GL70, DHEA & Lupus, dihydroepiandrosterone, prasterone, ASLERA™, for Treatment of Systemic Lupus Erythematosus in Women

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The Table of Contents

1   Table of Contents *
2    Executive Summary *
2.1 Background *
2.2 Efficacy *
2.3 Safety *
2.4 Conclusions *
3    Background *
3.1 Rationale for DHEA as a Therapy in SLE *
4    Development of GL701 for Systemic Lupus Erythematosus *
4.1 Clinical Studies Supporting Efficacy and Safety of GL701 in SLE *
4.2 Overview of Clinical Development Program for GL701 *
4.3 Pharmacology *
4.3.1 Background *
4.3.2 Pharmacokinetic Studies *
4.3.3 DHEA-S Levels from GL701 Controlled Clinical Studies *
5      Organization of Clinical Results *
6     Well controlled Studies *
6.1 Study GL94-01 (Corticosteroid Reduction Study) *
6.1.1 Protocol Development *
6.1.2 Entry Criteria *
6.1.3 Study Activities *
6.1.4 Patient Populations for Analysis *
6.1.5 Efficacy Variables *
6.1.6 Study Patient Population and Demography Results *
6.1.7 Dosing Information *
6.1.8 Efficacy Results *
6.1.9 SLE Scoring Instruments *
6.1.10 Study GL94-01 Conclusion *
6.2 Study GL95-02 (Improvement in SLE) *
6.2.1 Protocol Development *
6.2.2 Entry Criteria *
6.2.3 Study Activities *
6.2.4 Patient Populations for Analysis *
6.2.5 Primary Efficacy Variables *
6.2.6 Secondary Efficacy Variables *
6.2.7 Study Patient Population and Demography Results *
6.2.8 Patient Disposition *
6.2.9 Dosing Information *
6.2.10 Efficacy Results *
6.2.11 Study 95-02 Conclusion *
6.3 Well Controlled Studies, Foreign Source (Non-US IND) *
6.3.1 Study GBL96-01 (Disease improvement in SLE – Taiwan Study) *
6.3.2 Results *
6.3.3 Efficacy Results *
6.4 Published Studies Investigating DHEA in SLE (Stanford University Studies) *
6.5 Discussion of Efficacy *
6.5.1 Population Subsets *
6.5.2 Overview of Efficacy of GL701 in SLE *
7 Safety *
7.1 Organization of Safety Analyses *
7.1.1 Extent of Exposure *
7.1.2 Demographics *
7.2 Adverse Events *
7.2.1 All Adverse Events *
7.2.2 Severe Adverse Events *
7.2.3 Relationship of Adverse Events and Duration of Exposure to GL701 *
7.2.4 Early Termination from Study Drug *
7.2.5 Deaths *
7.2.6 Other Serious Adverse Events *
7.3 Clinical Laboratory Evaluation *
7.3.1 Hematology *
7.3.2 Liver Function Tests *
7.3.3 Renal Function Tests *
7.3.4 Serum Glucose *
7.3.5 Urinalysis *
7.3.6 Serum Complement, Anti DS DNA *
7.3.7 Serum Lipids *
7.3.8 Serum Hormone Levels *
7.4 Safety Issues of Potential Concern *
7.4.1 Acne and Hirsutism *
7.4.2 Hypertension *
7.4.3 Abdominal Pain *
7.4.4 Decreases in Serum Complement *
7.4.5 Serum Lipids *
7.4.6 Effects of GL701 on Sex Hormones *
7.5 Special populations *
7.5.1 Race *
7.5.2 Age, Sex, and Menopausal Status *
7.5.3 Pregnancy *
7.5.4 Drug Interactions *
7.5.5 Potential Interaction with Hydroxychloroquine for Serum Lipids *
7.6 Relationship of Dose to Safety *
8    Benefit/Risk Assessment *
8.1 Benefit *
8.2 Risks *
9    Bibliography *

Executive Summary

Background

Systemic lupus erythematosus (SLE) is a serious chronic, autoimmune, inflammatory disease that may affect the skin and joints, as well as internal organs and serous membranes. Approximately 65% of patients develop SLE between 16 and 55 years of age, and it is 8 to 10 times more common in women than in men.

Current therapies for active SLE are limited and include only hydroxychloroquine, corticosteroids, and immunosuppressive/cytotoxic drugs. Patients are exposed to multiple toxicities, many serious, during treatment with these drugs. Since patients are often dependent on steroids and immunosuppressive drugs, discontinuing them or reducing their dose may cause serious flares while continued use leads to multiple cumulative toxicities.

Although the etiology of lupus is unknown, hormonal influences seem to play a key role in disease development and progression. Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S, are the most abundant circulating steroid hormones in humans and are the principal androgens secreted by the adrenal gland. Circulating levels of DHEA and DHEA-S are reduced by approximately 50% in female SLE patients with active disease.

Two clinical studies conducted at Stanford University – one open-label and one double-blind, placebo-controlled - initially suggested that orally administered DHEA may improve manifestations of disease in mild to moderate SLE, reduce steroid requirements, reduce flares, and improve patient’s overall self-assessment of the status of her SLE.

The New Drug Application for GL701 (Genelabs’ formulation of prasterone [dehydroepiandrosterone, DHEA]) is based primarily on two double-blind placebo-controlled studies in women with SLE: Study GL94-01, which assessed the ability of GL701 to enable steroid reduction to 7.5 mg/day in steroid-dependent patients; and Study GL95-02, which assessed the effects of GL701 on overall signs and symptoms of SLE in patients with active disease. Long term safety data are provided from Study GL95-01, an open-label 1-year extension study. The application is also supported by a double-blind, placebo-controlled, non-US IND study conducted by a licensee in Taiwan (GBL96-01).

The GL701 clinical program has focused primarily on adult women with SLE inasmuch as approximately 90% of affected patients with this disease are women in their childbearing years.

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Efficacy

In Study GL94-01, women with mild to moderate SLE were randomized to receive GL701 100 mg/day, GL701 200 mg/day or placebo for 7 to 9 months to determine whether GL701 would allow reduction of prednisone to < 7.5 mg/day for 2 consecutive months including the last visit while improving or maintaining disease activity (responders). Study patients had been treated with prednisone 10 - 30 mg/day and either a) in the last 12 months attempted to taper prednisone dose but failed and had a stable prednisone dose for at least 6 weeks preceding the study, or b) in whom there had been no attempt to taper in the last 12 months and had been on a stable prednisone dose for at least 3 months preceding the study.

Patients returned at monthly visits, at which time corticosteroid dose was reduced by algorithm: prednisone dose (or its equivalent in other corticosteroids) was reduced if disease activity was stable or improved as assessed by the SLE Disease Activity Index (SLEDAI), a composite score which measures overall disease activity in multiple organ systems.

