P0312 - Long-Term Safety of Budesonide Oral Suspension for Eosinophilic Esophagitis: An Integrated Safety Analysis of Phase 1–3 Clinical Trial Data

Sunday, October 24, 2021

3:30 PM – 7:00 PM PT

Location: Shoreline Exhibit Hall

Has Audio

Award: Presidential Poster Award

Presenting Author(s)

Ikuo Hirano, MD

Northwestern University Feinberg School of Medicine
Chicago, IL, United States

Award: Presidential Poster Award

Ikuo Hirano, MD¹, Evan S. Dellon, MD², Sandeep K. Gupta, MD³, David A. Katzka, MD⁴, Margaret H. Collins, MD⁵, Abigail M. Wojtowicz, PhD⁶, Wenwen Zhang, PhD⁷, Mena Boules, MD⁶, Siddharth Bhatia, MD⁸, Nirav K. Desai, MD⁷
¹Northwestern University Feinberg School of Medicine, Chicago, IL; ²Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC; ³Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN; ⁴Mayo Clinic, Rochester, MN; ⁵Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH; ⁶Takeda Pharmaceuticals USA, Inc., Lexington, MA; ⁷Takeda Development Center Americas, Inc., Cambridge, MA; ⁸Takeda Pharmaceuticals International Co., Cambridge, MA

Introduction: Budesonide oral suspension (BOS) is an immediate-release swallowed topical corticosteroid developed for eosinophilic esophagitis (EoE). We present an integrated safety analysis of all clinical trials of BOS to provide the largest set of safety data on a topical corticosteroid for EoE to date.

Methods: Data were pooled from six trials (phase 1, SHP621-101; phase 2, MPI 101-01, MPI 101-06; phase 3, SHP621-301, SHP621-302 and SHP621-303) for all participants who received ≥1 dose of BOS (any trial) or induction placebo (MPI 101-01/MPI 101-06/SHP621-301). For the ongoing open-label study SHP621-303, data were collected until August 14, 2020 (interim data cut-off). Treatment groups were BOS 2.0 mg b.i.d., BOS any dose (including BOS 2.0 mg b.i.d.) and placebo. Adverse events (AEs), clinical laboratory testing, vital-sign monitoring and physical examinations were assessed (all trials). Dual-energy X-ray absorptiometry (DXA) (participants 11–17 years old) and adrenocorticotropic hormone (ACTH) stimulation tests (all participants) were performed in the phase 3 studies. Exposure-adjusted incidence rates were calculated for AEs and AEs of special interest (AESIs); AESIs were categorized as infections, systemic effects of corticosteroids, or gastrointestinal effects.

Results: Overall, 514 unique participants were included (BOS 2.0 mg b.i.d., n=292; BOS any dose, n=448; placebo, n=168). The BOS 2.0 mg b.i.d., BOS any dose and placebo groups totaled 87.2, 116.0 and 25.0 patient-years of exposure, respectively. BOS was well tolerated; most treatment-emergent AEs (TEAEs) were mild/moderate in severity (Table). The most common exposure-adjusted TEAEs (≥5% participants) and AESIs were upper respiratory tract infection, nasopharyngitis and sinusitis; TEAEs, AESIs and AEs leading to study or study drug discontinuation were more common in BOS- than placebo-treated participants (Table). AESIs of abnormal ACTH stimulation test and decreased blood cortisol were more frequent in the BOS 2.0 mg b.i.d. and BOS any dose groups (Table); most were mild/moderate and without other signs of adrenal insufficiency. DXA scans demonstrated no effect on growth (n=26); the intra-age distribution of TEAEs was similar for the BOS 2.0 mg b.i.d. and BOS any dose groups for participants 11–17 and ≥18 years old (data not shown). One death occurred (unrelated to BOS 2.0 mg b.i.d.).

Discussion: BOS was well tolerated, including at the highest dose (2.0 mg b.i.d.) and for maintenance therapy. Most TEAEs were mild/moderate in severity.

