LJPH new 10K is available. Very interesting history of LJP 394. Sorry for the length. I know everyone can find edgar.
Results of Clinical Trials
Based on our preclinical findings, we filed an Investigational New Drug ("IND") application for LJP 394 with the FDA in August 1994. In a double-blind, placebo-controlled Phase I clinical trial conducted in December 1994, healthy volunteers received LJP 394 and displayed no significant drug-related adverse effects and no immune reaction to the drug.
Our Phase II clinical trials included a single-dose trial, a repeat escalating-dose trial, and a dose-ranging trial. The single-dose clinical trial evaluated the safety of a single, 100 mg intravenous dose of LJP 394 in four female lupus patients by monitoring antibody levels, blood chemistry, vital signs and complement (inflammation-promoting proteins) levels for 28 days after dosing. LJP 394 was well tolerated by all four patients, with no drug-related adverse clinical symptoms and no clinically significant complement level changes. In addition, no linically significant immune complex formation (inflammation-promoting accumulation of antibodies and antigens) was observed, indicating the absence of an adverse immune response to LJP 394. A transient reduction in dsDNA antibody levels was also observed. These results were presented at the American College of Rheumatology's Annual International Conference in October 1996.
The repeat escalating-dose clinical trial involved two female patients, each receiving doses of 10, 10, 50, 50, 100 and 100 mg of LJP 394 at two-week intervals. After the 10-week dosing regimen, the patients were followed for six weeks. LJP 394 was well tolerated by both patients with no drug-related adverse clinical symptoms, no clinically significant complement changes, and no significant immune complex formation. Six weeks after the last dose, the antibody levels in both patients remained suppressed below baseline levels.
The dose-ranging trial evaluated 58 patients with mild lupus symptoms (53 females and five males). All patients were clinically stable and had dsDNA antibody levels exceeding those generally found in healthy individuals. The patients were organized into nine treatment groups at three dose levels (1 mg, 10 mg and 50 mg), and three frequencies (once per week, once every two weeks and once every four weeks.) Patients were randomized to one of the nine treatment groups so that at each dose and frequency, four to seven patients received LJP 394 and one patient received a placebo.
Patients in the weekly treatment groups showed a dose-response correlation between increasing doses of LJP 394 and reductions of levels of dsDNA antibodies. In patients treated weekly with 10 mg or 50 mg doses of LJP 394, antibodies to dsDNA were reduced by statistically significant levels and remained suppressed in certain patients for up to two months after the last dose. In the patient group treated weekly with 50 mg, the reductions in median levels of dsDNA antibodies were accompanied by increases in median levels of two important inflammation-related complement proteins, C3 and C4, which normally
decrease during active lupus renal disease and increase with clinical improvement. These study data suggest that complement levels and antibody levels were normalizing in parallel.
Throughout the dose-ranging trial, the drug was well tolerated with no clinically significant dose-related adverse reactions observed. Three patients experienced lupus renal flares, and three other patients were hospitalized as a result of transient adverse events that the treating clinicians believed were unrelated to the underlying disease or to LJP 394. Two of the patients with renal flares withdrew from the study, as did four patients who experienced exacerbations of lupus, and one patient who experienced herpes rash. However, no relationship was observed between the development of an adverse event and the
dose or frequency of administration of LJP 394.
In December 1996, we initiated a double-blind, placebo-controlled multi-center Phase II/III clinical trial of LJP 394. The purpose of the trial was to evaluate the safety of the drug and its potential to prevent renal flares, reduce disease severity and the need for immunosuppressive steroids/chemotherapy drugs and improve patients' quality of life. The trial enrolled over 200 patients and was conducted by LJPC and Abbott Laboratories in over 50 sites in North America and Europe as part of our joint development agreement with Abbott.
In May 1999, an interim analysis of the Phase II/III clinical trial of LJP 394 indicated that the trial was unlikely to reach statistical significance for the primary endpoint, time to renal flare and it was decided to stop the
study and evaluate the data. There were no statistically significant serious safety issues. In September 1999, Abbott and LJPC terminated the joint development agreement for LJP 394.