GL94-01 was the first study of its type to investigate steroid sparing as an endpoint in a therapeutic trial for SLE. Given that there was no precedent for design of steroid sparing studies in SLE, investigator experts could not determine during the planning of this study whether patients with low SLEDAI scores (indicative of low disease activity) should be enrolled, since a low SLEDAI score could either reflect suppression of disease activity by exogenous corticosteroid treatment or relatively inactive disease. If the latter were true, patients might be unnecessarily treated with doses of corticosteroids higher than necessary for maintenance of disease suppression.

Because this issue was impossible to resolve without any prior SLE investigation precedent, an assessment of overall responders by baseline SLEDAI score was conducted while the study was blinded to treatment assignments and showed that patients with low SLEDAI scores (e.g., SLEDAI < 2) had much higher responder rates than patients who entered with higher SLEDAI scores. As a consequence, FDA agreed to defining a subgroup of patients with baseline SLEDAI >2 as part of the efficacy analyses.

The study population consisted of 191 patients. The percent of patients who achieved sustained reduction to 7.5 mg/d for at least the last 2 months of the study ("responders") were as follows: for analysis of all randomized patients (N=191) 40.6% for placebo, 44.4% for GL701 100 mg, and 54.7% for GL701 200 mg, (P=0.110, GL701 200 mg vs. placebo). For the patient group with baseline SLEDAI >2 (N=137), responders were 28.9% for placebo, 38.3% for GL701 100 mg, and 51.1% for GL701 200 mg (P=0.031, GL701 200 mg vs. placebo). In this group, there was a dose response relationship (P=0.033 for linear trend).

Additionally, a treatment effect was evident for the total number of days over the entire 7 month period during which daily prednisone dose was < 7.5 mg/day with mean (median) days for all patients showing placebo 71.7 (66.5) vs. GL701 200 mg 92.1 (111.5 days), P <0.069; and for patients with baseline SLEDAI >2, placebo 59.7 (28.0) days vs. GL701 200 mg 93.4 (111.0) days, P <0.013 GL701 200 mg vs. placebo.

In summary, in GL94-01 more GL701 patients than placebo patients were responders: i.e., achieved sustained prednisone reduction without worsening of signs and symptoms of SLE. This difference approached significance in the intent-to-treat patients and achieved significance in those with baseline SLEDAI > 2. There was a dose-response relationship, with the numbers of responders in the GL701 group being intermediate between GL701 200 mg and placebo. The difference in responders appeared early in the study and was maintained for the duration of the study. The mean number of days with a daily dose of prednisone < 7.5 mg was significantly greater in the GL701 200 mg group.

In the second study, Study GL95-02, women with mild to moderate active SLE were randomized to placebo or GL701 200 mg/day for 12 months. The primary efficacy objective of the study was to demonstrate improvement or stabilization in the disease and/or its symptoms in women with active SLE. The study population was mild to moderate SLE, defined as patients receiving either no prednisone or up to 10 mg/day (or its equivalent of other corticosteroids). Active disease was initially defined by a criterion of a Systemic Lupus Activity Measure (SLAM) score of ³ 7, but following the findings from the earlier GL94-01 study, the protocol was amended while ongoing and blinded to also require baseline SLEDAI > 2.

Concomitant medications, including NSAIDs, glucocorticoids, anti-malarials, and immunosuppressives were required to be stable for at least 6 weeks prior to enrollment and were to be held stable throughout the duration of the study.

The primary efficacy variable or endpoint was "response." The response was a per-patient endpoint that integrated the three domains of SLE including disease activity, as measured by the SLEDAI and SLAM; quality of life or constitutional symptoms, as measured by the Patient Visual Analog Scale (VAS) and Krupp Fatigue Severity Score (KFSS); and organ damage, as assessed by clinical deterioration. A responder had to demonstrate improvement or stabilization of each of the above four scoring instruments, and also not experience "clinical deterioration."

Because there was no precedent for this composite responder definition, which had not been previously validated in a clinical trial, it became clear that it would be difficult to quantify "stabilization" of disease. As a consequence, allowance for minor variability in the scoring instruments was identified and proposed for the definition of responders. Therefore, prior to unblinding the study, a "tolerance window" was defined to ensure that minor variability in these instruments would not confound the primary efficacy analysis for determining improvement and/or stabilization.

An additional efficacy variable defined toward the end of Study GL95-02 was "definite flare" which was defined to be consistent with flare descriptors for the ongoing NIH sponsored SELENA (The Safety of Estrogen in Lupus Erythematosus National Assessment ) study in women with lupus, which commenced after the start date of this ongoing study.

Bone mineral density at baseline and at 12 months was measured at 8 study sites on selected patients who had been on corticosteroids for at least 6 months prior to study entry.

Three hundred and eighty-one (381) patients were randomized to Study GL95-02, of whom 346 were in the per-protocol population, which was defined in the statistical analysis plan and which consisted of patients who had been treated for at least 60 days and had at least 1 post baseline assessment. Of these, 265 patients also had baseline SLEDAI >2. Of the 35 patients not meeting the criteria for the per-protocol population, 32 had no post-baseline assessments. The other 3 were excluded because of a major protocol violation (one patient) or receiving less than 60 days study drug (2 patients).

Study GL95-02 confirmed the findings of the earlier study, GL94-01, in that patients with no or minimal SLE activity (defined as SLEDAI < 2) should be viewed separately from those with baseline SLEDAI > 2 since a significant (P < 0.001) treatment interaction with baseline SLEDAI > 2 (yes/no) was noted.

Among the per-protocol population (N = 346), the percent of patients who were responders were 45.5% of 176 placebo patients vs. 58.2% 170 GL701 200 mg patients, P=0.018; in those with baseline SLEDAI >2, the percent of patients who were responders were 48.0% of placebo vs. 65.9% of GL701 200 mg, P=0.005. In the intent-to-treat population (N = 381), there were also more responders in the GL701 group compared to the placebo group, 51.3% of 189 GL701 patients were responders compared to 42.2% of 192 placebo patients (p=0.074); in those with baseline SLEDAI > 2 group, 58.5% of 147 GL701 patients were responders compared to 44.5% of 146 placebo patients (P=0.017)

Both treatment groups showed improvement in individual scoring instruments, but the mean improvement for the GL701 group was greater than the placebo group for each instrument. In particular, for patients with baseline SLEDAI >2, the improvement in Patient VAS was greater in the GL701 group (P=0.057 GL701 vs. placebo).

Fewer patients in the GL701 group with baseline SLEDAI >2 experienced a definite flare: 31 (23.5%) of 132 GL701 patients had at least one definite flare compared to versus 41 (30.8%) of 133 placebo patients, a trend favoring GL701, but the difference was not statistically significant (P=0.201).

At eight investigator sites, thirty-seven of the patients who had been receiving chronic corticosteroids (> 6 months) prior to enrollment underwent bone mineral density measurements by DEXA scanning at baseline and at 12 months. In these patients receiving chronic corticosteroid treatment, there was a significant decrease in bone density in the placebo group. By contrast, bone density increased in the GL701 group. The differences at 12 months between GL701 and placebo were seen most prominently in the spine, where the mean decrease of 1.78% in bone density in the placebo group is compared to a mean increase of 1.83% in the GL701 group (P=0.004).

