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A Multicenter, Open-label Extension Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis (BEACON OLE)

A Multicenter, Open-label Extension Trial of HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis (BEACON OLE)

174

Sex: Male 34 (19.5%), Female 140 (80.5%) Age: mean (SD): 49.0 (12.1) years Race: White 134 (77.0%), Asian 21 (12.1%), other 9 (5.2%), Black or African American 5 (2.9%), American Indian or Alaska Native 2 (1.1%), and Native Hawaiian or Pacific Islander 2 (1.1%) Ethnicity: not Hispanic or Latino 103 (59.2%), Hispanic or Latino 71 (40.8%)

A total of 174 participants were enrolled (52 in fipaxalparant 300 mg BID, 62 in fipaxalparant 300 mg QD, and 60 in placebo). The safety and full analysis sets included 53 and 52 participants, respectively, in the fipaxalparant 300 mg BID group; 62 participants in each set for the fipaxalparant 300 mg QD group; and 59 and 60 participants, respectively, in the placebo group. The treatment was completed by 49 participants (28.2%). Treatment was discontinued early in 125 participants (71.8%). The most frequently reported reason for early treatment discontinuation was due to study terminated by sponsor [106 (60.9%)].

Duration of Exposure The median (range) duration of exposure was 6.29 (0.3, 12.2) months in the fipaxalparant 300 mg BID group, 7.62 (0.3, 13.1) months in the fipaxalparant 300 mg QD group, and 8.15 (0.1, 12.3) months in the placebo group. Treatment Emergent Adverse Events Treatment emergent adverse events were reported for 37 participants (69.8%) in the fipaxalparant 300 mg BID group, 34 participants (54.8%) in the fipaxalparant 300 mg QD group, and 35 participants (59.3%) in the placebo group. The most frequently reported adverse events by Preferred Term with incidence equal to or larger than 5% of participants in the 62 in fipaxalparant 300 mg BID, fipaxalparant 300 mg QD, or placebo groups, respectively, were diarrhoea (1.9%, 4.8%, 8.5%), dyspepsia (0.0%, 0.0%, 6.8%), gastrooesophageal reflux disease (3.8%, 3.2%, 5.1%), nausea (1.9%, 1.6%, 5.1%), vomiting (5.7%, 4.8%, 0.0%), COVID-19 (7.5%, 4.8%, 3.4%), nasopharyngitis (7.5%, 4.8%, 8.5%), pharyngitis (5.7%, 0.0%, 0.0%), urinary tract infection (5.7%, 4.8%, 5.1%), arthralgia (7.5%, 3.2%, 1.7%), skin ulcer (0.0%, 4.8%, 5.1%), and hypotension (0.0%, 6.5%, 0.0%). Grade equal to or larger than 3 Treatment Emergent Adverse Events Any Rheumatology Common Terminology Criteria (CTC) Grade equal to or larger than 3 TEAEs were reported for 4 participants (7.5%) in the fipaxalparant 300 mg BID group, 3 participants (4.8%) in the fipaxalparant 300 mg QD group, and 5 participants (8.5%) in the placebo group. Grade equal to or larger than 3 TEAEs reported in the fipaxalparant 300 mg BID group were nausea, vomiting, pneumonia bacterial, arthralgia, adnexa uteri cyst, cough, extremity necrosis, and peripheral ischaemia in 1 participant each (1.9%). In the fipaxalparant 300 mg QD group, the Grade equal to or larger than 3 TEAEs reported were stress cardiomyopathy, dengue fever, infectious pleural effusion, pneumonia bacterial, blood creatine phosphokinase increased, decreased appetite, pneumothorax, and pulmonary hypertension, in 1 participant each (1.6%). Grade equal to or larger than 3 TEAEs reported in the placebo group were cardiac failure, pericarditis, diverticulitis, pneumocystis jirovecii pneumonia, pneumonia, soft tissue infection, pulmonary arterial hypertension, and skin ulcer in 1 participant each (1.7%). Treatment Emergent Adverse Events Related to Study Treatment Overall, treatment related TEAEs were reported in 25 participants (14.4%). Treatment related TEAEs reported in equal to or larger than 2 participants in the fipaxalparant 300 mg BID group was dizziness (3.8%), in the fipaxalparant 300 mg QD group was urinary tract infection (3.2%), and in the placebo group were urinary tract infection and nausea (each 3.4%). Serious Adverse Events Serious adverse events (SAEs) were reported for 2 participants (3.8%) in the fipaxalparant 300 mg BID group, 2 participants (3.2%) in the fipaxalparant 300 mg QD group, and 5 participants (8.5%) in the placebo group. The most frequently reported SAEs by Preferred Term (equal to or larger than 1% participants in the fipaxalparant 300 mg BID, fipaxalparant 300 mg QD, or placebo groups, respectively) were cardiac failure, pericarditis, diverticulitis, pneumocystis jirovecii, pneumonia, soft tissue infection, pulmonary arterial hypertension, pulmonary oedema (each 0.0%, 0.0%, 1.7%); stress cardiomyopathy, dengue fever, pneumothorax, pulmonary hypertension (each 0.0%, 1.6%, 0.0%); arthralgia, cough, extremity necrosis, peripheral ischaemia (each 1.9%, 0.0%, 0.0%); and pneumonia bacterial (1.9%, 1.6%, 0.0%). No treatment related SAEs were reported during the study. Deaths No deaths were reported in this study. Treatment Emergent Adverse Events Leading to Treatment Discontinuation The TEAEs that led to treatment discontinuation were reported for 3 participants (5.7%) in the fipaxalparant 300 mg BID group, 1 participant (1.6%) in the fipaxalparant 300 mg QD group, and 1 participant (1.7%) in the placebo group. The TEAEs that led to treatment discontinuation in the fipaxalparant 300 mg BID group were diarrhoea, nausea, vomiting, dizziness, anxiety, rash, and extremity necrosis (1.9% each). The TEAEs that led to treatment discontinuation in the fipaxalparant 300 mg QD and placebo groups were hypotension (1.6%) and pneumocystis jirovecii pneumonia (1.7%), respectively. Adverse Events Meeting American College of Rheumatology-Composite Response Index in Systemic Sclerosis The TEAEs meeting American College of Rheumatology-Composite Response Index in Systemic Sclerosis (ACR-CRISS) were reported for 2 participants (3.8%) in the fipaxalparant 300 mg BID group and 1 participant (1.7%) in the placebo group. The preferred terms reported were forced vital capacity decreased and extremity necrosis (1.9% each) in the fipaxalparant 300 mg BID group. The preferred terms reported in the placebo group were pulmonary arterial hypertension and pulmonary oedema (1.7% each). Adverse Event of Special Interest The AESI, orthostatic hypotension, defined as a reduction in systolic blood pressure equal to or larger than 20 mmHg or diastolic blood pressure equal to or larger than 10 mmHg with associated symptoms was not reported in any study participant. Vital Signs Out of normal range values were observed for vital sign parameters such as temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation, in all 3 groups (fipaxalparant 300 mg BID, fipaxalparant 300 mg QD, and placebo). These abnormal values were transient and not clinically significant. Electrocardiogram Abnormal clinically significant findings in the ECG were observed in overall 5 participants with 1 from the placebo group and 4 from the fipaxalparant 300 mg QD group. The participant in the placebo group had an abnormal elevated PR at Week 28. In the 300 mg QD group, 1 participant showed sinus tachycardia with occasional premature ventricular complexes at Day 1 and sinus tachycardia at Week 4. For another participant in the same group, the ECG at Week 52 showed difference compared with the previous ECG. A separate participant in the 300 mg QD group showed abnormality in anterolateral leads at Week 52. Pulmonary hypertension was observed in another participant in the 300 mg QD at Week 52. Clinical Safety Laboratory Evaluation No participants met the criteria for Hy's law, defined as having alanine aminotransferase (ALT) or aspartate aminotransferase (AST) larger than 3 x upper limit of normal (ULN) and total bilirubin larger than 2 x ULN. Two participants (3.8%) in the fipaxalparant 300 mg BID group, and 2 participants (3.4%) in the placebo group had ALT larger than 3 x ULN. One participant (1.9%) in the fipaxalparant 300 mg BID group and 1 participant (1.7%) in the placebo group had AST larger than 3 x ULN. Three participants (5.7%) in the fipaxalparant 300 mg BID group, 1 participant (1.6%) in the fipaxalparant 300 mg QD group, and 3 participants (5.1%) in the placebo group had gamma-glutamyl transferase (GGT) larger than 2.5 x ULN. No participants in any of the three treatment groups had total bilirubin levels larger than 2 x ULN. No clinically significant changes from trial baseline were observed for hematology, chemistry, and urinalysis evaluations across groups from Week 1 to Week 52.

