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A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis (BEACON)

A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial of HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis (BEACON)

301

Sex: women (77.7 %) and men (22.3 %) Age: mean (standard deviation [SD]): 50.0 (12.0) years Race: White (79.1 %), Asian (11.3 %), other (4.0 %), Black or African American (3.0 %), American Indian or Alaska Native (1.0 %) and Native Hawaiian or Pacific Islander (1.0 %) Ethnicity: Not Hispanic or Latino (61.8 %) and Hispanic or Latino (38.2 %)

A total of 301 participants were randomized (100 QD, 101 BID, 100 placebo) and included in the intent-to-treat set. A total of 301 participants were included in the safety analysis set (100 QD, 102 BID, 99 placebo). Overall, 180 participants (59.8 %) completed the study treatment. Treatment was discontinued early in 121 participants (40.2 %). The most frequent reasons for early treatment discontinuation (equal to or larger than 5 % of participants overall) were due to participants terminated by sponsor (27.6 %) and participant decision (6.0 %). A total of 185 (61.5 %) participants completed the study and 116 (38.5 %) participants were discontinued early from study. The most frequent reasons for early study discontinuation were participants terminated by sponsor (28.6 %) and participant decision (8.6 %).

The median (range) duration of exposure was 11.83 (0.0, 12.3) months in the BID group, 11.96 (1.3, 12.4) months in the QD group, and 11.96 (2.3, 13.0) months in the placebo group. Treatment-emergent adverse events were reported for 84 participants (82.4%) in the fipaxalparant 300 mg BID group, 87 participants (87.0%) in the fipaxalparant 300 mg QD group, and 79 participants (79.8%) in the placebo group. The most frequently reported adverse events by preferred term (equal to or larger than 10% of participants in the BID, QD, or placebo groups, respectively) were urinary tract infection (6.9%, 16.0%, 7.1%), diarrhoea (2.9%, 7.0%, 13.1%), arthralgia (2.0%, 6.0%, 11.1%) and COVID-19 (5.9%, 10.0%, 9.1%). Grade equal to or larger than 3 adverse events were reported for 15 participants (14.7%) in the fipaxalparant 300 mg BID group, 20 participants (20.0%) in the fipaxalparant 300 mg QD group, and 5 participants (5.1%) in the placebo group. In the fipaxalparant 300 mg QD group, dengue fever was reported in 3 participants (3.0%) and appendicitis was reported in 2 participants (2.0%). Most of the grade equal to or larger than 3 adverse events were reported in a single participant (1.0%) across the BID, QD, or placebo groups. Serious adverse events were reported for 8 participants (7.8%) in the fipaxalparant 300 mg BID group, 9 participants (9.0%) in the fipaxalparant 300 mg QD group and 5 participants (5.1%) in the placebo group. Appendicitis was the only serious adverse event reported in 2 participants (2.0%) in the fipaxalparant 300 mg QD group and was not reported in the fipaxalparant 300 mg BID or placebo groups. Most of the serious adverse events were reported in a single participant (1.0%) across the BID, QD, or placebo groups. In the fipaxalparant 300 mg BID group and placebo group, 1 participant (1.0%) in each group experienced an adverse event that led to death was neuroendocrine carcinoma and acute respiratory failure, respectively. No participant experienced an adverse event led to death in the fipaxalparant 300 mg QD group. Adverse events that led to discontinuation of treatment were reported for 9 participants (8.8%) in the fipaxalparant 300 mg BID group, 4 participants (4.0%) in the fipaxalparant 300 mg QD group, and 2 participants (2.0%) in the placebo group. No preferred term for adverse events that led to discontinuation of investigational product was reported for more than 1 participant in any group. 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. Overall, there were 5 (1.7%) participants who experienced orthostatic hypotension; 3 participants (3.0%) in the fipaxalparant 300 mg QD group, and 2 participants (2.0%) in the placebo group. No events of orthostatic hypotension were reported in the fipaxalparant 300 mg BID group. Overall, 299 (99.3%) participants received concomitant medication on or after the first dose of study therapy. The most frequently (equal to or larger than 10%) used concomitant medications by preferred terms were mycophenolate mofetil (48.8%), folic acid (32.6%), methotrexate (26.2%), prednisone (25.9%), paracetamol (23.9%), omeprazole (22.6%), nifedipine (17.6%), colecalciferol (16.9%), amlodipine (16.3%), acetylsalicylic acid (15.6%), pantoprazole (15.6%), levothyroxine (12.6%), sildenafil (11.6%) and esomeprazole (10.3%). No participants met the criteria for Hy's law, defined as having alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) and total bilirubin > 2 x ULN. Four participants (3.9%) in the fipaxalparant 300 mg BID group, 3 participants (3.0%) each in the fipaxalparant 300 mg QD group, and placebo group had ALT > 3 x ULN. Four participants (3.9%) in the fipaxalparant 300 mg BID group and 2 participants (2.0%) in the fipaxalparant 300 mg QD group, and no participants in the placebo group had AST > 3 x ULN. Seven participants (6.9%) in the fipaxalparant 300 mg BID group, 4 participants (4.0%) in the fipaxalparant 300 mg QD group, and 3 participants (3.0%) in the placebo group had gamma-glutamyl transferase > 2.5 x ULN. One participant (1.0%) in each of the fipaxalparant 300 mg BID group and the fipaxalparant 300 mg QD group, and no participants in the placebo group had total bilirubin levels > 2 x ULN (Table 14-7.4.1). No clinically significant changes were observed in vital signs including systolic and diastolic blood pressure, mean arterial pressure, heart rate, respiratory rate, and temperature. No participant had a QTcF or QTcB value > 500 msec or an increase from baseline in QTcF or QTcB > 60 msec. Clinically significant abnormal findings were observed in 4 participants from the fipaxalparant 300 mg BID group. One participant reported non-serious adverse event of electrocardiogram PR prolongation (grade 2, drug related), led to study treatment discontinuation.