With respect to the objective of the GL95-02 study, the GL701 group had approximately a 35% increase in the proportion of responders, and a 24% decrease in proportion of patients with definite flares .

Supportive data for efficacy are provided from a non-US IND study conducted in Taiwan by a licensee. This study was similar in design except that it was a 6-month study. Ninety-seven percent (97%) of the patients entered with baseline SLEDAI >2; also, 97% of the patients were receiving corticosteroids at study entry. The primary endpoint was percent improvement in SLAM.

The GL701 group demonstrated a greater reduction from baseline for SLAM score in both mean and median scores as compared to the placebo group, but the difference was not significant. The difference in mean change in patient VAS was statistically significant. The GL701 group improved, while the placebo group worsened (P=0.005). Utilizing the same flare definition as in Study GL95-02, the GL701 group in the Taiwan study had fewer patients with at least one definite flare. The number of patients with definite flares in the GL701 group was decreased 46.0% compared to placebo (18.3% vs. 33.9%, p = 0.044 based on time to first flare).

Thus, the overall results of the primary and secondary efficacy analyses for the Taiwan study consistently showed benefit for GL701 in the treatment of SLE.

In summary, consistent efficacy findings have been observed across all studies and have demonstrated improvement in all three domains of SLE in GL701-treated patients. Reduction in manifestations of SLE or improvement in the area of SLE disease activity was demonstrated by the increase in proportion of responders and decrease in proportion of patients with flares. Achievement of sustained reduction of corticosteroids in corticosteroid-dependent patients, without worsening of disease, as well as improvement in bone mineral density in patients receiving corticosteroids chronically, are important benefits for the domain of SLE damage. Finally, a benefit in the patients’ overall assessment of quality of life or constitutional symptoms was demonstrated by improvement in the Patient VAS, a finding which was consistently observed in these studies.

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Safety

In the double-blind, placebo-controlled trials and the open-label extension study which followed completion of the double-blind studies, 387 women have received GL701 for at least 6 months; 242 for > 12 months, and 138 for > 18 months, and 36 for >24 months. The principal adverse events and biochemical changes associated with treatment with GL701 were principally related to its androgenic properties. No new unexpected safety findings emerged with continued treatment with GL701 for up to 2 years.

Adverse events that were each statistically significantly more common in GL701 200 mg-treated patients compared to placebo were acne (36.0% vs. 15.2%) and hirsutism (14.2% vs. 2.3%), as well as hypertension (7.9% vs. 2.7%) , hematuria (3.6% vs. 0.4%), and increased creatinine (2.4% vs. 0%). Acne and hirsutism were expected androgenic events; and the difference between placebo and GL701 was clinically meaningful as well as statistically significant. Hematuria, hypertension and creatinine increase occurred in only small numbers of patients. Their relationship to GL701 and their clinical significance wass less clear. These events were viewed in greater detail and are discussed in Section 7.4.

For hypertension, no differences between treatment groups were observed in a composite measure which integrated the number of patients experiencing new onset hypertension, or experiencing an increase in hypertension, or requiring an additional anti-hypertensive medication or an increase in dose of existing anti-hypertensive medications.

For the adverse events of "hematuria" or "creatinine increase," there was no consistent association with renal dysfunction.

Serious adverse events occurred in 38 GL701 200 mg, 7 GL701 100 mg, and 39 placebo patients. Only 3 of these events were assessed by the investigators as related to study drug: 2 in placebo and 1 in GL701.

For clinical laboratory assessments, there were no meaningful or significant differences between treatment groups in hematology or liver function parameters. BUN and creatinine levels did not change during study and were similar within or between treatment groups. Mean changes in 24-hour urine protein excretion increased in all treatment groups, but to a greater extent in GL701 patients. However, a few patients with very high values impacted 24-hour urine protein; and median changes were only slightly higher in the GL701 groups.

Decrease in serum complement changes, particularly C3, were more common among patients treated with GL701. Most patients remained within the normal range; 16% of patients on GL701 200 mg went from normal to low C3 (< 85 mg/dl), compared to 6% of placebo patients at last visit. Few of the patients who reduced complement exhibited other manifestations of renal lupus including worsening of proteinuria, new hematuria, or addition of new immunosuppressives; those that did occur were equally distributed between the GL701 and placebo-treated groups. An androgenic effect on hepatic complement synthesis is postulated as the cause for the reduced C3 complement rather than an effect on inflammation-related consumption.

Changes in serum lipids were consistent with changes associated with androgenic steroids. Total cholesterol, HDL-C, and triglycerides were decreased in GL701-treated patients in comparison to placebo patients (Figure 2-1). These changes were seen by three months with relatively little further progressive decrease. The mechanism of this androgenic-induced decrease in serum lipids is believed to be enhanced hepatic clearance of HDL-C and triglycerides.

Figure –1: Lipid Changes

The hormonal effects of GL701 were primarily androgenic in nature with significant increases in total testosterone, but primarily to levels at the upper range of normal for women. Serum estradiol did not change in pre-menopausal women, while in post-menopausal women, increases in serum estradiol were primarily to levels consistent with hormone replacement therapy. Only a few post-menopausal SLE patients achieved levels in the pre-menopausal range.

There were few reports of menstrual bleeding abnormalities either in pre- or post-menopausal patients suggesting there were no significant estrogenic effects on the endometrium. Additionally, mammography and uterine ultrasound measurements on some of the post-menopausal patients who had participated in these studies did not show evidence of neoplasia of the breast or hyperplasia or neoplasia of the endometrium.

There were 3 (1.5%) cases of breast cancer in 206 GL701-treated patients older than 45 years and 1 (4.2%) case in 24 placebo patients (never received GL701) of the same age group. Expressed as a rate per-patient year of observation for patients 45 years or older, these rates are 4.6/1000 for GL701 and 6.5/1000 for placebo. These are similar to breast cancer rates recently reported in the medical literature for post-menopausal women.

Taking this data as a whole, it would appear that increased risk, if any, of breast cancer associated with GL701 therapy should be low. GL701 therapy produces estradiol levels lower or similar to those with HRT and GL701 therapy is not accompanied by progestin therapy. The data from the GL701 clinical trials so far do not suggest an increased rate of breast cancer.

Conclusions

Four different studies, all in women with SLE, support the proposed indications for GL701:

Improvement in disease activity and/or its symptoms in women with mild to moderate systemic lupus erythematosus,
Reduction of corticosteroid requirements in women with mild to moderate systemic lupus erythematosus.

Improvement in GL701-treated patients has been consistently shown in Phase II studies conducted at Stanford University and subsequent studies conducted by the Sponsor and in Taiwan. Improvement has been demonstrated in all three domains of SLE.

