C0393 - Clinical Utility of Precision-Guided Dosing Tool for Infliximab During Maintenance Therapy of Inflammatory Bowel Disease

Monday, October 24, 2022

3:00 PM – 5:00 PM ET

Location: Crown Ballroom

Has Audio

Presenting Author(s)

Bincy Abraham, MD, MS, FACG

Houston Methodist Academic Institute
Houston, Texas

Award: Presidential Poster Award

Bincy Abraham, MD, MS, FACG¹, Shervin Rabizadeh, MD, MBA², Taha Qazi, MD³, Esther A. Torres, MD⁴, Ayesha Fatima, MD⁵, Ann D. Flynn, MD⁶, David Ziring, MD⁷, Robert Battat, MD⁸, Ryan Ungaro, MD, MS⁹, Corey A. Siegel, MD, MS¹⁰, Judith Gohndrone, PhD¹¹, Donald Lum, MD¹², Adria A. Condino, DO¹³, Daniel J. Stein, MD¹⁴, Jana G. Hashash, MD, MSc¹⁵, Waseem Ahmed, MD¹⁶, Catherine Rowan, MD¹⁷, Brad Pasternak, MD¹⁸, Akash Pandey, MD¹⁹, Gil Y. Melmed, MD²⁰, Jonathan Moses, MD²¹, Stephen B. Hanauer, MD²², Jean-Frederic Colombel, MD⁹, Thierry Dervieux, PharmD, PhD²³
¹Houston Methodist Academic Institute, Houston, TX; ²Cedars-Sinai Medical Center, Los Angeles, CA; ³Cleveland Clinic, Cleveland, OH; ⁴University of Puerto Rico, School of Medicine, San Juan, Puerto Rico; ⁵Beaumont Children’s Hospital, Troy, MI; ⁶University of Utah, Salt Lake City, UT; ⁷Cedars Sinai, Los Angeles, CA; ⁸Weill Cornell Medicine, New York, NY; ⁹Icahn School of Medicine at Mount Sinai, New York, NY; ¹⁰Dartmouth-Hitchcock Medical Center, Lebanon, NH; ¹¹Prometheus Laboratories, San Diego, CA; ¹²Oregon Clinic, Portland, OR; ¹³Pediatric Gastroenterology, Hepatology, and Nutrition of FL, P.A., Oldsmar, FL; ¹⁴Medical College of Wisconsin, Wauwatosa, WI; ¹⁵Mayo Clinic Florida, Jacksonville, FL; ¹⁶University of Colorado School of Medicine, Denver, CO; ¹⁷Mount Sinai Hospital, New York, NY; ¹⁸Phoenix Children's Hospital, Phoenix, AZ; ¹⁹Arnold Palmer Children Hospital, Orlando, FL; ²⁰Cedars Sinai Medical Center, Los Angeles, CA; ²¹UH Rainbow Babies and Children's Hospital, Cleveland, OH; ²²Northwestern University, Chicago, IL; ²³Prometheus, Irvine, CA

Introduction: A precision-guided dosing tool that uses Bayesian data assimilation was developed to forecast Infliximab (IFX) exposure. Our objective was to establish the utility of the tool in clinical decision making during IFX maintenance therapy when used reactively, to address inadequate disease control that results from suboptimal exposure, and proactively, to sustain exposure commensurate with disease remission in inflammatory bowel disease (IBD).

Methods: Blood specimens were collected, anytime beyond 20 days after a prior infusion in a prospective study (EMPOWER). Pharmacokinetic (PK) testing was conducted at Prometheus Laboratories (San Diego, CA). Serum IFX, antibodies to IFX (ATI) and albumin concentrations were all imputed with dosing regimen and weight in a Bayesian data assimilation tool to produce individualized PK profiles that forecasted IFX concentration and time to trough concentration below pre-specified thresholds (e.g., < 10 µg/mL). Forecasted exposure at various dosing regimens was also provided. Physician’s global assessment of disease activity was collected with the decision to change IFX dosing that resulted from PK test results. Statistical analysis consisted of Mann-Whitney and Fisher Exact test as appropriate.

Results: A total of 111 patients were assessed by 21 physicians. A change in IFX dose regimen was initiated in 51 patients (46%). Inadequate exposure and forecasted IFX levels below 10 µg/mL associated with dose intensification (76%, median IFX 6.3 µg/mL) (p< 0.01), with lower remission rate (23.5%) achieved in that group as compared to two other groups having better disease control and PK profiles (p< 0.001) (Table 1). Forecasted IFX levels below 10 µg/mL were associated with 4-fold higher likelihood of active disease (OR=4.1; 95%CI: 1.7-9.4) as compared to IFX levels above 10 µg/mL (p< 0.01). Time to trough below 10µg/mL was shorter in active disease (median: 46 days, IQR: 32-59) than in remission (median 57 days, IQR: 48-69) (p< 0.001). As presented in Figure 1, dose intensification using a 5 mg/kg every 4 weeks dosing regimen forecasted 2.3-fold higher IFX levels as compared to a 10 mg/kg every 8 weeks dosing regimen (median of 17.1 vs 7.4 µg/mL, respectively) (p< 0.001). Similar results were observed among patients presenting with disease remission.

