An anticipated Phase III trial of Riquent in lupus, meant to confirm data trends seen in a Phase II/III trial, brought about a similar result - good data trends but a missed primary endpoint, sending La Jolla Pharmaceutical Co.'s stock down 72.5 percent.
Steven Engle, La Jolla's CEO, said that even though the trial missed, the company is aiming in the right direction against the disease. Following data analysis it plans to meet with the FDA to decide the best course.
"Although the primary endpoint didn't meet our level of expectation, it appears we are working on the right problem," he told BioWorld Today. "What we've done is strengthen the argument that the antibodies are the culprit in this disease."
La Jolla's stock (NASDAQ:LJPC) shed $5.47 Tuesday to close at $2.08.
The primary endpoint in the trial was time to renal flare, which is defined as a significant, reproducible increase in serum creatinine, urine protein or blood in the urine. The study included 298 patients in the intent-to-treat group, defined as patients with high-affinity antibodies to Riquent. That population was chosen following analysis of results from an earlier Phase II/III trial, which overall did not meet its primary endpoints, but did when considering only those patients who had high-affinity antibodies to the drug.
The preliminary analysis did not show a statistically significant increase in time to renal flare. However, in the intent-to-treat population there were fewer renal flares, treatments with high-dose corticosteroids and/or cyclophosphamide (HDCC), and major SLE (systemic lupus erythematosus) flares in Riquent-treated patients compared with placebo-treated patients. The estimated median time to renal flare was 123 months in the Riquent-treated group and 89 months in the placebo-treated group. There were 41 renal flares, 17 in Riquent-treated patients and 24 in placebo-treated patients. There were 68 treatments with HDCC - 32 in the Riquent-treated group and 36 in the placebo-treated group. There were 82 major SLE flares in the trial, 35 in the Riquent arm and 47 in patients on placebo. None of the differences were statistically significant.
The Riquent and placebo lines for time to renal flare and for the changes in antibody levels were separating until weeks 46 to 48, the company said. In the first 46 weeks, 90 percent of renal flares occurred in the study in the placebo patients compared with 59 percent in the Riquent-treated patients. At weeks 44, 46 and 48, the incidence of renal flares was 20:10 (p=0.085), 22:10 (p=0.041) and 22:11 (p= 0.067), respectively, in favor of Riquent. At weeks 44, 46 and 48, the incidence of renal and/or major SLE flares was 43:27 (p=0.057), 46:28 (p=0.033) and 46:29 (p=0.061), respectively, in favor of Riquent.
The damage there is done, but what Engle and La Jolla are optimistic about are data that showed Riquent, formerly named LJP 394, reduced with statistical significance antibodies to double-stranded DNA when compared to the placebo group (p<0.001).
Knowing that antibodies to double-stranded DNA are believed to cause renal flares and other manifestations of lupus, and considering that "in every trial we have lowered the antibody levels," Engle said, show La Jolla is on the right track.
Add that the study showed a statistically significant inverse relationship between antibody and complement levels (p<0.001), then consider that complement C3 levels below normal at baseline correlated with an increased risk of renal flare (p<0.001), and the trial further solidified La Jolla's resolve that its technology and drug are working, the company said. And the drug was well tolerated for as long as 92 weeks.
Also, Engle and La Jolla said a change in medical practice might have contributed to the trial's missed endpoint. In the Phase II/III trial, 31 percent of patients in the Riquent arm were receiving immunosuppressive treatments at study entry and 34 percent in the placebo arm. For the Phase III trial, those figures increased to 50 percent for the Riquent arm and 41 percent for the placebo group.
"That's a sad commentary on the health of the patients, but it's also affecting our trial," Engle said.
Engle said that while the trial wasn't meant to "dramatically beat the effect of immunosuppressives" for lupus patients, "what we did plan was to provide a simple benefit with much less side effect and general immune suppression. It is core to why a drug like our drug should be approved."
However, even with all that said, the fact remains that "we still didn't get the primary endpoint," Engle said. What to do about that is not yet clear. The company will take several more weeks to finish analyzing the data, then approach regulatory authorities in both the U.S. and Europe.
"We can't predict past that point," Engle said, but added that the company will continue its follow-on safety trial.
Separately, La Jolla has LJP 1082 for antibody-mediated thrombosis that finished a Phase I/II trial last year. The product requires some toxicology work before another clinical trial is initiated, but the reduction of antibodies in the Riquent trial adds validity to La Jolla's technology and to LJP 1082, Engle said.
"In terms of one more large-scale trial, [the Riquent Phase III] does show our technology works in lowering antibodies," Engle said. "We won't change our direction."
When the Phase II/III trial missed, partner Abbott Laboratories, of Abbott Park, Ill., left the collaboration and Riquent remains unattached today. As of Sept. 30, the company had about $65 million in cash, cash equivalents and short-term investments. La Jolla has said it expected to have the financial legs to last through the fourth quarter if it did not need to ramp up for a Riquent launch, and Engle said Tuesday the company would further "manage our costs." In late November it filed a $125 million shelf registration statement. (See BioWorld Today, Sept. 21, 2000.)
But the biggest need on the horizon, Engle said, is "to get that conversation with the FDA to occur first."