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Background

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, inflammatory disease that may affect the skin and joints, as well as internal organs, such as the heart, lungs, kidneys, spleen, nervous system and serous membranes lining the lungs, heart and abdominal cavity. Approximately 65% of patients develop SLE between 16 and 55 years of age, and it is 8 to 10 times more common in women than in men (American College of Rheumatology Ad Hoc Committee, 1999).

Although the etiology of lupus is unknown, hormonal influences seem to play a key role in disease development and progression. Beyond the increased incidence in women, several studies have noted that alterations in estrogen and androgen metabolism occur in patients with lupus. Decreased levels of androgens (androstenedione, dehydroepiandrosterone [DHEA], DHEA-S, and testosterone) have been observed in female lupus patients, especially in those with active disease (Lahita, 1987; Jungers, 1983).

Patients with mild to moderate symptoms are usually managed with administration of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and sunscreens. However, NSAIDs may reduce glomerular filtration rates and renal blood flow, cause gastrointestinal bleeding and can be associated with hepatotoxicity. If symptoms are not well controlled by these therapies, the patient's treatment may be augmented by the addition of an antimalarial drug, such as hydroxychloroquine (Plaquenil), although chloroquine and quinacrine are used less frequently. Toxicities with these agents include retinopathy with hydroxychloroquine and chloroquine, aplastic anemia with quinacrine, skin pigmentation changes, as well as development of peripheral neuropathy and myopathy with hydroxychloroquine only.

Most lupus patients do not respond to conservative therapy and require glucocorticoids for control of disease activity. In the Johns Hopkins Lupus Cohort, comprising of 539 patients, 89% had used prednisone, 21% of whom had been treated on one or more occasions with doses over 60 mg/day for at least 2 months. Most patients had used prednisone at doses above 10 mg/day (Zonana-Nacach, 2000).

Despite the fact that they are the mainstay of treatment for most lupus patients, glucocorticoids are well-known to be associated with significant toxicity including ischemic cardiovascular disease, serious infection, hyperglycemia, hypertension, osteoporosis, muscle wasting, avascular necrosis of bone, and cataracts (Zonana-Nacach, 2000). Female SLE patients are at a 5-fold risk of osteoporotic fractures (Ramsey-Goldman, 1999), and a 1.6-fold risk of ischemic necrosis (Zonana-Nacach, 2000). Patients dying early from lupus succumb to complications of lupus and/or infection while those dying after 5 years of disease often succumb to atherosclerotic complications, which may be related in part to chronic corticosteroid therapy (Urowitz, 1999, 2000).

Flares occur commonly among SLE patients. In the Johns Hopkins Lupus Cohort, the incidence of flare was 0.65 per patient-year of follow-up with the median time from first study visit to a flare being 12 months (Petri, 1991). While most flares involve "minor" organ systems, i.e. constitutional (fatigue) musculoskeletal, and cutaneous, it is of interest that in the Hopkins cohort, prednisone dose was increased in 39.7% of the flares (Petri, 1991). Furthermore, of 261 patients, 56.3% were hospitalized over a 2 year period from 1989 to 1990 (Petri, 1992). Prednisone dose over 10 mg/day was one of the risk factors for infection requiring hospitalization (P=0.04), as was use of immunosuppressive drugs (P=0.003).

Thus, an extremely important goal in the treatment of SLE is to reduce glucocorticoids to the lowest dose required to maintain suppression of SLE activity. However, during glucocorticoid taper, patients may experience symptoms of steroid withdrawal (e.g., joint pain, malaise) and the underlying disease may flare, thus perpetuating the need for treatment with glucocorticoids to control flare in this disease.

More aggressive management is often warranted in the treatment of lupus. In the Johns Hopkins lupus cohort alone, 34% of patients were using cytotoxic drugs (Zonana-Nacach, 2000). Immunosuppressive agents such as azathioprine (Imuran) and cyclophosphamide (Cytoxan) are used for patients with life-threatening or major organ system involvement. Toxicities associated with administration of azathioprine include leukopenia, hepatitis, pancreatitis, nausea and vomiting, and infections. Cyclophosphamide can result in urinary bladder toxicity, sterility, teratogenic effects, infections, and cancer.

Progression of SLE is highly variable and is difficult to predict from one individual to another. Lupus remains a serious disease with a 10-year mortality rate of approximately 10 to 20% (Uramoto, 1999).

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Rationale for DHEA as a Therapy in SLE

DHEA is a naturally occurring steroid produced by the adrenal glands, testes, ovaries and brain. Its metabolite, DHEA sulfate (DHEA-S), is the most abundant circulating adrenal steroid in the human body and is converted by peripheral tissues containing DHEA sulfatases, including lymphocytes and macrophages, to DHEA. DHEA is in turn metabolized to androstenedione as well as other potent androgens: testosterone, dihydrotestosterone and estrogens, including estrone and estradiol. As a biologically inactive precursor, selective conversion of DHEA to other androgenic and estrogenic steroids enables metabolism on a tissue-specific basis, a concept known as "intracrinology" (Labrie, 1995).

Figure –1

Figure –1: Downstream Metabolites of DHEA

As described above, endogenous levels of androgens (androstenedione, DHEA, DHEA-S and testosterone) are decreased (approximately 50%) in women with SLE, especially in those with active disease (Lahita, 1987; Jungers, 1983).

The abnormalities contributing to low DHEA-S concentrations in this disease are poorly understood, but may be related to defects in the hypothalamic pituitary adrenal axis or direct suppression of adrenal androgen secretion by inflammatory cytokines including IL-1 and IL-6, the latter of which is significantly elevated in active SLE (Brink, 1999; Straub, 2000). DHEA has been shown in vitro to directly suppress release of IL-6, IL-1 and TNF-a from human mononuclear cells (Straub, 1998; Padgett, 1998) as well as IL-6 from bone marrow stromal cells (Gordon, 2000); whether these effects occur in vivo during treatment with DHEA, however, has not been determined.

Circulating levels of endogenous DHEA and DHEA-S, already low in active SLE disease, are further reduced during administration of glucocorticoids (Hedman, 1989).

PreclinicallyIn animal models of SLE, administration of androgens, including DHEA, resulted in delayed formation of anti double-stranded DNA antibodies (Siiteri, 1980; Roubinian, 1977; Roubinian, 1979a) and increased survival in hybrid NZB/NZW mice (Melez, 1980; Roubinian, 1979b, Lucas, 1985). Additionally, DHEA may be an important regulator of the immune system by up-regulating IL-2 secretion by activated T cells as demonstrated in both murine and human in vitro assays (Daynes, 1990a; Suzuki, 1991).