Efficacy Results: At baseline, the mean (SD) FVC % predicted was 91.62 (23.21) among 99 participants in the fipaxalparant 300 mg BID group, 89.65 (21.41) among 98 participants in the fipaxalparant 300 mg QD group, and 88.38 (19.65) among 98 participants in the placebo group. In the fipaxalparant 300 mg BID group, the least squares (LS) mean change from baseline at week 52 in FVC % predicted was -3.18 (standard error [SE] 0.95). The placebo-adjusted LS mean difference was -0.75 (95% CI: -3.37, 1.87; p = 0.572). In the fipaxalparant 300 mg QD group, the LS mean change from baseline at week 52 in FVC % predicted was -2.48 (SE 0.92). The placebo-adjusted LS mean difference was -0.05 (95% confidence interval (CI): -2.62, 2.51; p = 0.969). In the fipaxalparant 300 mg BID group, the LS mean change from baseline at week 52 in mRSS was -10.7 (SE 0.9). The placebo-adjusted LS mean difference was -1.8 (95% CI: -4.4, 0.7; p = 0.157). In the fipaxalparant 300 mg QD group, the LS mean change from baseline at week 52 in mRSS was -9.3 (SE 0.9). The placebo-adjusted LS mean difference was -0.5 (95% CI: -3.0, 2.0; nominal p = 0.690). Pharmacokinetics Results: PK trough concentrations after oral administration of 300 mg fipaxalparant in participants with diffuse cutaneous SSc were as follows: Following fipaxalparant 300 mg BID dosing regimen, mean (SD) fipaxalparant trough concentrations were 15600 (11200) ng/mL at week 4, 13300 (8660) ng/mL at week 16, 13600 (10800) ng/mL at week 28, 14400 (11900) ng/mL at week 40, and 11700 (10800) ng/mL at week 52. Following fipaxalparant 300 mg QD dosing regimen, mean (SD) fipaxalparant trough concentrations were 5840 (7030) ng/mL at week 4, 4540 (5760) ng/mL at week 16, 3890 (4220) ng/mL at week 28, 4960 (6310) ng/mL at week 40, and 3420 (4660) ng/mL at week 52.

