Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)

An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent adverse events (TEAEs) were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.

A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

Cmax is maximum observed concentration of drug in plasma.

Clast is the last observed concentration of drug in plasma.

Tmax is the time observed for the Cmax of tirabrutinib.

Tlast is the time observed for the Clast of tirabrutinib.

AUC is concentration of drug over time (area under the plasma concentration versus time curve).

AUC is concentration of drug over time (area under the plasma concentration versus time curve).

An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.

A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per CTCAE, version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

The effect of tirabrutinib on biomarkers was assessed through the CD63 basophil activation test (BAT) FlowCast assay, which was used to measure the percentage of CD63+ basophils and percentage inhibition of CD63 induction relative to baseline. CD63+ % inhibition was calculated as 100 - CD63+ % baseline. Baseline defined as day 1 predose.

BTK occupancy was assessed with the BTK occupancy assay, which was used to measure undetectable free BTK, normalized free BTK, normalized free BTK adjusted to baseline, and percentage BTK occupancy adjusted to baseline. % BTK occupancy adjusted was calculated as 100 * (1 - normalized free BTK adjusted to baseline). Normalized free BTK was calculated as Free BTK / Total BTK. Baseline defined as day 1 predose.

DAS28 score was used to measure the participant's disease activity or assessments of rheumatoid arthritis (RA) calculated using the tender joint counts (TJC) (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (PtGA) (visual analog scale: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

ACR TJC was an assessment of 68 joints. At each study visit, a joint evaluator assessed whether a particular joint was "tender" where presence of tenderness was scored as "1" and the absence of tenderness was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all tender joints. The range for TJC68 was 0 to 68, with a higher score indicating a greater degree of tenderness. A negative change from baseline indicates improvement.

ACR SJC was an assessment of 66 joints. At each study visit, a joint evaluator assessed whether a particular joint was swollen where presence of swelling was scored as "1" and the absence of swelling was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all swollen joints. The range for SJC66 was 0 to 66, with a higher score indicating a greater degree of swelling. A negative change from baseline indicates improvement.

SDAI is a composite measure that sums the TJC based on 28 joints (TJC28), SJC based on 28 joints (SJC28), PtGA, Physician's Global Assessment of Disease Activity (PhGA), and the CRP (in mg/dL). PtGA and PhGA assessed using Visual Analogue Scale (VAS) on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

PtGA was assessed by the participant using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to provide the patient's overall assessment of how the arthritis is doing. A mark was placed on the horizontal line to assess the current arthritis disease activity. The lowest mark indicated 'no arthritis activity', and the highest mark indicated 'extremely active arthritis'. A negative change from baseline indicates improvement.

PhGA was assessed by the physician using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to measure the physician's assessment of the patient's current disease activity. A mark was placed on the horizontal line to assess the disease activity (independent of the participant's self-assessment). The lowest mark indicated 'no disease activity', and the highest mark indicated 'maximum disease activity'. A negative change from baseline indicates improvement.

The participant assessed their pain severity using a VAS on a scale of 0 (no pain) to 100 (severe pain). A horizontal visual analog scale was used to assess the patient's current level of pain. A mark was placed on the horizontal line to assess the severity of pain. The lowest mark indicated 'no pain', and the highest mark indicated 'unbearable pain'. A negative change from baseline indicates improvement.

The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually administered by the participant. Responses in each functional category were collected as 0-3 [0 (without any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. A negative change from baseline indicates improvement.

ACR20 response is achieved when the participant has: ≥ 20% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 (0 and 100 indicating no disease activity and maximum disease activity); patient's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating unbearable pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); high-sensitivity CRP (hsCRP).

ACR70 response is achieved when the participant has: ≥ 70% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 [0 and 100 indicating no disease activity and maximum disease activity]; patient's pain assessment using VAS on a scale of 0-100 [0 indicating no pain and 100 indicating unbearable pain]; HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 [0 and 3 indicating without difficulty and unable to do]; hsCRP.

Hybrid ACR evaluates the improvement in active RA by combining elements of the ACR20, ACR50, and ACR70 with a continuous score of the mean change in core set measures. The percentage improvement from baseline was computed in each of the components of the ACR. The average percent improvement was calculated and used with the participant's ACR20, ACR50, and ACR70 status to compute the hybrid ACR response, with a positive change indicating improvement.

Clinical remission is defined as DAS28-CRP < 2.6. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

Low disease activity is defined as DAS28-CRP ≤ 3.2. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

Clinical remission is defined as CDAI ≤ 2.8. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

Low disease activity is defined as CDAI ≤ 10. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

Clinical remission is defined as SDAI ≤ 3.3. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

Low disease activity is defined as SDAI ≤ 11. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.