Primary At baseline of this extension study, the mean (SD) FVC % predicted was 91.69 (22.53) among 51 participants in the fipaxalparant 300 mg BID group, 85.44 (20.79) among 58 participants in the fipaxalparant 300 mg QD group, and 84.72 (20.65) among 54 participants in the placebo group. The overall decline of 3.55 percentage points (SD = 10.9) in FVC % predicted from trial baseline was observed at Week 52. The mean (SD) declines from the trial baseline at Week 52 in FVC % predicted was 7.95 (15.36) in the fipaxalparant 300 mg BID group, 1.36 (8.46) in the fipaxalparant 300 mg QD group, and 0.82 (4.09) in the placebo group. No efficacy trend in FVC % predicted was observed. Pharmacokinetic Results: Following fipaxalparant 300 mg BID dosing regimen, mean (SD) fipaxalparant trough concentrations in the placebo cohort were 15700 (11100) ng/mL at Week 4, 17100 (9130) ng/mL at Week 16, 13600 (8560) ng/mL at Week 28, and 15000 (7770) ng/mL Week 40. Mean (SD) fipaxalparant trough concentrations in the 300 mg QD cohort were 3780 (4550) ng/mL at Day 1, 11100 (7540) ng/mL at Week 4, 13000 (9600) ng/mL at Week 16, 11000 (8400) ng/mL at Week 28, and 11900 (5980) ng/mL Week 40. Mean (SD) fipaxalparant trough concentrations in the 300 mg BID cohort were 14900 (10900) ng/mL at Day 1, 14500 (10900) ng/mL at Week 4, 12600 (10900) ng/mL at Week 16, 12900 (8660) ng/mL at Week 28, and 12300 (9330) ng/mL at Week 40.

