HPP737 in Adult Patients With Plaque Psoriasis

This is a multicenter, randomized, double-blind, double-dummy, active parallel-controlled Phase III clinical trial evaluating the efficacy and safety of oral HPP737 in adult patients with moderate-to-severe chronic plaque psoriasis. The study is sponsored by Newsoara Biopharma Co., Ltd. (Shanghai) and has been approved by the National Medical Products Administration (NMPA) .

HPP737 is a novel, potent, and selective oral phosphodiesterase type 4 (PDE4) inhibitor in development for the treatment of psoriasis. PDE4 is an intracellular enzyme that increases the production of pro-inflammatory mediators and decreases the production of anti-inflammatory mediators, making it a validated therapeutic target for inflammatory diseases such as psoriasis. Preclinical and early clinical data indicate that HPP737 has demonstrated potent inhibition of interleukin-23 (IL-23) and tumor necrosis factor-alpha (TNF-α) production. HPP737 is designed to preferentially inhibit PDE4B, which is associated with anti-inflammatory activity, while limiting PDE4D engagement, which is believed to drive dose-limiting side effects, such as gastrointestinal distress. In Phase I studies, HPP737 was generally well-tolerated with a favorable safety profile.

Study Design: This study consists of three periods: a Screening Period, a Treatment Period, and a Safety Follow-up Period.

Screening Period (Day -14 to Day -1): Potential participants undergo screening procedures to assess eligibility based on inclusion and exclusion criteria.

Treatment Period (Week 0 to Week 16): Eligible participants are randomized in a 2:1 ratio to receive one of the following double-blind, double-dummy treatments for 16 weeks:

HPP737 20 mg orally once daily (experimental group, n≈404) Apremilast (active comparator) orally twice daily according to its approved dosing regimen (active comparator group, n≈202) Safety Follow-up Period (14 days after last dose): Following the completion of the 16-week treatment period, participants enter a safety follow-up period. This follow-up visit occurs 14 days after the last dose of study medication.

Study Population: Approximately 606 participants are planned to be enrolled in China. Eligible participants are adults aged ≥18 years with a confirmed clinical diagnosis of stable moderate-to-severe chronic plaque psoriasis and a history of psoriasis of at least 6 months.

Primary Objectives:

1. To evaluate the efficacy of HPP737 20 mg compared with apremilast in patients with moderate-to-severe chronic plaque psoriasis, as measured by the proportion of participants achieving at least of a reduction of 75% in Psoriasis Area and Severity Index (PASI) (PASI 75) at Week 16.
2. To evaluate the efficacy of HPP737 20 mg compared with apremilast in patients with moderate-to-severe chronic plaque psoriasis, as measured by the proportion of participants achieving a static Physician's Global Assessment (sPGA) score of "clear" (0) or "almost clear" (1) at Week 16.

The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol has been reviewed and approved by the institutional review boards or ethics committees of all participating sites.

• HPP737 (Drug): HPP737 capsules for oral administration.
• Placebo matching HPP737 (Drug), also known as Placebo: Placebo capsules matching HPP737 for oral administration.
• Apremilast (Drug), also known as Otezla: Apremilast tablets for oral administration.
• Placebo matching Apremilast (Drug), also known as Placebo: Placebo tablets matching Apremilast for oral administration.

Primary outcomes

• To evaluate proportion of subjects at Week 16 achieving at least a 75% reduction(improvement) from baseline in PASI (Psoriasis Area and Severity Index) score (PASI 75); [From enrollment to end of treatment at 16 weeks]
• To evaluate proportion of subjects at Week 16 achieving sPGA (Static Physician's Global Assessment) rating of "clear (score 0) or almost clear (score 1)" [From enrollment to end of treatment at 16 weeks]

Secondary outcomes

• To evaluate proportion of subjects achieving PASI 75 response at Week 1, 2, 4, 8, and 12; [From enrollment to end of treatment at 1, 2, 4, 8, and 12 weeks]
• To evaluate proportion of subjects achieving at least a 50% reduction in PASI (PASI 50) at Week 1, 2, 4, 8, 12, and 16; [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks]
• To evaluate proportion of subjects achieving at least a 90% reduction in PASI (PASI 90) at Week 1, 2, 4, 8, 12, and 16; [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks]
• To evaluate proportion of subjects achieving at least a 100% reduction in PASI (PASI 100) at Week 1, 2, 4, 8, 12, and 16; [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks.]
• To evaluate change from baseline in PASI score, and percent change from baseline in PASI score at Week 1, 2, 4, 8, 12, and 16; [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks]
• To evaluate proportion of subjects achieving sPGA (Static Physician's Global Assessment) rating of "clear (score 0) or almost clear (score 1)" at week 1, 2, 4, 8, and 12; [From enrollment to end of treatment at 1, 2, 4, 8, and 12 weeks]
• To evaluate change from baseline in Body Surface Area (BSA) score, and percent change from baseline in BSA score at Week 1, 2, 4, 8, 12, and 16; [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks]
• To evaluate change from baseline in Dermatology Life Quality Index (DLQI) score, and percent change from baseline in DLQI score Week 1, 2, 4, 8, 12, and 16. [From enrollment to end of treatment at 1, 2, 4, 8, 12, and 16 weeks.]
• To evaluate incidence and severity of adverse events [From ICF signed to end of study follow-up at 18 weeks.]
• To evaluate pharmacokinetic characteristics of subjects at Week 0, Week 4, Week 8, and Week 16 [From enrollment (Week 0) to end of treatment at 4,8,16 weeks.]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Subjects must voluntarily sign the informed consent form prior to the initiation of any trial-related procedures, be able to communicate effectively with the investigators, and understand and comply with the requirements of this trial;
* Age at the time of signing the informed consent form: age ≥18 years, regardless of sex;
* Clinically diagnosed patients with stable plaque psoriasis (Zhendingxing Banquzhuang Yinxie Bing), with a psoriasis history of ≥6 months before randomization;
* Diagnosed with moderate to severe plaque psoriasis and meeting the following criteria at screening: 1) PASI (Psoriasis Area and Severity Index), score ≥10; and sPGA (Static Physician's Global Assessment) score ≥3; and BSA (Body Surface Area) score ≥10%
* Body Mass Index (BMI): 18 kg/m2 ≤ BMI ≤ 35 kg/m2.

