frequency of patients experiencing at least one treatment emergent adverse event in the drug-treated group was less than in the placebo group.

Within 72 hours of the completion of infusion of study medication, four Ruconest patients (7 percent) experienced six adverse events: sneezing, procedural headache, back pain, skin burning sensation, an increase in fibrin D-dimer and lipoma. Within the same period, four placebo patients (22 percent) experienced four adverse events: sinus congestion, vasomotor rhinitis, diarrhea and dyspepsia. Thromboembolic events, anaphylaxis or neutralizing antibodies to C1 inhibitor were not observed in any patient.

There was one patient in the Ruconest group who experienced a serious adverse event (abdominal hernia at day 79) that was assessed by the investigator as not related to the study drug.

Pharming, of Leiden, the Netherlands, conducted the trial, called Study 1310, under a special protocol assessment agreement with the FDA, and the study is intended to support the submission of a biologics license application in the U.S. in the first half of next year.

Plasma-derived products have been limited by supply from going into "a number of very interesting indications that one could explore, and obviously we intend to do that" with Ruconest, Wierenga told BioWorld Today. "In a way, HAE is a stepping stone for us to advance the product into other areas," beyond even HAE prophylaxis, he said.

"We're fleshing out the scenarios in a more detailed fashion, and we haven't talked about them yet," Wierenga said, but areas such as ischemic reperfusion injury, organ rejection and vascular leak appear promising.

'Too Late' For Pharming?

"Bone marrow transplant patients have significant vascular leak immediately after transplant, and there really isn't an intervention possible there," Wierenga said. Acute severe pancreatitis could be another in a "long list of very interesting and legitimate [indications], but we want to make sure we have the right disease along with the right drug and the right dose," he said.

In HAE, Ruconest (called Rhucin overseas) gets orphan eligibility from the FDA by virtue of being recombinant, hence safer, than plasma-derived products, Wierenga said.

But Jan De Kerpel, analyst at KBC Securities in Brussels, Belgium, said the news about Ruconest is too little and too late for Pharming, since Ruconest would be the fifth product to the U.S. market in the orphan disease.

As a company, Pharming is running out of options, since big pharma firms have not exhibited any appetite for its transgenic animal platform, while developing countries have not shown much enthusiasm either. "We've not seen any reasonable partnership," De Kerpel told BioWorld Today.

The firm's best hope might lie in a takeover by one of its partners, but neither Santarus nor its European distributor, Swedish Orphan Biovitrum AB, of Stockholm, Sweden, has shown any interest in acquiring the company.

Santarus licensed from Pharming exclusive rights to commercialize Ruconest in North America for the treatment of acute attacks of HAE, as well as other potential future indications. Under the terms of the license agreement, Pharming gets a $10 million milestone payment as a result of the successful Phase III trial. (See BioWorld Today, Sept. 15, 2010.)

Santarus' stock (NASDAQ:SNTS) closed Wednesday at $8.82, down 34 cents.

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