The study was terminated early due to futility and the decision was not related to any safety concerns associated with fipaxalparant.

Feb. 23, 2026

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2011230044

Sato Toshiyuki

PPD-SNBL K.K.

St. Lukes Tower 12F 8-1 Akashicho, Chuo-ku, Tokyo

Toshiyuki.Sato@ppd.com

Sato Toshiyuki

PPD-SNBL K.K.

St. Lukes Tower 12F 8-1 Akashicho, Chuo-ku, Tokyo

+81-3-6821-0847

Toshiyuki.Sato@ppd.com

Complete

Nov. 07, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Written informed consent.
2. Completed the double-blind Treatment Period (Week 52) in Trial HZNP-HZN-825-301; subjects prematurely discontinued from trial drug in Trial HZNP-HZN-825-301 for reasons other than safety or toxicity can be included at the discretion of the Investigator after completing Trial HZNP-HZN-825-301 scheduled visits, including Week 52 assessments.
3. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

1. Anticipated use of another investigational agent for any condition during the course of the trial.
2. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-301 (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
3. Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 4 weeks after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period. Women are considered of childbearing potential if they are not postmenopausal and not surgically sterile (documented bilateral salpingectomy, bilateral oophorectomy or hysterectomy). A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Fertile male subjects must use a condom throughout the trial and for 4 weeks after the last dose of trial drug. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
4. Pregnant or lactating women.
5. Any new development with the subject's disease or condition or any significant laboratory test abnormality during the course of Trial HZNP-HZN-825-301 that, in the opinion of the Investigator, would potentially put the subject at unacceptable risk.
6. Subjects will be ineligible if, in the opinion of the Investigator, they are unlikely to comply with the trial protocol or have a concomitant disease or condition that could interfere with the conduct of the trial.

Both

Diffuse Cutaneous Systemic Sclerosis (Diffuse Cutaneous SSc)

The dose regimen for all subjects will be HZN-825 300 mg BID. Subjects will take 2 HZN-825 150 mg tablets orally in the morning and evening with a meal.

The primary endpoint is the change from both Baselines in FVC % predicted at Week 52.

1. Change from both Baselines in HAQ-DI at Week 52.
2. Change from both Baselines in MDGA at Week 52.
3. Change from both Baselines in PTGA at Week 52.
4. Change from both Baselines in the Physical Effects subscale of the SSPRO-18 at Week 52.
5. Change from both Baselines in the Physical Limitations subscale of the SSPRO-18 at Week 52.
6. Proportion of subjects with an mRSS decrease of more than or equal to 5 points and 25% from both Baselines at Week 52.
7. Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at Week 52.
8. Proportion of subjects with an improvement in more than or equal to 3 of 5 core measures from both Baselines: more than or equal to 20% in mRSS, more than or equal to 20% in HAQ-DI, more than or equal to 20% in PTGA, more than or equal to 20% in MDGA and more than or equal to 5% for FVC % predicted at Week 52 (ACR-CRISS-20).
9. Change from both Baselines in the SSPRO-18 at Week 52.
10. Change from both Baselines in each scale of the UCLA SCTC GIT 2.0 and the total GIT score at Week 52.
11. Change from both Baselines in Raynaud's phenomenon using the Raynaud's Assessment at Week 52.
12. Change from both Baselines in the SHAQ at Week 52.
13. Change from both Baselines in SScQoL scores at Week 52.
14. Change from both Baselines in SF-12 scores at Week 52.
15. Change from both Baselines in pain and pain component scale scores at Week 52.
16. Change from both Baselines in the FACIT-F score at Week 52.
17. Change from both Baselines in the mRSS at Week 52.
18. Change from both Baselines in lung fibrosis based on HRCT at Week 52.
19. Change from both Baselines in DLCO at Week 52.
20. Change from both Baselines in serum and plasma biomarkers associated with LPAR1 pathway, inflammation and/or fibrosis at Week 52.
21. Change from both Baselines in swollen and tender joint count, digital ulcer assessment and joint contracture assessment at Week 52.
Safety and Tolerability Endpoints
1. Incidence of TEAEs and the AESI (orthostatic hypotension).
2. Concomitant medication use.
3. Change from both Baselines in vital signs.
4. Change from both Baselines in 12-lead ECG measurements.
5. Change from both Baselines in clinical safety laboratory test results.
Pharmacokinetic Endpoint
1. Pre- and post-dose concentrations of HZN-825 and metabolite(s).

+81-11-706-7061

Sept. 19, 2023

ARGENTINA/AUSTRIA/CHILE/FRANCE/GERMANY/GREECE/ISRAEL/ITALY/KOREA, REPUBLIC OF/MEXICO/NETHERLANDS/POLAND/PORTUGAL/ROMANIA/SERBIA/SPAIN/SWITZERLAND/UNITED KINGDOM/UNITED STATES