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Trial registered on ANZCTR


Registration number
ACTRN12623000417684p
Ethics application status
Submitted, not yet approved
Date submitted
31/03/2023
Date registered
27/04/2023
Date last updated
27/04/2023
Date data sharing statement initially provided
27/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
First-in-Human Study of Oral SDC-1801 in Healthy Adults and Adults with Plaque Psoriasis (Part 4 - Adults with Plaque Psoriasis)
Scientific title
A First-in-human, Phase I, Randomised, 4-part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Food Effects, and Pharmacodynamics of Single Ascending and Multiple Ascending Oral Doses of SDC-1801 in Healthy Adults or Adults with Plaque Psoriasis (Part 4 - Adults with Plaque Psoriasis)
Secondary ID [1] 309359 0
SDC-1801-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Plaque Psoriasis 329562 0
Condition category
Condition code
Inflammatory and Immune System 326491 326491 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 4 of this study will have a randomised, double-blind design, and consist of 2 sequential dose cohorts (Cohorts Psoriasis Dose i and Psoriasis Dose ii). Each cohort will consist of 12 participants with moderate to severe plaque psoriasis.
Cohort Psoriasis Dose i will only start after the Safety Review Committee (SRC) meeting has taken place to review the available safety, tolerability, and pharmacokinetic (PK) data from all previous cohorts, and the members of the SRC have decided that it is appropriate to initiate Part 4 of the study and the doses that should be used. The doses that are selected for Part 4 of the study will have been demonstrated to be well tolerated, and exposure at those doses would not have exceeded that seen at the no-observed-adverse-effect level (NOAEL) (in the most sensitive toxicology species, the dog) in other Parts of the study. Recruitment to Cohort Psoriasis Dose ii may start as soon as recruitment to Cohort Psoriasis Dose i has completed.
The participants in each cohort will be randomised in a 3:1 ratio to multiple doses of SDC-1801 or matching placebo. SDC-1801 or placebo will be administered as an oral capsule/s OD (once daily) or BID (twice daily) for 14 days. On Day 1 and Day14 (to minimise any effect of food on PK assessments), the study drug will be administered after an overnight fast of at least 8 hours and if a BID dose regimen is chosen, the second dose will be administered at approximately 8pm following a 4-hour fast.
To check dosing compliance, while in the Clinical Pharmacology Unit (CPU), participants will have their mouths examined following dosing to determine that the dose has been swallowed. For dosing that occurs outside of the CPU, dosing visits will be conducted as nurse home visits or study staff will telephone participants to remind them to take the dose.
The participants will be confined to the CPU from mid-afternoon or evening of Day -1 to Day 5; then participants will be discharged temporarily from the CPU on Day 5. Participants will return to the CPU daily between Day 6 to Day 12 for study assessments and study drug administration.
Participants will be re-admitted to CPU residence from Day 13 to Day 15, and then will be discharged from CPU residence on Day 15. Participants will return to the CPU daily between Day 16 to Day 19 (approximately 120 hours after the final dose of study drug) for study assessments. A follow-up visit will take place 14 ± 3 days after administration of the final dose of study drug.
Each participant will be in the study for approximately 8 weeks (Screening Visit to Follow-up Visit) and will receive a maximum of 14 or 27 doses of SDC-1801 or placebo.
Intervention code [1] 325789 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules are available to match the 5 mg, 10 mg, and 50 mg dosage strengths of SDC-1801 capsules. The placebo capsules are the same formulation as SDC-1801 capsules, but without SDC-1801 (i.e. they contain only the excipients of SDC-1801 capsules), and are a hydroxypropylmethylcellulose (HPMC) capsule comprising a VCaps® Plus Swedish orange body and cap.
Control group
Placebo

Outcomes
Primary outcome [1] 334335 0
To evaluate the safety and tolerability of 14 days dosing with oral SDC-1801 compared with placebo in participants with plaque psoriasis. Withdrawal information, and the reasons for withdrawal will be collected via the eCRF.
Timepoint [1] 334335 0
Participants in the study will have the following safety assessments conducted from their presentation to the clinic at Screening (up to 28 days prior to dosing) to Day 28 following their first dose.
Primary outcome [2] 334475 0
Primary Outcome 1

Vital Signs:

Body temperature (via typmanic thermometer), pulse rate (via automated device), respiratory rate (via observation), systolic and diastolic blood pressure (via an automated device) and blood oxygen saturation (via pulse oximeter) will be measured at the following timepoints.
Timepoint [2] 334475 0
- Screening
- Day -1
- Day 1: pre-dose, 2h, 4h, 8h, 12h
- Day 2: 24 hours post first dose
- Day 4: 72 hours post first dose
- Day 6: 120 hours post first dose
- Day 7: 144 hours post first dose
- Day 10: 216 hours post first dose
- Day 12: 264 hours post first dose
- Day 14: pre-dose, 2h, 4h, 8h, 12h
- Day 15: 24 hours post Day 14 dose
- Day 17: 72 hours post Day 14 dose
- Day 19: 120 hours post Day 14 dose
- Day 28 post first dosing visit: follow-up visit
Primary outcome [3] 334476 0
Primary Outcome 2

ECG:

ECGs will be recorded via the use of a standard 12 lead ECG machine, with measurements taken in triplicate, at the following time points.
Timepoint [3] 334476 0
- Screening
- Day 1: pre-dose, 1h, 2h, 4h, 6h, 8h and 12h
- Day 2: 24h post-dose
- Day 14: pre-dose, 1h, 2h, 4h, 6h, 8h and 12h
- Day 15: 24h post Day 14 dose
- Day 28 post first dosing visit: follow-up visit
Secondary outcome [1] 420290 0
Primary Outcome 3:

Clinical Laboratory Samples:

Clinical Laboratory samples of blood and urine (for haematology, blood chemistry and urinalysis) will be collected and measured at:
Timepoint [1] 420290 0
- Screening
- Pre-dose (day 1)
- Day 2 (24 hours) post-dose
- Day 6 (120 hours) post-dose
- Day 10 (216 hours) post-dose
- Day 12 (264 hours) post-dose
- Day 15 (24 hours) post-Day 14 dose
- Day 28 (post first dosing visit): follow-up visit
Secondary outcome [2] 420826 0
To evaluate the multiple dose PK of oral SDC-1801 in adults with psoriasis.

The following parameters, where appropriate, will be determined for SDC-1801 and its metabolites by noncompartmental analysis using individual concentration-time profiles in plasma and urine:

• Plasma: Cmax, Tmax, C24, Cav, AUC24, AUC from the time of dosing to time t (AUC0-t), AUC0-8, t½, terminal rate constant, Rac.

• Urine: Ae tau and CL r.
• Dose-standardized parameters (Cmax/dose, C24h/dose or CT/dose, AUC/dose and Ae%).
Timepoint [2] 420826 0
PK samples for SDC-1801 and its metabolites will be taken from participants in Part 4 of the study, at the following timepoints:

- Day 1: pre-dose, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h post-first dose
- Day 2: 24 h post-first dose
- Day 4: 72 h post-first dose
- Day 6: 120h post-first dose
- Day 7: 144h post-first dose
- Day 10: 168h post-first dose
- Day 12: 264h post-first dose
- Day 13: 288h post-first dose
- Day 14: pre-Day 14 dose, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h post Day 14 dose
- Day 15: 24 hours post Day 14 dose
- Day 16: 48 hours post Day 14 dose
- Day 17: 72 hours post Day 14 dose
- Day 18: 96 hours post Day 14 dose
- Day 19: 120 hours post Day 14 dose

