Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis

Clinical response to treatment for ASAS20 was assessed according to ASAS20 criteria. Treatment response for ASAS20 was defined as an improvement by a decrease of ≥20% and ≥1unit on a 0 (no pain) - 10 (most severe pain) numerical rating scale (NRS) in at least 3 of the 4 ASAS improvement criteria (ASAS-IC) domains: assessment of physical function (measured by Bath Ankylosing Spondylitis Functional Index [BASFI]), back pain (0-10 NRS), participant global assessment (0-10 NRS) and inflammation (measured as the mean of the last 2 Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] questions) and no worsening (increase in score) of ≥20% and ≥1 unit on a 0-10 NRS in the remaining 4th domain.

Clinical response to treatment for ASAS40 was assessed according to ASAS40 criteria. Treatment response for ASAS40 was defined as an improvement by a decrease of ≥40% and ≥2 units on a 0 (no pain)-10 (most severe pain) NRS in at least 3 of the 4 ASAS-IC domains (participant global assessment, back pain, physical function and inflammation) and no worsening (increase in score) at all in the remaining 4th domain.

Participants were classified as having achieved ASAS partial remission if they had a value ≤ 2 units on a 0 -10 NRS in each of the 4 domains: (participant global assessment, back pain, physical function and inflammation) of the ASAS-IC.

ASDAS consists of five components: (Total back pain assessed by BASDAI question 2 on a 0 [no pain] - 10 [most severe pain] NRS, participant global of disease activity on a 0 [none] - 10 [severe] NRS, peripheral pain/swelling assessed by BASDAI question 3 on a 0 [none] - 10 [most severe pain] NRS, duration of morning stiffness assessed by BASDAI question 6 on a NRS from 0 [0 hour] - 10 [2 or more hours] and hs-CRP in mg/L). ASDAS score was calculated as follows: 0.121 x total back pain + 0.110 x participant global of disease activity + 0.073 x peripheral pain/swelling + 0.058 x duration of morning stiffness + 0.579 x ln(CRP + 1). The scores were categorized as: inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity (> 3.5).

BASDAI comprises of a 0 (no pain) -10 (very severe pain) NRS, used to answer 6 questions (Q) related to symptoms of AS (fatigue/tiredness, neck, back or hip pain, pain / swelling in joints, discomfort in tender areas, morning stiffness duration and morning stiffness severity). The BASDAI total score was calculated by computing the mean of Q5 and Q6 and adding it to the sum of Q1 to Q4. This score was then divided by 5. BASDAI total score=Q1+Q2+Q3+Q4+[Q5+Q6/2]/5. The total BASDAI score ranges from 0=none to 10=severe, where lower score indicated less disease activity.

The range of motion was measured by the BASMI (11-point scale) including chest expansion in cm. It composed of 5 clinical measurements associated with a score: tragus to wall distance, modified schober's test, lateral spinal flexion, intermalleolar distance and cervical rotation. BASMI score was calculated by dividing the total of the score by 5, and the score ranges from 0-10. Higher BASMI score indicates more severe limitation of movement.

ASspiMRI-a scoring system was used on all MRIs to score the level of the disease. MRIs were obtained using 1.0 or 1.5 Tesla scanners and phased array coils. Sagittal images of the upper (C2 to T10) and lower (T8 to S1) spine were used using both T1 weighted spin echo and fat saturated Short Tau Inversion Recovery (STIR) sequences. Each vertebral body unit was given an activity score based on the amount of bone marrow edema or erosion. Both T1 and STIR sequences were analyzed for change. Total spine ASspiMRI-a score in the Berlin modification range from 0 to 69 with higher scores indicating higher disease activity. A negative value in total spine ASspiMRI-a score change from baseline indicates an improvement from baseline. The higher the negative value the higher the reduction of inflammation.

ASAS 5/6 responder had an improvement of 20% in 5 of 6 domains (physical function, back pain, participant global assessment, inflammation, spinal mobility and acute phase reactants) of ASAS-IC without deterioration in the 6th domain. Spinal mobility was assessed by the mean of the 5 BASMI scores on the 11-point scale (score ranges from 0-10) and the hs-CRP for the acute phase reactant.

The difference between maximal inspiration and expiration to the nearest 0.1 cm was recorded. The best of 2 tries were recorded.

44 swollen joints were examined including sternal, clavicular, elbow, shoulder, wrist, knee, metacarpophalangian, interphalangian, metatarpophalangian and metatarsophalangeal joints.

Participant's blood samples were collected at screening, baseline before dosing and at every visit to evaluate the level of hs-CRP. The hs-CRP is a protein marker in the blood associated with inflammation with higher values indicating a greater degree of inflammation.

ASAS consists of 4 individual components: Participant global assessment to assess the disease activity over the last week on a 0 (no pain) - 10 (severe pain) NRS; back pain which consist of the mean of the nocturnal back pain and the total back pain at every visit on a 0 (no pain) - 10 (most severe pain) NRS; inflammation measured as the mean of the last 2 BASDAI questions (intensity and duration of morning stiffness) and physical function measured as mean of 10 scores of BASFI at every visit on 0 (easy) -10 (impossible) NRS. Lower score corresponds to a better functioning.