Emisphere Technologies Inc. said Tuesday that its Phase III trial of oral heparin failed to show superiority to Aventis SA's injected Lovenox in preventing deep-vein thrombosis in patients undergoing total hip replacement surgery.
The design of the study, called the PROTECT 1 trial, required at least a 10 percent reduction in DVTs, or blood clots, in order to demonstrate superiority.
"We are all extremely disappointed and a little shocked," Emisphere Chairman and CEO Michael Goldberg said during a conference call.
Emisphere's stock (NASDAQ:EMIS) plummeted $5.80 Tuesday, or 51.3 percent, to close at $5.16.
Heparin is an anticoagulant/antithrombotic agent. The trial to evaluate the safety and efficacy of oral solution heparin using Emisphere's oral drug delivery technology, (sodium N-[8-(2 hydroxybenzoyl) amino] caprylate), or SNAC, included 2,288 patients. Emisphere's business is based on the development of new chemical entities that allow macromolecules to be absorbed through oral administration.
Patients were dosed three times a day for 30 days with the oral solution of heparin, compared to a 10-day dosing regimen with Lovenox by injection.
Emisphere, of Tarrytown, N.Y, was surprised by the better-than-expected results of Lovenox, Goldberg said. Based on data available at the time of the trial design, the company expected 30 percent of the patients treated with Lovenox to have a blood clot at the end of the 30 days. Instead, 27 percent of Lovenox patients had clots. Twenty-eight percent to 29 percent of oral heparin patients developed blood clots.
Goldberg said it was clear that not all patients participating in the study took oral heparin consistently. He also said that some physicians likely had prescribed other anticoagulants, such as aspirin, in conjunction with Lovenox, which may have improved its results.
For example, Goldberg said that one group in Russia that was treated throughout the 30 days in a hospital setting showed results that were much closer to what the company had anticipated.
In light of the results, Goldberg said the company no longer would study the liquid heparin and a follow-up study, PROTECT 2, has been canceled. However, the company said it would continue to develop heparin in solid-dosage form.
"Patients voted with their performance and the message to us is clear: Develop the solid-dosage form and do not develop the liquid any further," he said.
Heparin is the only one of Emisphere's formulations that is in a liquid form, Goldberg said.
Robert Baughman Jr., senior vice president of development at Emisphere, said a positive from the study was that it demonstrated that Emisphere's delivery system successfully moves macromolecules across the epithelial membrane.
"We've used our delivery agent for 30 days in patients now," Baughman said, noting that the company "badly wanted to look at the safety" of its delivery agent and that the PROTECT 1 trial represents the longest duration for one of Emisphere's delivery agents to be in use in patients.
The delivery agent, he said, proved safe.
Also as a result of the Phase III failure, Emisphere executives said they will reduce the company's burn rate, originally projected to be $90 million in 2002, through a reduction in activity, such as the previously planned PROTECT 2 trial, and by reducing staff. They suggested that it would be about 30 days before they could give a clearer picture of how the changes will be implemented.
Carol Werther, senior biotech analyst at Adams, Harkness & Hill in Boston, said she was "very disappointed" that the trial failed. In her estimation, the trial showed that the drug worked, and if the company had simply tried to show equivalence, rather than superiority to standard treatment, it might have had different results. "Clearly," she said, "there is reason to go forward with the solid dosage."
Werther said in a research note prior to the conference call that her model was dependent upon oral liquid heparin sales beginning in 2004, but she has since changed the model. Based on the failure, she estimated that the company would have losses of $50 million this year.
Baughman said the company's goal is always to partner and to maintain a focus on its technology, rather than build its own staff for sales and marketing. Emisphere has four major strategic alliances.
Novartis AG, of Basel, Switzerland, is using Emisphere's technology in the development of salmon calcitonin for osteoporosis. That product is in multinational Phase II trials in Europe in a single-tablet formulation. Novartis is responsible for clinical development and commercialization of salmon calcitonin.
Eli Lilly and Co., of Indianapolis, is in a Phase I trial evaluating oral recombinant human parathyroid hormone (Forteo) for osteoporosis and human growth hormone (Humatrope) for growth hormone deficiency and hypopituitary dwarfism, both using Emisphere technology.
Emisphere also has a partnership with Regeneron Pharmaceuticals Inc., of Tarrytown, to develop the protein compound Axokine as a treatment for obesity and its complications. That program is still in preclinical studies, Baughman said. (See BioWorld Today, March 10, 2000.)
Emisphere also has a collaboration with Cubist Pharmaceuticals Inc., of Lexington, Mass., which in-licensed daptomycin and plans to study its use with Emisphere delivery systems. That program also is in preclinical studies, Baughman said.
Emisphere is developing a product to deliver insulin orally, for which it has completed four Phase I studies in healthy patients and in Type II diabetics. It also is developing an oral formulation of cromolyn to treat allergies, for which it has completed a Phase I trial.
Emisphere wants to partner heparin, but the news of the PROTECT trial's failure to demonstrate superiority will make that more difficult, Werther wrote in a research note.