Eligibility
Key inclusion criteria
1. Able and willing to comply with the protocol requirements and to sign the ICF as approved by the IEC/IRB, prior to any Screening evaluations.
2. History of plaque psoriasis for at least 6 months prior to the Screening visit.
3. No significant flare in psoriasis for at least 3 months before Screening (information obtained from medical chart, participant's physician, or directly from the participant).
4. Has moderate to severe plaque psoriasis at baseline as defined by a PASI score greater than or equal to 10 and a PGA score greater than or equal to 3 at Screening and Day -1.
5. Body surface area (BSA) covered by plaque psoriasis greater than or equal to 10% at Screening and Day -1.
6. Must be a candidate for phototherapy or for systemic treatment of psoriasis.
7. Must agree to avoid prolonged exposure to the sun and avoid other ultraviolet light sources (e.g. tanning beds) during the study period and for 7 days after the last dose of study drug.
8. Between 18-70 years of age (inclusive) on the date of signing the ICF.
9. BMI of 18-42 kg/m2 (inclusive) and a total body weight >50 kg (110 lb). BMI = weight (in kg)/height (in metres).
10. Negative for SARS-CoV-2 infection on Day -1.
11. Negative screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, methadone, phencyclidine, tricyclic antidepressants) and alcohol at Screening and on Day -1.
12. Male participants with female partners of childbearing potential must be willing to comply with highly effective means of contraception prior to the first dose of study drug, during the clinical study, and for at least 90 days plus 5 half-lives of SDC-1801 after the last dose of study drug.
13. Female participants of childbearing potential must agree to the use a highly effective method of contraception prior to the first dose of study drug, during the clinical study, and for 30 days plus 5 half-lives of SDC-1801 after the last dose of study drug, and to pregnancy testing throughout the study.
14. Female participants of non-childbearing potential must meet at least 1 of the following criteria:
• Achieved postmenopausal status (naturally sterile), defined as cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and a serum FSH concentration within the postmenopausal range.
• Undergone a documented hysterectomy and/or bilateral oophorectomy.
• Have medically confirmed ovarian failure.
15. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
16. No evidence of active or latent or inadequately treated infection with Mycobacterium TB as defined by the following:
• Negative IGRA (the following assays are acceptable: QFT-G test, T-SPOT TB, QFT-GIT) performed during Screening or within 3 months prior to Screening.
AND
• No history of either untreated or inadequately treated latent or active TB infection.
A participant who is currently being treated for either latent or active TB infection is to be excluded.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants are excluded from the study if one or more of the following criteria apply:
1. Evidence of erythrodermic, pustular, or predominantly guttate psoriasis.
2. Currently have drug-induced psoriasis (e.g. a new onset of psoriasis or an exacerbation of psoriasis from beta blockers, calcium channel blockers, antimalarial drugs, or lithium).
3. Planned initiation of, or changes to, concomitant medication that could affect psoriasis (e.g. antimalarial drugs or lithium) are to occur within 2 weeks prior to randomisation and/or during the study.
4. Participant has immune-mediated conditions commonly associated with psoriasis, such as psoriatic arthritis, uveitis, inflammatory bowel disease, that require systemic treatment (including corticosteroids, immunosuppressants, or biologics). Note: Participants with immune-mediated conditions that do not require systemic treatment may be included in the study. Certain therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) may be permitted, but should be discussed with the Medical Monitor prior to determination of participant eligibility.
5. Participant has any clinically significant medical condition, evidence of an unstable clinical condition (e.g. cardiovascular, renal, hepatic, haematologic, gastrointestinal, endocrine, pulmonary, immunologic), or vital signs/physical/laboratory/ECG abnormality that would, in the opinion of the Investigator, put the participant at undue risk or interfere with interpretation of study results.
6. Any of the following abnormalities in clinical laboratory tests at Screening:
• ALT or AST values greater than or equal to 3 fold the ULN.
• Total bilirubin greater than or equal to 2 fold the ULN.
• Haemoglobin level less than 11 g/dL (less than 110g/L).
• White Blood cell less than 3.5 x 109/L (less than 3500/mm3).
• Absolute neutrophil count less than 1.8 x 109/L (less than 1800/mm3).
• Absolute lymphocyte count less than 1.0 x 109/L (less than 1000/mm3).
• Platelet count less than 100 x 109/L (less than 100000/mm3).
• Serum creatinine level above the ULN or an estimated creatinine clearance
Less than or equal to 80 mL/min, using the Cockcroft-Gault formula; if calculated creatinine clearance is less than or equal to 80 mL/min a 24-hour urine collection may be performed to assess renal function.
7. Any psychiatric condition (including recent or active suicidal ideation or behaviour) that meets any of the following criteria:
• Suicidal ideation associated with actual intent and a method or plan in the past year:
“Yes” answers on items 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) (Appendix 3: Psychiatric Rating Scales).
• Previous history of suicidal behaviours in the past 5 years: “Yes” answer (for events that occurred in the past 5 years) to any of the suicidal behaviour items of the C-SSRS.
• Any lifetime history of serious or recurrent suicidal behaviour.
8. Any current major psychiatric disorder that is not covered by Criterion 7.
9. History of deep vein thrombosis or pulmonary embolism.
