P-101 Anti-MAdCAM Antibody PF-00547659 in Crohnʼs Disease
Bibliographic record
Abstract
The fully human anti-MAdCAM monoclonal antibody PF-00547659 is being developed to treat inflammatory bowel disease. It interrupts the a4b7 integrin-MAdCAM-1 interaction, thereby selectively inhibiting leukocyte migration from the bloodstream into the intestinal wall but not the central nervous system Patients with moderate to severe Crohn's disease (HBI >8 and hsCRP ≥5 mg/L or intestinal stoma and active disease on imaging or endoscopy) who failed prior treatment with anti-TNF and immunosuppressant (IS) agents underwent a lumbar puncture (LP) followed by 3 doses of 225 mg PF-00547659 at 4 week intervals. A 2nd LP was performed after the last dose and CSF analyzed by flow cytometry. Clinical Crohn's disease activity was measured throughout using the Harvey Bradshaw Index (HBI). The efficacy outcomes of interest were the rate of response (decrease in HBI ≥3 points) and the rate of remission (HBI <5) at week 12 in evaluable patients. All the responders in the study were eligible for enrollment into an open label extension study with up to 19 months of treatment Forty-nine patients were enrolled (28 women, 21 men) in 8 European centers; mean (SD) age = 38.1 (11.8) yr, CD duration = 12.7 (6.2) yr, hsCRP = 16.3 (19.9) mg/L (Geometric mean hsCRP = 7.0). Fourteen patients had stomas and hence were not evaluable for HBI; 29 (59%) were seropositive for antibody to the JC virus. All had failed previous treatment with thiopurines (TP) and either infliximab and/or adalimumab. Twenty-six had also failed methotrexate (MTX). Ten patients (7 evaluable) were taking IS at study entry: 7 TP and 4 MTX (1 took both TP and MTX). As observed efficacy results are shown in the Table. At week 12, the geometric mean of hsCRP declined from baseline 7.0 mg/L to 5.7 mg/L (-16%). A full induction course of the highest clinical dose of PF-00547659 did not affect CSF lymphocytes while it resulted in increased circulating b7+ lymphocytes indicating that it is pharmacologically active. Overall good safety and tolerability was observed with low rates of adverse events. All subjects have completed study treatment and 4 subjects were in follow up at the time of the targeted data extraction. Selective inhibition of white blood cell translocation to the gut with PF-00547659 in patients with moderate to severe Crohn's disease and prior treatment with anti-TNF and IS drugs is associated with high rates of disease response and remission by week 12 in the open label TOSCA study. Administration was safe, and side effects were generally those seen in this population. The results of the TOSCA study support the gut selectivity and the CNS-sparing mechanism proposed for PF-00547659.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".