In November 1999, we announced encouraging initial results for LJP 394 from the analyses of the data from the Phase II/III clinical trial showing a certain group of patients treated with LJP 394 had fewer renal flares and
treatment with high-dose corticosteroids and/or cyclophosphamide. These results were based on an analysis of the trial using a new blood test developed at LJPC
that appears to predict which patients will respond to drug treatment. Developed in 1998, the new blood test measures the strength of the binding between LJP 394 and a patient's antibodies to dsDNA. We found that it predicted which patients in a previous Phase II dose-responsive trial responded to drug treatment as measured by changes in antibody affinity following drug treatment.
In May 2000, we completed the affinity analysis of more than 99% of the North American patients' samples. The affinity analysis showed that 89% of these patients had high-affinity antibodies to LJP 394 ("high-affinity" patients). The high-affinity patients treated with drug experienced significantly longer time to renal flare, the primary endpoint of the trial, (p=0.008), fewer renal flares
(p=0.008), longer time to treatments with high-dose corticosteroids and/or cyclophosphamide (p=0.002) and fewer exposures high-dose corticosteroids and/or cyclophosphamide (p=0.001) when compared to the placebo-treated group
Also in the Phase II/III study, mean levels of circulating antibodies to dsDNA in patients treated with LJP 394 were reduced by a statistically significant amount relative to placebo during drug treatment. Levels of an
important complement protein, C3, improved when antibodies were reduced. In lupus patients, this inflammation-related protein decreases during active renal disease and increases with clinical improvement. The concurrent reduction of antibodies to dsDNA and increase in C3 complement levels is biologically consistent. As noted earlier, this effect had been observed in a previous Phase II study of LJP 394 in 58 lupus patients.
Results from the Phase II/III lupus study suggest two ways to improve the clinical trial design of a Phase III trial:
- eliminate the "off" periods, and
- use doses of 100 mg per week
The Phase II/III trial design included periods during which patients received no drug for approximately two months (the "off" periods) and weekly doses of 50 mg over three months (the "on" periods). When patients were on drug, mean levels of antibodies to dsDNA decreased. Unfortunately, mean levels of antibodies to dsDNA increased when patients were off drug. During the first four months, when patients were treated with 100 mg per week, there were nine renal
flares in the placebo-treated group and four in the drug-treated group. Furthermore, for high affinity patients, during the first four months, there were eight renal flares in the placebo-treated group and only one renal flare in
the drug-treated group (p=0.035).
Based on these observations and following discussions with the FDA, we initiated a Phase III clinical trial in September 2000 to demonstrate the safety and efficacy of LJP 394 for lupus. In the trial, patients will be treated with 100 mg per week of LJP 394 or with placebo and there will be no "off" periods.
The Phase III clinical trial is a double-blind, placebo-controlled study, which will be, conducted at over 60 major medical centers in North America and Europe. The Company plans to enroll approximately 300 lupus patients to evaluate the potential of LJP 394 to prevent or delay renal flares, reduce the need for treatment with high-dose corticosteroids and/or chemotherapy drugs, and improve
a patient's quality of life. Completion of the trial is expected in 2002.
We believe that the blood test we developed can identify lupus patients who are most likely to respond to LJP 394 and we will use this affinity assay to identify the patients to be included in the efficacy analysis of the Phase III trial. We have filed a patent application on this new blood assay.
In September 2000, the FDA granted us orphan drug designation for LJP 394 for the treatment of lupus kidney disease. The Orphan Drug Act provides for seven years of marketing exclusivity in the U.S. and enables the Company to
obtain research funding, tax credits for certain research expenses, and a waiver of the application user fees.
In October 2000, we presented additional data from the Phase II/III trial at the 64th Meeting of American College of Rheumatology concerning the effect of LJP 394 treatment on patients with impaired renal function. In a predefined group of patients with poor renal function, there were more renal flares in the patients treated with placebo than in the patients treated with LJP 394 (p=0.046). In a group of patients with poor renal function and with high-affinity antibodies to LJP 394, there were six renal flares in patients treated with placebo and no renal flares in patients treated with drug (p=0.004).
In January 2001, we announced that approximately 90% of patients enrolled in each of three previous clinical trials had high-affinity antibodies to LJP 394, prior to drug treatment. The ratios for the trials were: 89% (186/211) in the Phase II/III trial, 94% (29/31) in the Phase II trial completed in 1996 and 90% (54/60) in the Phase II trial completed in 1999. Patients in the Phase
II/III trial had moderate to severe disease and a history of renal flares. Patients in the two Phase II trials had mild to moderate disease. Placebo and drug-treated groups had similar percentages at baseline in each clinical trial. |