Exclusion Criteria:

* Presence of other forms of psoriasis (e.g., guttate psoriasis, pustular psoriasis, erythrodermic psoriasis) diagnosed at screening, in addition to chronic plaque psoriasis;
* Patients with drug-induced psoriasis (including but not limited to newly onset or exacerbated psoriasis caused by β-blockers \[beta-receptor blockers\], calcium channel blockers, or lithium preparations)
* Subjects with other skin diseases that may interfere with clinical assessment (such as severe bacterial, fungal, or viral skin infections), chronic diarrhea, severe gastrointestinal diseases (such as active peptic ulcer, gastrointestinal tract disorders, etc.), or a history of inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), or other active autoimmune inflammatory diseases (mixed connective tissue disease, idiopathic inflammatory myopathy, etc.);
* History of congenital or acquired immunodeficiency;
* Severe infection or systemic infection within 4 weeks prior to randomization, requiring oral and/or intravenous anti-infective therapy; or hospitalization due to infection;
* Medical history, symptoms, and examination results during screening indicating that the subject has active tuberculosis (TB); Note: Subjects with a negative T-cell test for Mycobacterium tuberculosis infection (T-SPOT test) during the screening period are eligible for inclusion in this study. Subjects with a positive T-SPOT result during the screening period are required to undergo TB-related clinical evaluation (TB-related clinical evaluations conducted within 12 weeks prior to randomization may be directly utilized for assessment). If the TB-related clinical evaluation confirms active tuberculosis, the subject shall not be enrolled in this study; if the evaluation confirms non-active tuberculosis, the subject may be included. If the study center is unable to perform the T-SPOT test, an interferon-gamma release assay (IGRA) may also be used for TB screening, and the handling of IGRA results should follow the same procedures as for the T-SPOT test.
* History of moderate to severe heart failure (New York Heart Association \[NYHA\] functional classification ≥ Class III), or occurrence of cardiovascular or cerebrovascular events or other serious events within 3 months prior to randomization, as judged by the investigator to be unsuitable for participation in this clinical trial;
* History of malignancy in any organ system within 5 years prior to randomization, except for malignancies with low risk of metastasis and death, such as adequately treated carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin, etc.;
* History of depression and/or suicidal ideation or any suicidal behavior at screening or baseline based on Columbia-Suicide Severity Rating Scale (C-SSRS) assessment (Appendix 6). If the subject answers "Yes" to any question on the C-SSRS questionnaire, or if the investigator assesses clinical risk, these subjects will be excluded;
* Presence of clinically severe, progressive, or uncontrolled diseases during the screening period, including but not limited to the respiratory system, cardiovascular system, endocrine system, hematological system, skeletal system, and nervous system, where participation in the trial may pose unacceptable risk to the subject or interfere with interpretation of data, as assessed by the investigator;
* Use of the following psoriasis (Yinxie Bing) treatments/medications prior to randomization: 1) Within 2 weeks prior to randomization, the subject has received topical treatment for psoriasis, such as glucocorticoids, vitamin D3 derivatives, or retinoids. However, subjects are permitted to use the following topical treatments: non-medicated shampoos and emollients (i.e., those not containing glucocorticoids or vitamin D3 derivatives). Within 4 weeks prior to randomization, the subject has received phototherapy/photochemotherapy (including but not limited to psoralen and ultraviolet A (PUVA) phototherapy, ultraviolet B (UVB)) or non-biologic systemic therapies (including but not limited to systemic glucocorticoids, leflunomide, cyclophosphamide, azathioprine, methotrexate, cyclosporin, retinoids, mycophenolate mofetil, traditional Chinese medicines for the treatment of psoriasis, or other small-molecule targeted agents for the treatment of psoriasis). Tumor necrosis factor-α (TNF-α) antagonists: (1) Use of a TNF-α antagonist (e.g., adalimumab, infliximab, golimumab, etanercept, certolizumab pegol) within a specified period prior to randomization (such as within 12 weeks before randomization); (2) or history of prior use of two or more TNF-α antagonists before randomization; 4) Within 24 weeks prior to randomization, the subject has used other biologic agents, including but not limited to IL-17 inhibitors, IL-23 inhibitors, or IL-12/IL-23 inhibitor class drugs.
* Receipt of a live attenuated vaccine within 12 weeks prior to randomization, or planned receipt of a live attenuated vaccine during the trial period;
* Subjects who previously had poor efficacy with other PDE4 (phosphodiesterase-4) inhibitors (such as apremilast, Hemay005, etc.)
* Participation in and receipt of any interventional clinical trial treatment within 1 month prior to randomization;

• Jianzhong Zhang, Principal investigator, Peking University People's Hospital