	BOS 2.0 mg b.i.d. (n=292)	BOS any dose (n=448)	Placebo (n=168)
TEAEs and SAEs, n (%)
Any TEAE	224 (76.7)	337 (75.2)	98 (58.3)
Any SAE	22 (7.5)	25 (5.6)	1 (0.6)
Any severe TEAE	25 (8.6)	31 (6.9)	4 (2.4)
Any life-threatening TEAE	5 (1.7)	5 (1.1)	0 (0.0)
TEAEs related to study drug	105 (36.0)	128 (28.6)	29 (17.3)
SAEs related to study drug^‡	1 (0.3)	1 (0.2)	0 (0.0)
TEAEs related to EoE	41 (14.0)	41 (9.2)	6 (3.6)
Hospitalizations due to TEAE	17 (5.8)	19 (4.2)	1 (0.6)
TEAE leading to study drug discontinuation	19 (6.5)	19 (4.2)	5 (3.0)
TEAE leading to study discontinuation	16 (5.5)	21 (4.7)	4 (2.4)
Deaths related to study drug	0 (0.0)	0 (0.0)	0 (0.0)
Deaths unrelated to study drug^§	1 (0.3)	1 (0.2)	0 (0.0)
Patient-years of exposure, years^¶	87.2	116.0	25.0
Most common exposure-adjusted TEAEs experienced by ≥5% of participants in any treatment group, n (%) [r]^\|\|
Upper respiratory tract infection	28 (9.6) [32.1]	38 (8.5) [32.8]	5 (3.0) [20.0]
Nasopharyngitis	24 (8.2) [27.5]	42 (9.4) [36.2]	9 (5.4) [36.0]
Sinusitis	22 (7.5) [25.2]	31 (6.9) [26.7]	4 (2.4) [16.0]
Nausea	21 (7.2) [24.1]	24 (5.4) [20.7]	3 (1.8) [12.0]
Vomiting	20 (6.8) [22.9]	25 (5.6) [21.6]	6 (3.6) [24.0]
Esophageal candidiasis	17 (5.8) [19.5]	24 (5.4) [20.7]	2 (1.2) [8.0]
Influenza	16 (5.5) [18.3]	23 (5.1) [19.8]	2 (1.2) [8.0]
Cough	16 (5.5) [18.3]	24 (5.4) [20.7]	4 (2.4) [16.0]
Diarrhea	16 (5.5) [18.3]	24 (5.4) [20.7]	6 (3.6) [24.0]
Headache	12 (4.1) [13.8]	29 (6.5) [25.0]	2 (1.2) [8.0]
Overall AESIs (any), n (%)
Infections and infestations	124 (42.5)	188 (42.0)	34 (20.2)
Adrenal effects	35 (12.0)	35 (7.8)	6 (3.6)
Fractures	10 (3.4)	13 (2.9)	3 (1.8)
CNS/mood effects	50 (17.1)	77 (17.2)	13 (7.7)
Metabolic effects	35 (12.0)	38 (8.5)	5 (3.0)
Cardiac effects	17 (5.8)	17 (3.8)	0 (0.0)
Exposure-adjusted AESIs, n (%) [r]^\|\|
Infections and infestations
SAE	4 (1.4) [4.6]	4 (0.9) [3.4]	0 (0.0) [0.0]
SAEs related to study drug	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
Severe AESIs	3 (1.0) [3.4]	4 (0.9) [3.4]	0 (0.0) [0.0]
Resulted in discontinuation of study drug**	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
Experienced by ≥10 participants in any treatment group
Upper respiratory tract infection	28 (9.6) [32.1]	38 (8.5) [32.8]	5 (3.0) [20.0]
Nasopharyngitis	24 (8.2) [27.5]	42 (9.4) [36.2]	9 (5.4) [36.0]
Sinusitis	22 (7.5) [25.2]	31 (6.9) [26.7]	4 (2.4) [16.0]
Esophageal candidiasis	17 (5.8) [19.5]	24 (5.4) [20.7]	2 (1.2) [8.0]
Influenza	16 (5.5) [18.3]	23 (5.1) [19.8]	2 (1.2) [8.0]
Oral candidiasis	12 (4.1) [13.8]	15 (3.3) [12.9]	0 (0.0) [0.0]
Viral gastroenteritis	10 (3.4) [11.5]	12 (2.7) [10.3]	3 (1.8) [12.0]
Ear infection	8 (2.7) [9.2]	11 (2.5) [9.5]	1 (0.6) [4.0]
Systemic effects of corticosteroids
Adrenal effects
SAE	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
SAEs related to study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Severe AESIs	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
Resulted in discontinuation of study drug^††	7 (2.4) [8.0]	7 (1.6) [6.0]	0 (0.0) [0.0]
Fractures
SAE	2 (0.7) [2.3]	3 (0.7) [2.6]	0 (0.0) [0.0]
SAEs related to study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Severe AESIs	1 (0.3) [1.1]	2 (0.4) [1.7]	1 (0.6) [0.0]
Resulted in discontinuation of study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
CNS/mood effects
SAE	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
SAEs related to study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Severe AESIs	1 (0.3) [1.1]	1 (0.2) [0.9]	2 (1.2) [8.0]
Resulted in discontinuation of study drug	1 (0.3) [1.1]	1 (0.2) [0.9]	2 (1.2) [8.0]
Metabolic effects
SAE	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
SAEs related to study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Severe AESIs	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
Resulted in discontinuation of study drug	2 (0.7) [2.3]	2 (0.4) [1.7]	0 (0.0) [0.0]
Cardiac effects
SAE	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
SAEs related to study drug	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Severe AESIs	0 (0.0) [0.0]	0 (0.0) [0.0]	0 (0.0) [0.0]
Resulted in discontinuation of study drug	1 (0.3) [1.1]	1 (0.2) [0.9]	0 (0.0) [0.0]
Experienced by ≥10 participants in any treatment group
Abnormal ACTH stimulation test	12 (4.1) [13.8]	12 (2.7) [10.3]	3 (1.8) [12.0]
Decreased blood cortisol	12 (4.1) [13.8]	12 (2.7) [10.3]	2 (1.2) [8.0]