10. Major surgery within 8 weeks prior to Day -1 or major surgery planned during study.
11. Hospitalised in the 3 months prior to Day -1 for asthma, has ever required intubation for treatment of asthma, currently requires oral corticosteroids for the treatment of asthma, or has required more than one short-term (less than or equal to 2 weeks) course of oral corticosteroids for asthma within 6 months prior to Day -1.
12. Received any live-attenuated vaccine within 4 weeks prior to Day 1 or plans to receive a live-attenuated vaccine during the study and up to 4 weeks or 5 half lives of the study drug (whichever is longer) after the last dose of study drug administration.
13. History of cancer or lymphoproliferative disorder within 5 years prior to Day -1. Participants with successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be excluded.
14. Active bacterial, viral, fungal, mycobacterial or other infection (including atypical mycobacterial disease), or any major episode of infection that required hospitalisation or treatment with parenteral antimicrobials within 12 weeks prior to Day -1, or oral antimicrobials within 4 weeks prior to Day -1.
15. History of chronic or recurrent infectious disease (including but not limited to chronic renal infection, chronic chest infection, recurrent urinary tract infection, fungal infection [with the exception of superficial fungal infection of the nailbed], or infected skin wounds or ulcers) within the last 2 years.
16. History of an infected joint prosthesis or received antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced.
17. Active herpes infection, including herpes simplex 1 and 2 and herpes zoster (demonstrated on physical examination and/or medical history) within 8 weeks prior to Day 1.
18. History of known or suspected congenital or acquired immunodeficiency state or condition that would compromise the participant's immune status in the opinion of the Investigator (e.g. history of splenectomy, primary immunodeficiency).
19. Positive results for HBsAg, antibodies to hepatitis B core antigens (anti-HBc), HCV, or HIV.
20. Any prior treatment with lymphocyte depleting agents/therapies (e.g. alkylating agents [e.g.
cyclophosphamide or chlorambucil], total lymphoid irradiation).
21. Gastrectomy, clinically significant diabetic gastroenteropathy, or any condition possibly affecting oral drug absorption.
22. History of clinically significant drug or alcohol abuse within 1 year prior to Day 1.
23. Herbal supplements and hormone replacement therapy must be discontinued 28 days prior to the first dose of study drug. Limited use of non-prescription medications that are not believed to affect participant safety or the overall results of the study may be permitted on a case-by-case basis following approval by the Sponsor. Occasional paracetamol (maximum dose of 2 g/day and 10 g/2 weeks) is permitted for use at any time during the study.
24. Given >50 mL blood or plasma within 30 days of Screening or >500 mL blood or plasma within 56 days of Screening (during a clinical study or at a blood bank donation).
25. Received systemic JAK inhibitors or participated in any other studies with JAK inhibitors within 3 months prior to first dose of this study drug.
26. Currently receiving a non-biological investigational drug or device or has received one within 4 weeks or 5 of its half-lives (whichever is longer) prior to Day 1.
27. Received any marketed or investigational biological agent within 12 weeks or 5 of its halflives (whichever is longer) prior to Day 1 (except those listed in Exclusion Criterion 28 and 29 that are to be excluded for 6 months).
28. History of lack of response to any therapeutic agent targeting IL-12, IL-17, and/or IL-23 (e.g. ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, risankizumab) at approved doses after at least 12 weeks of therapy, and/or received one of these therapies within 6 months prior to Day 1.
29. Received rituximab or other immune-cell depleting therapy within 6 months prior to Day 1.
30. Current treatment with strong or moderate CYP3A4 inhibitors (such as itraconazole) or has received moderate or strong CYP3A4 inhibitors within 4 weeks prior to Day 1.
31. Used any topical medication that could affect psoriasis (including corticosteroids, retinoids, vitamin D analogues [such as calcipotriol], anthralin [dithranol], tar, JAK inhibitors, or keratolytics) within 2 weeks prior to Day 1. Non-medicated emollients are permitted.
32. Received any narrowband ultraviolet B (UVB) phototherapy (including tanning beds) or excimer laser within 4 weeks prior to Day 1.
33. Psoralens with ultraviolet A light (PUVA) treatment within 4 weeks prior to Day 1.
34. Used any other systemic treatment that could affect psoriasis (including oral, intravenous, intra-articular, intrathecal, intramuscular, or intralesional corticosteroids, oral retinoids, immunosuppressive/immunomodulating medication, methotrexate, cyclosporine, or apremilast) within 4 weeks prior to Day 1. For systemic JAK inhibitors see criterion 25.
35. Investigator or other study site staff who is directly involved in the conduct of the study and their relatives.
36. Pregnant participants or planning to become pregnant during the study.
37. Breastfeeding participants.
38. Use of tobacco (equivalent of smoking 10 or more cigarettes/day) or any other nicotine containing products at Screening.
39. Consumption of grapefruit, grapefruit juice, or citrus fruits (e.g. Seville oranges, pomelos) within 7 days prior to the first dose of study drug and until collection of the final PK blood sample.
40. Require treatment with beta blockers or calcium channel blockers in the 4 weeks prior to the first dose of study drug.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Treatment allocation will be managed by the unblinded site Pharmacy using a randomisation list provided by the Sponsor. At the point of randomisation, participants will be assigned to the next available randomisation number in sequence.