Discussion: Our study suggests that the precision-guided dosing tool provides clinical utility and helps with dose adjustments in both interval changes as well as dose intensification.

Figure: Figure 1: Forecasted IFX Exposure at various dose and interdose intervals, given the individual PK parameters

Table 1: Patient Characteristics (n=111), by treatment intervention based on test results.

Variable	IFX Dose Regimen Reduction N=17	IFX Dose Regimen Continuation N=60	IFX Dose Regimen Intensification N=34	Overall Population N=111
Patient Characteristics
Age (years)	16 (14-19)	32 (18-45)	32 (17-46)	26 (16-44)
Female (%, n/N)	44.1% (7/17)	43.3% (26/60)	44.1% (15/34)	43.2% (48/111)
CD/UC/Indeterminate	13/3/1	36/15/8	22/9/3	71/27/12
Weight (Kg)	64 (43-76)	71 (61-92)	69 (61-92)	70 (60-84)
Dose mg/Kg	10.0 (9.0-10.4)	8.2 (5.0-10.0)	5.5 (5.0-10.0)	8.0 (5.1-10.0)
Interdose interval (weeks)	6 (5-8)	8 (6-8)	8 (6-8)	8 (6-8)
PGA Remission Status, remission (%, n/N)	70.6% (12/17)	41.7% (25/60)	23.5% (8/34)	40.5% (45/111)

Clinical PK Measurements
Measured IFX levels (µg/mL)	23.3 (17.2-28.5)	12.9 (7.2-20.6)	8.0 (5.2-14.7)	12.5 (7.2-20.9)
ATI status (%, n/N)	0% (0/17)	10.0% (6/60)	11.8% (4/34)	9.0% (10/111)
Albumin (g/dL)	4.1 (4.0-4.3)	4.0 (3.6-4.2)	3.9 (3.7-4.2)	4.0 (3.7-4.2)
Clearance (L/day)	0.19 (0.15-0.22)	0.27 (0.20-0.33)	0.28 (0.22-0.35)	0.25 (0.19-0.31)
Time to Trough < 10 µg/mL (weeks)	11 (10-12)	7 (6-9)	6 (4-7)	7 (6-9)
Forecasted Trough (µg/mL)	26.2 (20.1-34.5)	12.7 (8.6-17.6)	6.3 (3.1-9.4)	11.6 (6.5-19.5)
Forecasted Trough < 10 µg/mL	0% (0/17)	31.7% (19/60)	76.5% (26/34)	40.5% (45/111)

Table:
Results are presented as median (IQR) or %, as appropriate.

Disclosures:

Bincy Abraham: AbbVie – Consultant, Speakers Bureau. Bristol Myers Squibb – Consultant, Speakers Bureau. Eli Lilly – Consultant, Speakers Bureau. Janssen – Consultant, Speakers Bureau. Medtronic – Consultant. Pfizer – Consultant, Speakers Bureau. Takeda – Consultant, Grant/Research Support, Speakers Bureau.

Shervin Rabizadeh: pfizer – Consultant. Prometheus – Advisor or Review Panel Member.

Taha Qazi: Abbvie – Advisor or Review Panel Member, Speakers Bureau. Iterative Scopes – Consultant. Janssen – Advisory Committee/Board Member, Speakers Bureau. Prometheus Laboratories – Advisor or Review Panel Member.

Esther Torres: AbbVie – Grant/Research Support.

Ayesha Fatima indicated no relevant financial relationships.

Ann Flynn indicated no relevant financial relationships.

David Ziring: AbbVie Pharmaceuticals – Speakers Bureau.

Robert Battat: Prometheus – Consultant.

Ryan Ungaro: AbbVie – Grant/Research Support. Boehringer Ingelheim – Grant/Research Support. Eli Lilly – Consultant. Janssen – Consultant. Pfizer – Consultant, Grant/Research Support. Takeda – Consultant.

Corey Siegel: Abbvie – Consultant, Grant/Research Support. Jannsen – Consultant. Lilly – Consultant, Grant/Research Support. MiTest Health, LLC – Intellectual Property/Patents, Owner/Ownership Interest. Napo Pharmaceuticals – Consultant. Pfizer – Advisor or Review Panel Member, Consultant, Grant/Research Support. Prometheus – Consultant. Prometheus Biosciences – Consultant. Takeda – Advisor or Review Panel Member, Grant/Research Support, Royalties.

Judith Gohndrone: Prometheus Laboratories – Employee.

Donald Lum: AbbVie – Speakers Bureau. Janssen – Speakers Bureau. Takeda – Speakers Bureau.