Table: Table. Summary Of TEAEs, Exposure-Adjusted TEAEs Per 100 Patient-Years Experienced By ≥5% Of Participants In Any Treatment Group And Exposure-Adjusted AESIs Per 100-Patient Years,* By Preferred Term†

*AESIs of special interest were identified as those that could be related to long-term corticosteroid use and were grouped into three categories: infection events; events related to potential systemic effects of corticosteroids (including sub-categories of adrenal effects and fractures); events related to gastrointestinal effects (data not shown). TEAEs of candidiasis were treated with antifungal medication; none of the TEAEs of candidiasis were severe/serious or resulted in study discontinuation.
†Mean (standard deviation) participant exposure to study drug for the BOS 2.0 mg b.i.d., BOS any dose and placebo groups was 62.1 (51.1), 47.1 (46.7) and 13.0 (3.5) weeks, respectively.
‡One event of esophageal herpes simplex infection was considered possibly related to study drug, and possibly related to the participants EoE. This event did not lead to discontinuation of study drug and resolved 21 days after onset.
§One death occurred in a participant who was receiving BOS 2.0 mg b.i.d., which was a suicide that was considered by the investigator to be unrelated to study drug.
¶Total exposure years were calculated as the sum of exposure years among participants in a treatment group.
||Exposure years for participants who experienced TEAEs were calculated as follows: (date of first TEAE − date of first dose +1)/365.25. Exposure years for participants who did not experience TEAEs were calculated as follows: (date of last dose − date of first dose +1)/365.25.
**One participant who was receiving BOS 2.0 mg b.i.d. discontinued study drug as a result of an infection/infestation (esophageal candidiasis); this was determined by the investigator to be probably related to study drug, and resolved within 14 days of discontinuation.
††Although AESIs of adrenal effects (any TEAE) were similar for BOS- versus placebo-treated patients (data not shown), a greater proportion of BOS-treated patients (2.0 mg b.i.d. and any dose) experienced adrenal effects that resulted in discontinuation of study drug.
ACTH, adrenocorticotropic hormone; AE, adverse event; AESI, adverse event of special interest; CNS, central nervous system; n, number of participants experiencing the event; r, the exposure-adjusted frequency per 100 patient-years; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

Disclosures:

Ikuo Hirano: Adare Pharmaceuticals – Consultant, Grant/Research Support. Allakos – Consultant, Grant/Research Support. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. EsoCap Biotech – Consultant. Gossamer Bio – Consultant. Lilly – Consultant. Meritage Pharma Inc. – Consultant, Grant/Research Support. Receptos/Celgene – Consultant, Grant/Research Support. Regeneron Pharmaceuticals – Consultant, Grant/Research Support. Shire, a Takeda company – Consultant, Grant/Research Support.

