A Phase II Study to Evaluate Safety and Efficacy of ALX-0061 in Subjects With Systemic Lupus Erythematosus

Number and percentage of mBICLA responders at Week 24 and Week 48

The composite index mSRI-4 enables quantification of decrease and increase in disease activity in a broad spectrum of manifestations thereby offering a comprehensive assessment of SLE disease status. mSRI combines advantages from 3 validated measurement tools. The mSRI-4 criteria for response are:

1. modified SLE disease activity index 2000 (mSLEDAI-2K): ≥ 4 point reduction (covers global disease improvement),
2. British Isles Lupus Assessment Group 2004 (BILAG-2004): no new A domain score and no more than 1 new increase to B (covers organ-specific disease improvement),
3. Physician's Global Assessment (PGA) (is used as validity and safety net for items that were not addressed by the other two indices): < 10% increase from Baseline (no worsening) When all 3 criteria are met, the subject is a mSRI-4 responder at that time point.

Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation.

The mSRI-5 criteria for response are:

1. mSLEDAI-2K: ≥ 5 point reduction
2. BILAG-2004: no new A domain score and no more than 1 new increase to B domain score
3. PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 5 were considered for the derivation of that endpoint.

Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation.

The mSRI-6 criteria for response are:

1. mSLEDAI-2K: ≥ 6 point reduction
2. BILAG-2004: no new A domain score and no more than 1 new increase to B domain score
3. PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 6 were considered for the derivation of that endpoint.

Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation

The mSRI-7 criteria for response are:

1. mSLEDAI-2K: ≥ 7 point reduction
2. BILAG-2004: no new A domain score and no more than 1 new increase to B domain score
3. PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 7 were considered for the derivation of that endpoint.

Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation.

The mSRI-8 criteria for response are:

1. mSLEDAI-2K: ≥ 8 point reduction
2. BILAG-2004: no new A domain score and no more than 1 new increase to B domain score
3. PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 8 were considered for the derivation of that endpoint.

Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation.

The Systemic Lupus Erythematosus Disease Activity Index 2000 is a 1-page weighted score for 24 items (seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, etc). The manifestations felt to be most commonly contributing to disease activity are included and scored based on the presence (= 1 multiplied by weight) or absence (= 0) within 30 days prior to the evaluation. The total score ranges from 0-105 (= sum of individual scores), with 105 being higher disease activity. mSLEDAI-2K derives from the standard index by omitting low complement. Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline mSLEDAI-2K Score and geographic region as covariates. A negative change from baseline reflects an improvement.

Normal Improvement: all A scores at baseline improved to B/C/D, and all B scores improved to C or D.

Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint

Enhanced improvement: all A scores at baseline improved to B/C/D, and all B scores improved to C or D and no worsening between consecutive visits from baseline up to the considered visit Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint

The British Isles Lupus Assessment Group 2004 (BILAG-2004) is a comprehensive composite clinical index that has been developed based on the principle of a physician's intention to treat using a nominal consensus approach. In the index, the nine systems (not organs) considered are: constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, renal, ophthalmic and hematological. Disease activity in each of the nine systems is categorized into five levels: grades A (= severe disease activity requiring systemic high dose oral corticosteroids, i.v. pulse corticosteroids, etc.) to E (= system never involved).

BILAG total score is derived by assigning the following value to each grade and summing the sores over all organ systems:

A = 12, B = 8, C = 1, D/E = 0. The total score ranges from 0-108, with 108 representing high disease activity in all 9 systems requiring high doses of corticosteroids, starting/increasing immunosuppressive drugs, etc.

An improvement is defined as an A score at Baseline improved to B/C/D, or a B score improved to C or D.

Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint

An improvement is defined as an A score at Baseline improved to B/C/D, or a B score improved to C or D.

Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint

The physician makes a mark between 0 ("no disease") and 100 mm ("severe disease") on the visual analogue scale (VAS) to indicate disease activity (independent of the subject's self-assessment).

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline PGA score and geographic region as covariates.

A negative change from baseline reflects an improvement.

The subject makes a mark between 0 ("very good") and 100 mm ("very bad") on the VAS to indicate how the subject is doing, while considering all the ways SLE affects him/her.

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline Patient's Global Assessment and geographic region as covariates.

A negative change from baseline reflects an improvement.

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline proteinuria and geographic region as covariates

Efficacy Laboratory Parameters (Urinalysis) - Active Urine Sediment Number of subjects who were urine sediment negative at Baseline, but positive at Week 24 and Week 48, respectively.

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline serum creatinine and geographic region as covariates

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline eGFR and geographic region as covariates

Defined as non-protocol allowed increase in steroid dose, start i.v. or i.m. steroids, or start or increase of immunosuppressant

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline prednisone equivalent total daily dose and geographic region as covariates

Number and percentage of subjects whose prednisone equivalent dose was >7.5 mg/day at baseline and reduced to ≤7.5 mg/day during Weeks 40-48 without experiencing a BILAG-2004-defined or mSFI-defined severe flare after the first prednisone equivalent dose decrease.

Number and percentage of subjects who discontinued Prednisone (or equivalent) by Week 48 without experiencing a BILAG-2004-defined or mSFI-defined severe flare

The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SF-36 Score and geographic region as covariates. A positive change denotes an improvement.

The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.

Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SF-36 Score and geographic region as covariates. A positive change denotes an improvement.

Twenty-eight joints are assessed for swollenness (a score of 1 for a joint denotes a presence of swollenness). The sum is derived to create a total score (ranging from 0 to 28; where the highest score indicate all 28 joints are swollen). Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SJC28 Score and geographic region as covariates. A negative change denotes an improvement.

Twenty-eight joints are assessed for tenderness (a score of 1 for a joint denotes a presence of tenderness). The sum is derived to create a total score (ranging from 0 to 28; where the highest score indicate all 28 joints are tender). Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline TJC28 Score and geographic region as covariates. A negative change denotes and improvement.

CLASI Activity is scored based on erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss and nonscarring alopecia. Evaluation of erythema and scale/hyperkeratosis is based on a table: rows represent anatomical areas and columns represent major clinical symptoms. The extent of involvement for each of the skin symptoms is documented for each anatomic area (erythema: 0=absent, 1=pink, 2=red, 3=dark red; scale: 0=absent, 1=scale, 2=verrucous/hypertrophic). Mucous membrane involvement and acute hair loss are scored based on the presence (=1) or absence (=0).

Nonscarring alopecia is scored as 0=absent, 1=diffuse/non-inflammatory, 2=focal or patchy in 1 quadrant, 3=focal or patchy in >1 quadrant. The total score ranges from 0-70, with higher scores indicating more severe skin disease.

Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline CLASI Activity Score and geographic region as covariates. Negative change = improvement

CLASI Damage is scored based on dyspigmentation and scarring. Evaluation of dyspigmentation and scarring is based on a table: rows represent anatomical areas and columns represent major clinical symptoms. The extent of involvement for each of the skin symptoms is documented for each anatomic area (dyspigmentation: 0=absent, 1=present; scarring: 0=absent, 1=scarring, 2=severely atrophic scarring or panniculitis). Subjects are also asked whether dyspigmentation due to SLE lesions usually remains visible for >12 months, which is considered permanent and results in doubling of the dyspigmentation score. Scarring alopecia is scored as follows: 0=absent, 3=1 quadrant, 4=2 quadrants, 5=3 quadrants, 6=affects the whole skull. Total score ranges from 0-56, with higher scores indicating more damaged skin.

Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline CLASI Damage Score and geographic region as covariates. Negative change = improvement.