Adria Condino: Prometheus Laboratories Inc. – Independent Contractor.

Daniel Stein: Abbvie – Consultant, Speakers Bureau. Brystol Myers Squibb – Advisory Committee/Board Member, Speakers Bureau. Janssen – Speakers Bureau. Pfizer – Speakers Bureau. Takeda – Speakers Bureau.

Jana Hashash indicated no relevant financial relationships.

Waseem Ahmed indicated no relevant financial relationships.

Catherine Rowan: Prometheus Laboratories – Collaborating on research but not personally receiving financial compensation..

Brad Pasternak indicated no relevant financial relationships.

Akash Pandey indicated no relevant financial relationships.

Gil Melmed: Abbvie – Consultant. Boehringer-Ingelheim – Consultant. Bristol-Myers Squibb – Consultant. Ferring – Consultant. Janssen – Consultant. Oshi – Consultant. Pfizer – Consultant, Grant/Research Support. Shield – Consultant. Shionogi – Consultant. Takeda – Consultant.

Jonathan Moses: AbbVie – Speakers Bureau.

Stephen Hanauer: Abbvie – Advisor or Review Panel Member, Advisory Committee/Board Member, Grant/Research Support, Speakers Bureau. allergan – Consultant, Grant/Research Support. Amgen – Consultant, Grant/Research Support. Arena – Advisor or Review Panel Member, Advisory Committee/Board Member. BMS – Advisory Committee/Board Member, Grant/Research Support, Speakers Bureau. Boehringer-Ingelheim – Advisor or Review Panel Member, Advisory Committee/Board Member. gilead – Consultant, Grant/Research Support. gossamer – Advisor or Review Panel Member. gsk – Consultant, Grant/Research Support. Janssen – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. lilly – Grant/Research Support. Merck – Consultant. Novartis – Consultant. Pfizer – Advisor or Review Panel Member, Advisory Committee/Board Member, Speakers Bureau. prometheus – Advisory Committee/Board Member, Consultant, Grant/Research Support. Protagonist – Advisor or Review Panel Member, Advisory Committee/Board Member. seres – Consultant. seres therapeutics – Consultant. Takeda – Advisor or Review Panel Member, Advisory Committee/Board Member, Consultant, Speakers Bureau.

Jean-Frederic Colombel: AbbVie – Consultant, Grant/Research Support. Amgen – Consultant. Arena – Consultant. BMS – Consultant. Boehringer Ingelheim – Consultant. Celgene Corporation – Consultant. Celltrion – Personal Fees. Eli Lilly – Consultant. Enterome – Personal Fees. Ferring Pharmaceuticals – Consultant. Galmed Research – Consultant. Galxo Smith Kline – Consultant. Genentech – Consultant. Genfit – Stock Options. Imedex – Consultant. Immunic – Consultant. Intestinal Biotech Development – Stock Options. Intestinal Biotech Development – Stock Options. Iterative Scopes – Consultant. Janssen Pharmaceuticals – Advisory Committee/Board Member, Consultant, Grant/Research Support. Kaleido Biosciences – Consultant. MedImmune – Personal Fees. Merck – Consultant. Microba – Consultant. Novartis – Consultant. PBM Capital – Consultant. Pfizer – Consultant. PPM Services – Personal Fees. Protagonist Therapeutics – Consultant. Sanofi – Consultant. Second Genome – Personal Fees. Seres – Personal Fees. Shire – Personal Fees. Takeda – Advisory Committee/Board Member, Consultant, Grant/Research Support. Theradiag – Personal Fees. TiGenix – Consultant. Vifor – Consultant.

Thierry Dervieux: Prometheus Laboratories – Employee.

Bincy Abraham, MD, MS, FACG¹, Shervin Rabizadeh, MD, MBA², Taha Qazi, MD³, Esther A. Torres, MD⁴, Ayesha Fatima, MD⁵, Ann D. Flynn, MD⁶, David Ziring, MD⁷, Robert Battat, MD⁸, Ryan Ungaro, MD, MS⁹, Corey A. Siegel, MD, MS¹⁰, Judith Gohndrone, PhD¹¹, Donald Lum, MD¹², Adria A. Condino, DO¹³, Daniel J. Stein, MD¹⁴, Jana G. Hashash, MD, MSc¹⁵, Waseem Ahmed, MD¹⁶, Catherine Rowan, MD¹⁷, Brad Pasternak, MD¹⁸, Akash Pandey, MD¹⁹, Gil Y. Melmed, MD²⁰, Jonathan Moses, MD²¹, Stephen B. Hanauer, MD²², Jean-Frederic Colombel, MD⁹, Thierry Dervieux, PharmD, PhD²³. C0393 - Clinical Utility of Precision-Guided Dosing Tool for Infliximab During Maintenance Therapy of Inflammatory Bowel Disease, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.