The study was discontinued 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/jRCT2031220221

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

July. 18, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Written informed consent.
2. Male or female between the ages of 18 and 75 years, inclusive, at Screening.
3. Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with a total score of equal to or more than 9.
4. Classified as having skin involvement proximal to the elbow and/or knee.
5. At the time of enrollment, less than 36 months since the onset of the first SSc manifestation, other than Raynaud's phenomenon.
6. Skin in the forearm suitable for repeat biopsy (only applicable to the first 110 subjects for whom biopsy will be performed).
7. mRSS units of equal to or more than 15 at Screening.
8. FVC of equal to or more than 45% predicted at Screening, as determined by spirometry.
9. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

1. Positive for anti-centromere antibodies.
2. Diagnosed with sine scleroderma or limited cutaneous SSc.
3. Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogrens syndrome.
4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
5. Any of the following cardiovascular diseases:
a. uncontrolled, severe hypertension (>=160/100 mmHg) or persistent low blood pressure (systolic blood pressure <90 mmHg) within 6 months of Screening,
b. myocardial infarction within 6 months of Screening,
c. unstable cardiac angina within 6 months of Screening.
6. DLCO <40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit.
7. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunction and/or Raynauds phenomenon/digital ulcers.
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed).
9. Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic drug within 4 weeks prior to Screening, including cyclophosphamide, azathioprine (Imuran) or other immunosuppressive or cytotoxic medication. Avoiding the use of listed prohibited treatments must not be considered detrimental and must be indicated by the treating physician. Exceptions include mycophenolate mofetil (CellCept), mycophenolic acid (Myfortic), methotrexate and low-dose prednisone, as follows: use of CellCept equal to or less than 3 g/day, Myfortic equal to or less than 2.14 g/day, methotrexate equal to or less than 15 mg/week and prednisone equal to or less than 10 mg/day (or equivalent dosing of glucocorticoids) is allowed. See Table 9.1 in the protocol for full details. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for equal to or more than 6 months and the dose must have been stable for equal to or more than 16 weeks prior to the Day 1 Visit. Prednisone must have been at a stable dose for equal to or more than 8 weeks prior to the Day 1 Visit. It is acceptable to be on background low-dose prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit. Subjects must not be withdrawn from any standard-of-care treatment that is considered necessary for the clinical management of the subject in order to fulfill the trial eligibility requirements.
10. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed).
11. Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.
12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
13. 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.
14. Pregnant or lactating women.
15. Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject.
16. Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial.
17. Known history of positive test for human immunodeficiency virus.
18. Active hepatitis (any of the following at Screening)
Hepatitis B:
Positive hepatitis B surface antigen
positive for anti-hepatitis B core antibody (anti-HBcAb) and a positive test for hepatitis B surface antibody (HBsAb) and presence of hepatitis B virus DNA
positive for HBcAb and a negative test for HBsAb and presence of hepatitis B virus DNA
Hepatitis C:
positive anti-hepatitis C virus (anti-HCV) and positive HCV RNA.
19. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis or moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment by Child-Pugh scoring system.
20. Previous organ transplant (including allogeneic and autologous marrow transplant).
21. International normalized ratio >2, prolonged prothrombin time >1.5 x the upper limit of normal (ULN) or partial thromboplastin time >1.5 x ULN at Screening.
22. Alanine aminotransferase or aspartate aminotransferase >2 x ULN.
23. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.
24. Total bilirubin >2 x ULN. Subjects with documented diagnosis of Gilberts syndrome may be enrolled if their total bilirubin is <=3.0 mg/dL.
25. Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.
26. Known history of severe allergy or reaction to any component of the investigational product formulation.

Both

Diffuse Cutaneous Systemic Sclerosis

Administer HZN-825 once daily (QD) or twice daily (BID)

Change in FVC % predicted from Baseline to Week 52.

1. Change from Baseline in HAQ-DI at Week 52.
2. Change from Baseline in MDGA at Week 52.
3. Change from Baseline in PTGA at Week 52.
4. Change from Baseline in the Physical Effects subscale of the SSPRO-18 at Week 52.
5. Change from Baseline in the Physical Limitations subscale of the SSPRO-18 at Week 52.
6. Proportion of subjects with an mRSS decrease of >=5 points and 25% from Baseline 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 >=3 of 5 core measures from Baseline: >=20% in mRSS, >=20% in HAQ-DI, >=20% in PTGA, >=20% in MDGA and >=5% for FVC % predicted at Week 52 (ACR-CRISS-20).

+81-3-3541-5151

May. 12, 2022

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