In Part 4 of the study, participants will be randomised to SDC-1801 or matching placebo in a 3:1 ratio.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis
All data collected in this study will be documented using summary tables, figures, and subject data listings.

Absolute values and change from baseline in physical examinations, clinical laboratory
evaluations, vital signs assessments, and ECG parameters will be summarised by visit and by treatment group. The frequency of participants with safety laboratory results outside of normal reference ranges will be tabulated by treatment and visit. Abnormal physical examination findings will be listed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/06/2023
Actual
Date of last participant enrolment
Anticipated
7/05/2024
Actual
Date of last data collection
Anticipated
4/06/2024
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 24445 0
Nucleus Network - Melbourne
Recruitment hospital [2] 24446 0
Nucleus Network Brisbane Clinic - Herston
Recruitment postcode(s) [1] 40026 0
3004 - Melbourne
Recruitment postcode(s) [2] 40027 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 313556 0
Commercial sector/Industry
Name [1] 313556 0
Sareum Limited
Country [1] 313556 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
Pharmaceutical Solutions Australia Pty Ltd
Address
C/O - BDO
Level 11, 1 Margaret Street
Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 315334 0
Commercial sector/Industry
Name [1] 315334 0
Pampisford Pty Ltd
Address [1] 315334 0
Level 17, HWT Tower, 40 City Road, Southbank VIC 3006
Country [1] 315334 0
Australia
Other collaborator category [1] 282605 0
Commercial sector/Industry
Name [1] 282605 0
Pharmaceutical Solutions Australia Pty Ltd
Address [1] 282605 0
C/O - BDO
Level 11, 1 Margaret Street
Sydney NSW 2000
Country [1] 282605 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 312737 0
Alfred Health Ethics Committee
Ethics committee address [1] 312737 0
55 Commercial Road
Melbourne, Vic 3004
Ethics committee country [1] 312737 0
Australia
Date submitted for ethics approval [1] 312737 0
29/03/2023
Approval date [1] 312737 0
Ethics approval number [1] 312737 0

Summary
Brief summary
SDC-1801 is a small molecule tyrosine kinase 2 (TYK2)/janus kinase 1 (JAK1) inhibitor entering clinical development for the treatment of participants with inflammatory diseases such as psoriasis. The nonclinical good laboratory practice (GLP) toxicology and safety pharmacology studies indicate that it is appropriate to cautiously assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SDC-1801 in the context of a well-designed, first-in-human (FIH) study.

It is reasonable to say that the risk of adverse events (AEs) for JAK inhibitors are broadly similar to those for other biological disease modifying antirheumatic drug (bDMARD) classes. However, concealed within this, there are also important differences between JAK inhibitors and bDMARDs. Tofacitinib and baricitinib have AE profile characteristics that distinguish them from the other bDMARD classes, with signals including an increased risk of herpes zoster reactivation, elevation in lipids, and decreases in haemoglobin and lymphocytes (including natural killer cells).

Based on available nonclinical data, SDC-1801 is a potent and selective small molecule TYK2/JAK1 inhibitor currently in development for inflammatory and autoimmune indications, and it has the potential to have an improved safety profile and similar efficacy profile compared with other JAK inhibitors and specific TYK2 inhibitors.

The chosen sample sizes will provide sufficient data to make an initial assessment of the safety, tolerability, and PK of SDC-1801. in both healthy volunteers and participants with plaque psoriasis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125726 0
Dr Sam Francis
Address 125726 0
Nucleus Network
Level 5, Burnet Tower
89 Commercial Road
Melbourne, Victoria, 3004
Country 125726 0
Australia
Phone 125726 0
+61 466 640 801
Fax 125726 0
+61 3 9001 5810
Email 125726 0
[email protected]
Contact person for public queries
Name 125727 0
Tim Mitchell
Address 125727 0
Sareum Ltd
2A Langford Arch
Cambridge CB22 3FX
United Kingdom
Country 125727 0
United Kingdom
Phone 125727 0
+44 1223 497703
Fax 125727 0
Email 125727 0
[email protected]
Contact person for scientific queries
Name 125728 0
John Reader
Address 125728 0
Sareum Ltd
2A Langford Arch
Cambridge CB22 3FX
United Kingdom
Country 125728 0
United Kingdom
Phone 125728 0
+441223497704
Fax 125728 0
Email 125728 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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