Two clinical studies conducted at Stanford University - one open-label and one double-blind, placebo-controlled¾ initially suggested that orally administered DHEA may improve manifestations of disease in mild to moderate SLE (van Vollenhoven, 1994, 1995). In the placebo-controlled study, concomitant doses of glucocorticoids were decreased, while disease activity as assessed by SLE Disease Activity Index (SLEDAI) score and patient and physician assessment (Visual Analog Scale [VAS]) stabilized or improved. Patient assessment of disease activity improved significantly in the DHEA group compared with placebo, and the number of disease flares (determined clinically by the investigator) experienced by the DHEA treatment group was significantly less than in the placebo treatment group (van Vollenhoven, 1995).

Based on the pre-clinical and clinical observations noted earlier, including the pilot studies at Stanford University, the development of GL701 (Genelabs’ formulation of prasterone [dehydroepiandrosterone, DHEA]) in SLE was initiated. GL701 is a pharmaceutical preparation of prasterone, and should be distinguished from DHEA currently marketed as dietary supplements, which are unregulated as to purity or potency, and may vary substantially in content (as much as 0 to 150% of labeled amount) (Parasampuria, 1998).

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Development of GL701 for Systemic Lupus Erythematosus

Clinical Studies Supporting Efficacy and Safety of GL701 in SLE

Four different studies, all in women with SLE, support the proposed indications:

Improvement in disease activity and/or its symptoms in women with mild to moderate systemic lupus erythematosus
Reduction of corticosteroid requirements in women with mild to moderate systemic lupus erythematosus

These studies are summarized below by number and in Table 4-1.

GL94-01, a randomized, parallel group double-blind placebo-controlled study comparing placebo to 100 mg/day and 200 mg/day of GL701, where the primary efficacy variable was "steroid sparing", or reduction in corticosteroids in corticosteroid dependent patients, without worsening of disease activity.

GL95-02, a randomized, parallel group double-blind placebo-controlled study comparing placebo to 200 mg/day of GL701 in patients with active SLE, where the primary efficacy variable was improvement or stabilization of disease activity while maintaining a constant dose of corticosteroids and other SLE medications.

GBL96-01, (a foreign (Taiwan) study conducted by a licensee, not under US IND), a randomized, parallel group double-blind design, placebo-controlled study comparing placebo to 200 mg/day GL701, where the objective was improvement in SLE disease activity while maintaining a constant dose of corticosteroids and other SLE medications.

GL95-01, an open-label extension study in which patients who completed therapy in either one of the double-blind trials (GL95-02 or GL94-01) received open-label GL701. This study provides long term safety information for GL701.

Additional supportive efficacy data come from publications of the studies conducted by Stanford University in which DHEA was studied under an investigator IND (#37,873) (van Vollenhoven, 1994, 1995).

Also study GL97-01, a randomized, parallel group, double-blind, placebo-controlled study in men with SLE is also ongoing, with 28 patients enrolled. The study remains blinded and as of the date of this submission, only serious adverse event data (blinded to treatment group) are available.

Table 4–1: GL701 Clinical Studies

Study No.	Patient Population	Objective	Total Patients		Duration of Treatment	Duration of Study	Design
Well Controlled Studies
GL94-01	Women with active SLE	Reduction in corticosteroids in corticosteroid dependent patients, without worsening of disease activity	191		7-9 mos.	6/94 – 6/96	Prospective, Randomized Double-blind, Placebo-controlled
GL95-02	Women with active SLE	Improvement or stabilization of SLE	381		12 mos.	2/96 – 6/99	Prospective, Randomized Double-blind, Placebo-controlled
GL97-01	Men with active SLE	Improvement in SLE	28		12 mos. + 12 mos. Open label	1/98 - On-going	Prospective, Randomized Double-blind, Placebo-controlled
Well Controlled Studies, Foreign Source
GBL96-01 (Non-US IND)	Women with active SLE in Taiwan	Improvement of SLE		120	6 mos.	2/97 – 7/99	Prospective, Randomized Double-blind, Placebo-controlled
Uncontrolled Studies
GL95-01	Patients who completed either GL94-01 or GL95-02	Long term safety evaluation in open-label extension study for patients completing either of the US double-blind studies		371	12 mos.	3/95 – 9/00	Open-label Extension
Studies Reported in the Medical Literature
van Vollenhoven, 1995	Women with SLE	Improvement in SLE	28		3 mos.	Not Reported	Prospective, Randomized Double-blind, Placebo-controlled
van Vollenhoven, 1999	Patients with severe SLE (men and women)	Improvement in SLE	19		6 mos.	Not Reported	Prospective, Randomized Double-blind, Placebo-controlled
van Vollenhoven, 1998	Women with SLE	Safety and Efficacy	50		12 mos	Not Reported	Open-label
Barry, 1998	Women with SLE	Dose response	23		6 mos	Not Reported	Open-label

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Overview of Clinical Development Program for GL701

The GL701 clinical program has focused primarily on adult women with SLE inasmuch as approximately 90% of affected patients with this disease are women in their childbearing years (American College of Rheumatology Ad Hoc Committee, 1999). Additionally, the hormonal rationale (low levels of endogenous DHEA in women with lupus) for using DHEA and other androgens in women with lupus is not as well established for the male or pediatric lupus population.

Designing a clinical development plan in SLE was particularly difficult because SLE is preeminently a multi-system disease and because no drugs have been approved for SLE in over 40 years. In particular, although there had been treatment trials for organ-specific manifestations, with the possible exception of a smaller withdrawal study of hydroxychloroquine in SLE (Canadian Hydroxychloroquine Study Group, 1991) there had been no experience with large, well-controlled treatment trials which examined overall efficacy for lupus. As a result, there were no pre-existing models for clinical trial design, key enrollment criteria, and, especially important, no established efficacy endpoints.

Because of the multi-system nature of SLE, it is difficult to specify a single primary efficacy endpoint, further compounding the difficulty in designing clinical trials in SLE. Additionally, although there are a number of SLE scoring instruments, such as the SLEDAI or Systemic Lupus Activity Measure (SLAM), none has been validated for assessing change in disease activity in a controlled clinical trial.

Such issues relating to the design of controlled clinical studies in SLE were discussed with the US Food and Drug Administration (FDA) and consultants prior to initiating the clinical studies of GL701. Reduction in corticosteroid dose was seen as a desirable outcome of treatment that could serve as an efficacy endpoint. It was agreed that one study, a Phase II/III efficacy study, would use steroid sparing as an endpoint.

While the Phase II/III steroid sparing study was ongoing, plans for a second Phase III study were initiated. The intended purpose of the second study was to evaluate improvement in disease manifestations as an efficacy endpoint, rather than steroid sparing. However, prior to the finalization of its protocol and due to the lack of previous clinical trial experience in the area of SLE, the FDA suggested that the GL701 clinical development plan be subjected to an Advisory Committee review. In March 1995, a closed session meeting of the Arthritis Advisory Committee (AAC) was held to discuss some fundamental issues surrounding the GL701 clinical development program, including the design of a second Phase III clinical study. In that meeting, a "per-patient" endpoint was identified as generally favored. Genelabs’ plan to use "steroid sparing" as an endpoint in the first pivotal trial and an endpoint of improvement in disease manifestations was deemed adequate to support an NDA.