Evan Dellon: Abbott Laboratories – Consultant. Adare Pharmaceuticals/Ellodi Pharmaceuticals – Consultant, Grant/Research Support. Aimmune Therapeutics – Consultant. Allakos – Consultant, Grant/Research Support. Amgen – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant, Grant/Research Support. Avir Pharma – Consultant. Banner Life Sciences – Grant/Research Support. Biorasi – Consultant. Calypso Biotech – Consultant. Celldex Therapeutics, Inc. – Consultant. EsoCap Biotech – Consultant. GlaxoSmithKline – Consultant, Grant/Research Support. Gossamer Bio – Consultant. Holoclara – Grant/Research Support. Landos Biopharma – Consultant. Lilly – Consultant. Meritage Pharma Inc. – Grant/Research Support. Miraca Life Sciences – Grant/Research Support. Morphic Therapeutic – Consultant. Nutricia – Grant/Research Support. Parexel/Calyx Clinical Research Solutions – Consultant. Receptos/Celgene/Bristol Myers Squibb – Consultant, Grant/Research Support. Regeneron Pharmaceuticals – Consultant, Grant/Research Support. Robarts Clinical Trials Inc./Alimentiv Inc. – Consultant. Salix Pharmaceuticals – Consultant. Sanofi – Consultant. Shire, a Takeda company – Consultant, Grant/Research Support.

Sandeep Gupta: Abbott – Consultant. Adare Pharmaceuticals – Consultant. Allakos – Consultant. DBV Technologies – Consultant. Gossamer Bio – Consultant. MedScape – Consultant. QOL Medical – Consultant. Receptos/Celegene/Bristol Myers Squibb – Consultant. Shire, a Takeda company – Grant/Research Support. UpToDate – Consultant.

David Katzka: Receptos/Celgene – Consultant. Shire, a Takeda company – Grant/Research Support.

Margaret Collins: Allakos – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant, Grant/Research Support. Calypso Biotech – Consultant. EsoCap Biotech – Consultant. GlaxoSmithKline – Consultant. Meritage Pharma Inc. – Grant/Research Support. Receptos/Celgene – Consultant, Grant/Research Support. Regeneron Pharmaceuticals – Consultant, Grant/Research Support. Robarts Clinical Trials Inc./Alimentiv, Inc. – Consultant. Shire, a Takeda company – Consultant, Grant/Research Support.

Abigail Wojtowicz: Takeda Pharmaceutical Company Limited – Stockholder/Ownership Interest (excluding diversified mutual funds). Takeda Pharmaceuticals USA, Inc. – Employee.

Wenwen Zhang: Takeda Development Center Americas, Inc. – Employee. Takeda Pharmaceutical Company Limited – Stockholder/Ownership Interest (excluding diversified mutual funds).

Mena Boules: Takeda Pharmaceutical Company Limited – Stockholder/Ownership Interest (excluding diversified mutual funds). Takeda Pharmaceuticals USA, Inc. – Employee.

Siddharth Bhatia: Takeda Pharmaceutical Company Limited – Stockholder/Ownership Interest (excluding diversified mutual funds). Takeda Pharmaceuticals International Co. – Employee.

Nirav Desai: Takeda Development Center Americas, Inc. – Employee. Takeda Pharmaceutical Company Limited – Stockholder/Ownership Interest (excluding diversified mutual funds).

Ikuo Hirano, MD¹, Evan S. Dellon, MD², Sandeep K. Gupta, MD³, David A. Katzka, MD⁴, Margaret H. Collins, MD⁵, Abigail M. Wojtowicz, PhD⁶, Wenwen Zhang, PhD⁷, Mena Boules, MD⁶, Siddharth Bhatia, MD⁸, Nirav K. Desai, MD⁷. P0312 - Long-Term Safety of Budesonide Oral Suspension for Eosinophilic Esophagitis: An Integrated Safety Analysis of Phase 1–3 Clinical Trial Data, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.