Neither a fizzled merger nor worries over clinical trial supply of its osteoporosis drug Preos kept NPS Pharmaceuticals Inc. from forging ahead with the pivotal Phase III study and meeting the primary endpoint of reducing vertebral fractures in the top-line data analysis.
The company's stock (NASDAQ:NPSP) gained $1.95 Tuesday to close at $28.89.
"We have a large number of patients with asymptomatic disease, people who are at high risk of first fracture," said Robert Lindsay, chief of medicine at Helen Hayes Hospital in West Haverstraw, N.Y., and head of the independent data and safety monitoring board for the study. "The data here support the concept that we can use agents such as [Preos] in that population. I see no reason, since patients with vertebral fractures were also included in the study, why an agent such as Preos cannot be used in severe cases of osteoporosis also."
Preos, recombinant parathyroid hormone, is in the same class as Indianapolis-based Eli Lilly and Co.'s Forteo (teriparatide), which was approved in November with a premium price tag of $20 per dose and racked up sales of $25.9 million in the fourth quarter. NPS intends to submit a new drug application for Preos to the FDA later this year, but officials would not specify the label to be sought.
David Clark, vice president of operations for Salt Lake City-based NPS, acknowledged that more osteoporosis drugs are coming down the pike.
"One thing that gives us some comfort is that there are only two anabolic drugs that will be on the market in the foreseeable future - the Lilly drug and ours," he told BioWorld Today.
Reducing the incidence of new or worsened vertebral fractures in postmenopausal women with mild to moderate osteoporosis was the specific endpoint of the NPS pivotal trial. Randomized, double blinded and placebo controlled, the study - known as Treatment of Osteoporosis, or TOP - was held at 152 centers worldwide and enrolled about 2,600 postmenopausal women with osteoporosis, as defined by low bone mineral density (BMD), a measure determined by the number of standard deviations from the young adult mean, or the T score.
The average pretrial vertebral T score of study participants was -3.0. Patients, 81 percent of whom had not yet experienced a vertebral fracture, got either a daily subcutaneous injection of 100 mcg of Preos or placebo, plus daily supplements of calcium (700 mg) and vitamin D (400 IU) over a period of 18 months.
An analysis of all patients given at least one dose of Preos or placebo showed a statistically significant (p=0.001) drop in the relative risk of vertebral fractures for patients in the treatment group compared to placebo.
The rate of vertebral fractures in the placebo group was 3.4 percent (42 new vertebral fractures), consistent with mild to moderate disease severity, while the rate of vertebral fractures in the Preos-treated group was 1.4 percent (17 new vertebral fractures and one worsened vertebral fracture), which amounts to a 59 percent relative reduction in vertebral fracture risk.
A 68 percent relative reduction in vertebral fracture risk (p=0.006) was achieved in patients treated with Preos who entered the trial without a previous fracture.
By the 12th month, patients given daily Preos, calcium and vitamin D had a 60 percent reduction in the relative risk of new vertebral fractures - not a statistically significant level (p=0.122). Overall, patients treated with Preos had fewer total fractures at non-vertebral sites compared to placebo patients, but those differences were not statistically significant, either.
"We're dealing with a relatively mild population, and I think it's pretty good that we got statistical significance in the first vertebral fracture [endpoint]," Lindsay said.
Subgroup analysis with regard to those measurements and other clinical endpoints is ongoing. What can be determined so far is that the average change in vertebral BMD in all patients given at least one dose of Preos was 7 percent, relative to placebo (p<0.001). Other measures of bone growth and quality were positive and consistent with previous human trials, NPS officials said.
Adverse events were comparable in both arms, with the two most frequent in the Preos group being elevated levels of serum and urine calcium, which were generally consistent with observations from the Phase II study. Usually the problem was resolved when patients were tested again, Clark said. If the retest yielded elevated results, physicians would try lowering the amount of the calcium supplement. If that didn't work, they would adjust the frequency of drug dosage.
Other frequent side effects included headaches, nausea, dizziness and vomiting. About 9 percent of patients getting Preos dropped out of the study as a result of elevated levels of serum or urine calcium, or due to side effects, while about 2 percent of placebo patients dropped out due to one or more of those side effects.
In all, about 16 percent of Preos-treated patients dropped out of the TOP study due to any side effect, compared to approximately 10 percent of patients in the placebo group.
Secondary endpoints in the study included evaluation of fractures at bone sites other than the spine, changes in BMD and other measures of new bone growth and quality. NPS said further details about the data will be offered later.
About 1,700 study participants have enrolled to receive Preos as part of an ongoing open-label extension study known as OLES.
In June, NPS' proposed merger with Enzon Pharmaceuticals Inc., of Bridgewater, N.J., fell apart. NPS had planned to offer about $750 million in stock for Enzon, but the companies could not agree on a stock conversion rate. (See BioWorld Today, June 6, 2003.)
The glitch in drug supply arose a year earlier, when the maker of the dual-chamber injection pen used to administer Preos was unable to keep up with the Phase III trials while meeting specifications for the device, but NPS was soon able to fix the problem by making changes in the manufacturing process.
NPS' injector pen is a dual-chamber carpule with 14 days of dosing once the drug is reconstituted inside the pen. Lilly's Forteo is given by way of a disposable device with about one month of dosing, and must be kept refrigerated. NPS officials said they will have an even more improved version of the Preos pen by the time the drug is launched.