As expected, experienced gained during the trials had an inevitable impact on the final detailed statistical analysis plan for each study. However, consistent with the principles in the final FDA guidance document "E9 Statistical Prinicples for Clinical Trial" (ICH guideline Guidance on Statistical Principles for Clinical Trials), the statistical analysis plans were finalized before the blind was broken and all confirmatory analyses were based on the protocol (including procotol/IND amendments) for each study.

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Pharmacology

Background

GL701 provides an exogenous source of DHEA, which is the major hormone produced by the adrenal glands. DHEA, a 19-carbon steroid synthesized within the adrenal gland, is secreted primarily as its sulfated ester metabolite, DHEA-S, which is the most abundant circulating steroid in the human, up to a 30-fold concentration greater than cortisol. On a molar basis, endogenous circulating concentrations of DHEA-S are approximately 250 and 500 times higher than those of DHEA in women and men, respectively (Carlstrom, 1988; Labrie, 1997).

The direct biological actions of DHEA and DHEA-S remain unknown as no functional receptor for either is known, but both are metabolized to androgenic and estrogenic steroids in nonadrenal tissues and serve as a mechanism for delivery of androgen and estrogen precursor substrate to target tissues. These target tissues can adjust the formation and metabolism of sex steroids to local requirements to reflect the peripheral conversion of DHEA or DHEA-S into more potent steroids without release into the extracellular space (Labrie, 1995). Secretion of DHEA is synchronous with cortisol, with a diurnal variation, while DHEA-S levels show little variation during the day. Blood levels of DHEA-S are high in the fetus and decline to near zero after birth, increasing again prior to puberty, and peaking at age 20 to 25. From puberty on, DHEA-S blood levels in men are significantly higher than those in women (Orentreich, 1984). Unlike cortisol, levels of DHEA-S decline progressively thereafter, to approximately 5 to 10% of peak values at age 60 to 70 (Orentreich, 1984; Carlstrom, 1988; Labrie, 1997). Age, genetic factors and gender account for a wide variation in circulating levels of DHEA and DHEA-S (Rotter, 1985).

Orally administered DHEA undergoes rapid sulfoconjugation in intestinal cells to DHEA-S (Baulieu, 1965). The average ratio of the serum concentration of DHEA-S to DHEA is approximately 500-800:1.

Both DHEA and DHEA-S are bound to serum albumin, globulins and steroid sex hormone binding globulin (SHBG) (Dunn, 1981). Approximately 88.1% of circulating DHEA is bound to albumin, 7.88% to SHBG, and < 0.1% to cortisol binding globulin, leaving 3.93% unbound in normal women in the follicular phase of the menstrual cycle (Dunn, 1981).

DHEA-S is strongly bound to albumin in blood and undergoes renal tubular reabsorption (Longcope, 1995), both of which contribute to its very slow clearance from blood and its long half-life.

Arlt (1998, 1999) reported in females a mean DHEA t_1/2 of 8.9 ± 3.6 and 7.6 ± 2.7 hours following oral administration of DHEA 50 or 100 mg, respectively, and a t_1/2 for DHEA-S of 13.2 ± 2.7 and 12.1 ± 2.8 hours following oral administration of DHEA 50 and 100 mg, respectively.

In a Genelabs’ sponsored single-dose pharmacokinetic study (GL97-02), the half-life (t_1/2) was calculated to be approximately 20 hours for DHEA and DHEA-S. However, these calculations are confounded by variable endogenous (i.e. circadian variability) DHEA and DHEA-S levels. These may be further confounded by possible negative feedback mechanisms for suppression of DHEA release. The more relevant approach to estimating the t_1/2of DHEA and DHEA-S can be determined from the other Genelabs’ sponsored steady-state pharmakokinetic study (GL99-01). This study showed that steady-state was reached at 2 days, which equates to a half-life of approximately 7-8 hours for both DHEA and DHEA-S (see Figure 4-1).

Figure 4-1: Achievement of Steady-State DHEA and DHEA-S (GL99-01)

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Pharmacokinetic Studies

One prednisone interaction study after oral administration of GL701 to pre-menopausal women and two bioequivalence studies in pre- and post-menopausal women have been conducted to support the pharmacokinetics of GL701. Brief summaries of the relevant data from the studies are provided below.

Prednisone Interaction Study (GL96-02)

The objective of this study was to assess prednisolone, prednisone pharmacokinetics pre- and post- GL701 treatment as well as pharmacokinetics of DHEA and DHEA-S during chronic oral administration of GL701 to 14 healthy pre-menopausal women.

The study was comprised of two inpatient phases. Baseline evaluations were conducted within 4 days of onset of menses and included collection of a 24-hour serum profile of endogenous circulating DHEA and DHEA-S concentrations. On the next day, a single oral dose of prednisone, 20 mg, was administered following which prednisone/prednisolone blood levels were measured over the next 32 hours. Subjects then received GL701 200 mg/day for 30 days.

On Day 29, again within 4 days of onset of menses, administration baseline procedures were repeated, including collection of 24-hour DHEA and DHEA-S profiles following adminstration of GL701 200 mg. On Day 30, subjects received GL701 200 mg coadministered with a single oral dose of prednisone 20 mg and blood samples were collected serially up to 32 hours for assessment of prednisone, prednisolone, and DHEA/ DHEA-S blood levels.

Results

Pharmacokinetic parameters of prednisolone from 20 mg prednisone, as assessed by C_max, t_1/2, and AUC were not affected by 200 mg/day of GL701 in multiple doses. Chronic administration of GL701 200 mg/day did not affect the plasma protein binding of prednisolone . After multiple doses of GL701 of 200 mg/day, the ratio of prednisolone to prednisone area-under-the-curve (AUC) was not affected.

Administration of GL701 produced levels of DHEA and DHEA-Ssignificantly greater than endogenous plasma concentration. Mean (SD) maximal concentrations (C_max) measured for DHEA and DHEA-S, without correction for endogenous DHEA and DHEA-S, were 1.66 (0.54) and 975 (260) mg/dl , while T_maxoccurred at 3.0 (1.3) and 2.4 (0.9) hours, respectively. Mean area-under-the curve values were 20.84 (6.42) and 11489 (4682) mg· hr/dl.

Pharmacokinetic Assessments in Post Menopausal Women (GL99-01)

Pharmacokinetic data was collected as part of two different bioequivalence studies (Studies GL97-02 and GL99-01). GL97-02, was a single dose study with GL701 200 mg and the other study, GL99-01, was a 7-day GL701 200 mg study. Since the 7-day study (GL99-01) collected pharmacokinetic assessments as well as limited pharmacodynamic data using the proposed GL701 commercial formulation, data from only this study is presented.

Study GL99-01 was an open-label, randomized, multiple dose, steady-state, two-treatment cross-over pharmacokinetics/pharmacodynamics study in post-menopausal women. The objective of this study was to demonstrate bioequivalence between a GL701 lot containing a single polymorph form of prasterone (DHEA), which is the proposed commercial forumlation and a lot of GL701 used in a pivotal clinical trial (containing mixed polymorph forms of prasterone). Trough levels of DHEA and DHEA-S were obtained daily for 6 days during treatment, and a full pharmacokinetic profile was obtained on day 7 for each of two GL701 drug lots. A one week washout period was required between treatments.

Results

A total of 39 subjects completed the two period cross-over study. The mean multiple dose pharmacokinetic parameters for adjusted (baseline substracted) serum DHEA and DHEA-S concentrations are summarized in Tables 4-2 and 4-3 for the proposed commercial formulation. One subject was not evaluable because many of her Day 7 serum concentrations were below the Day 1 endogenous concentration.

Table –2: Summary of Estimated Mean Pharmacokinetic Parameters for Serum DHEA (N=38) Adjusted for Baseline

Parameters	GL701 Mean (SD)
Parameters
AUC_(144-168) (mg· hr/dl)	8.359 (3.668)
C_max (mg/dl)	0.939 (0.655)
T_max (hr)	2.5 (0.6)

Table –3: Summary of Estimated Mean Pharmacokinetic Parameters for Serum DHEA-S (N=38) Adjusted for Baseline

Parameters	GL701 Mean (SD)
Parameters
AUC_(144-168) (mg· hr/dl)	13995 (4800)
C_max (mg/dl)	1295 (358)
T_max (hr)	2.4 (0.5)

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DHEA-S Levels from GL701 Controlled Clinical Studies

Serum levels of DHEA-S, obtained 24 hours after last dose, were measured in both GL94-01 and GL95-02. As shown in Figures 4-2 and 4-3 below, pharmacologic levels of DHEA-S were achieved at last visit 10 to 20 times higher than baseline with mean levels for GL701 200 mg of 800 to 900 m g/dl for both studies. These levels are also much higher than the upper range of normal, approximately 260 m g/dl, for DHEA-S in healthy subjects. In Study GL94-01, dose proportionality a clear dose relationship was shown, with mean levels in the GL701 100 mg group approximately 50% of those in the GL701 200 mg group.

Figure 4-2: Serum DHEA-S Levels at Baseline (BL), Month 1 and Last Visit (GL94-01)

Figure 4-3: Serum DHEA-S Levels at Baseline (BL) and Last Visit (GL95-02)

In Study GL95-02, approximately 55% of patients were receiving corticosteroids (prednisone or other corticosteroids) at study entry. As shown in Figure 4-4 below, those patients on corticosteroids had much lower endogenous levels of DHEA-S, compared to those not receiving corticosteroids. These lower endogenous DHEA-S levels may represent suppression of DHEA production by corticosteroids, greater severity of disease in patients receiving corticosteroids, or both. This figure also demonstrates that administration of GL701 200 mg achieves DHEA-S levels far above baseline, even in those receiving corticosteroids.

Figure 4-4: DHEA-S Serum Levels by Baseline and Last Visit Prednisone Use

Organization of Clinical Results

Because the two primary efficacy, placebo-controlled studies, GL94-01 (corticosteroid reduction) and GL95-02 (improvement in SLE) had very different study designs and efficacy endpoints, pooling of efficacy data is not meaningful. Consequently, results pertinent to the efficacy of GL701 in SLE are presented by individual study. Similarly, the supportive efficacy results of the Taiwan Study, GBL96-01, are presented separately.

Pertinent data to the safety of GL701 are pooled from the two primary efficacy, double-blind, placebo-controlled studies. Additional safety data, presented separately, is available from the double-blind placebo-controlled study conducted in Taiwan, GBL96-01. Long term safety of GL701 is assessed by analyzing the data from patients who participated in the double-blind, placebo-controlled studies, GL95-02 and GL94-01, and subsequntly enrolled in the open-label extension study GL95-01. Depending on their treatment assignment in the placebo-controlled studies, such patients either continued to receive GL701 or switched from placebo to GL701 upon enrolling in the open-label extension study.

Well controlled Studies

Study GL94-01 (Corticosteroid Reduction Study)

Study GL94-01was a Phase II/III study assessing two different doses of GL701. This study compared the proportion of patients achieving sustained reduction of daily corticosteroid dose, without worsening of signs and symptoms of SLE, in the placebo and GL701 groups. Duration of treatment was approximately 7 months.

Protocol Development

Based on pre-IND discussions with FDA and consultants, it was decided that the primary efficacy variable for the corticosteroid reduction study should be, for patients who were corticosteroid dependent, a reduction of the patients’ current prednisone dose to 7.5 mg/day (upper limit of physiologic levels) or less, without worsening of SLE.

The design of the steroid sparing study was a forced titration; i.e., the patient’s steroid dose at each monthly visit was to be reduced, by algorithm, if her disease activity was stable or improved. However, when a patient worsened or flared, the associated increase in corticosteroid dose, if any, required to treat the patient’s exacerbation was at the physician’s discretion and not by algorithm. The steroid reduction algorithm was based on the patient’s disease activity improving or being stable, which was defined as no change in or a decrease in SLEDAI score in comparison to her previous visit. As such, one of the issues discussed at the pre-study investigator meeting was whether patients with low SLEDAI scores, and especially those with SLEDAI scores of 0, should be enrolled into the study. There was concern that those patients with low SLEDAI scores had inactive disease, and therefore would not be affected by steroid reduction, i.e., might not be steroid dependent. However, some investigators and consultants felt that if patients were truly dependent on steroids, their low SLEDAI scores represented active disease suppressed by corticosteroids, which would worsen or flare as soon as their corticosteroids were reduced. Therefore, because there was no experience with such trials, it was decided not to exclude patients with low SLEDAI scores. The concern regarding enrollment of potentially inactive SLE patients was revisited prior to unblinding of the study.

In addition it was recognized that because of the forced downward titration of steroid dose as the patients’ disease improved or remained stable, other evaluations of disease activity such as SLEDAI, etc., would not be expected to improve.

The doses and regimen for this study of 100 or 200 mg GL701 to be taken in the morning as a single dose were selected empirically on the basis of the previous clinical experience from the Stanford University studies. The treatment period was defined as 7 months, unless an additional 1-2 months was required to demonstrate sustained steroid reduction in patients who achieved physiological levels only by month 6 or 7. The 7-month period appeared to be an appropriate amount of time to identify efficacy, especially based upon the evidence of efficacy that was seen at 3 months in the Stanford University studies.

In early 1997, due to previous concerns regarding enrollment of patients with inactive SLE into Study GL94-01, it was recognized that a relatively large number of patients with low SLEDAI scores at baseline, especially SLEDAI = 0, had been enrolled. Therefore, a pooled response rate (while the study was ongoing and blinded) was evaluated categorized by baseline SLEDAI score was evaluated. It was noted that an unexpectedly high response rate (treatment group combined response rate of approximately 65%) was evident in those patients with the mildest disease (baseline SLEDAI < 2), with an inflexion point or sharply decreasing response rate for patients with baseline SLEDAI values > 2 (Figure 6-1).

Figure 6–1: Percent Responders Based on SLEDAI Score

Based on these findings, in March 1997, FDA agreed to a proposal for prospectively (i.e., prior to breaking the blind) defining a subgroup of patients with active disease, i.e., patients with baseline SLEDAI > 2 as part of the efficacy analysis in that study was made. The data base was finalized and locked in April 1997, the study analyzed and a final report submitted to the FDA in October 1997.

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Entry Criteria

Study patients were women with mild to moderate corticosteroid-dependent SLE, characterized by chronic treatment with prednisone 10 - 30 mg/day and either a) in the last 12 months attempted to taper prednisone dose but failed and had a stable prednisone dose for at least 6 weeks preceding the study, or b) in whom there had been no attempt to taper in the last 12 months and had been on a stable prednisone dose for at least 3 months preceding the study. Patients receiving immunosuppressive medications were excluded from the study.

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Study Activities

Patients returned at monthly visits for up to 7 to 9 months. At each visit, assessments included SLEDAI, KFSS, SF-36, Patient VAS and Physician VAS. Corticosteroid dose was to be reduced by an algorithm: Prednisone dose (or its equivalent in other corticosteroids) was reduced if disease activity was stable or improved by SLEDAI score (SLEDAI score remained the same or decreased in comparison to the previous monthly visit). Prednisone was tapered according to the following schedule:

If daily prednisone dose was:	Dose reduction was:
>0 - £ 5 mg	1 mg/day
>5 mg - £ 10 mg	2.5 mg/day
>10 mg - £ 30 mg	5.0 mg/day
> 30 mg	Taper at Investigator’s discretion

If the SLEDAI score had worsened (increased) since the prior monthly visit, the daily dose of prednisone could be increased at the investigator’s discretion. Thus, while patients who received baseline prednisone doses > 30 mg were excluded from participation in the study, patients could receive a prednisone dose > 30 mg during the course of the study if medically indicated.

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Patient Populations for Analysis

The primary population for analysis of efficacy was defined as all randomized patients (i.e., the intent-to-treat population). Additionally, as described above, patients with baseline SLEDAI >2 were a predefined group for analysis, and therefore analyses are presented for all patients and for patients with baseline SLEDAI > 2.

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Efficacy Variables

A responder was defined as a patient who achieved a decrease in prednisone dose to 7.5 mg/day or less, sustained for no less than three consecutive scheduled visits, including the termination visit (i.e., two consecutive months), on or after the Month 7 Visit. If a patient achieved a lowering to 7.5 mg/day or less at Visit 6 or 7, but if she had not been at this dose for 2-months, then the patient could remain on study an additional 1 to 2 months.

A second efficacy variable was the percent decrease in prednisone dose comparing the prescribed prednisone (or steroid equivalent) dose at Baseline (Qualifying Visit) and the last visit prednisone (or steroid equivalent) dose. Additional efficacy variables included mean changes from baseline for the SLE scoring instruments and number days prednisone dose was £ 7.5 mg.

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Study Patient Population and Demography Results

The study population of 191 patients consisted of women, primarily Caucasian (60%) and African-American (26%). Key demographic and baseline characteristics are summarized in Tables 6-1 and 6-2. There were some differences between the groups, though none was statistically significant. Baseline mean DHEA-S levels were much higher in the GL701 200 mg group. However, this probably represents the effect of three patients with very high levels, which may be attributed to laboratory error or treatment with DHEA from another source: these patients had baseline levels of 2608, 1345, and 264 m g/dl. The standard deviation for the GL701 200 mg group was 364.73, and the median values were similar in all three groups.

Mean and median prednisone dose was highest in the placebo group (15.2 and 15.0 mg/day) and lowest in the GL701 200 mg group (13.7 and 10.0 mg/day), but the difference was not significant among the three groups (p = 0.178).

Among the patients with baseline SLEDAI > 2, the treatment groups showed similar small differences in demographic and baseline characteristics, but the imbalance in baseline mean prednisone dose was significant among the three treatment groups (p = 0.039).

Table 6-1: Demographic Characteristics (GL94-01)

	All Patients			Baseline SLEDAI >2
Parameter	Placebo N = 64	GL701 100mg N = 63	GL701 200mg N = 64	Placebo N = 45	GL701 100mg N = 47	GL701 200mg N = 45
Mean (Median) Age	41 (39)	40 (39)	40 (41)	41 (39)	39 (39)	40 (41)
Caucasian	44 (69%)	36 (57%)	35 (55%)	31 (69%)	26 (55%)	23 (51%)
African-American	17 (27%)	16 (25%)	17 ( 27%)	12 (27%)	12 (26%)	11 (24%)
Hispanic	0 (0%)	8 (13%)	9 (14%)	0 (0%)	6 (13%)	9 (20%)
Post-Menopausal	21(33%)	21 (33%)	12 (19%)	17 (38%)	15 (32%)	10 (22%)
Pre-Menopausal	43 (67%)	42 (67%)	52 (81%)	28 (62%)	32 (68%)	35 (78%)

Table 6-2: Baseline Characteristics (GL94-01)

	All Patients			Baseline SLEDAI >2
Parameter	Placebo N = 64	GL701 100 mg N = 63	GL701 200 mg N = 64	Placebo N = 45	GL701 100 mg N = 47	GL701 200 mg N = 45
DHEA-S Mean (Median) m g/dl	29.0 (22.0)	28.9 (17.0)	86.5 (18.0)	29.1 (22.0)	32.3 (17.0)	116.4 (18.0)
Prednisone Dose, Mean (Median) mg/d	15.2 (15.0)	13.7 (12.5)	13.7 (10.0)	15.7 (15.0)	13.6 (12.5)	13.0 (10.0)
Antimalarial Use (%)	33 (51.6%)	27 (42.9%)	33 (51.6%)	21 (46.7%)	15 (31.9%)	22 (48.9%)
SLEDAI Score, Mean (Median)	6.4 (4.0)	5.5 (4.0)	5.9 (6.0)	8.7 (7.0)	7.0 (6.0)	8.1 (6.0)
Patient VAS, Mean (Median)	49.1 (48.5)	46.4 (47.0)	46.8 (47.5)	51.7 (55.0)	46.4 (47.0)	46.4 (49.0)
Physician VAS, Mean (Median)	28.0 (23.0)	26.0 (24.0)	23.3 (21.5)	34.6 (33.0)	29.4 (28.0)	28.5 (26.0)
KFSS, Mean (Median)	5.3 (5.7)	5.1 (4.9)	5.4 (5.7)	5.3 (5.9)	5.0 (4.9)	5.3 (5.4)

Patient Disposition

The proportion of patients discontinuing study for any cause was similar in all three treatment groups (Figure 6-2). More

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