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PRIVILEGED & CONFIDENTIAL — ATTORNEY WORK PRODUCT
DRAFT — NOT FOR SUBMISSION
ANNOTATED DRAFT — PROPOSED PRESCRIBING INFORMATION
VELONATIB® (velonatib hydrochloride) tablets, for oral use
NDA No. 215-847 — sNDA (Psoriasis Indication)
Revision 3 — October 15, 2022
Prepared by: Sean Morrissey & Christopher Aiken, Calderwood & Harkness LLP
Reviewed by: Joel Strauss, Calderwood & Harkness LLP; Dr. Karen Hessler, SVP Regulatory Affairs, Penterra Pharmaceuticals Corp.
Matter No.: 1018-00005
Explanatory Note: Annotations appearing in brackets throughout this document (denoted by "[C&H Note:" or similar conventions) reflect Calderwood & Harkness LLP commentary, questions, and open items for Penterra Regulatory Affairs review. These annotations are attorney work product and are not intended for inclusion in any document submitted to the U.S. Food and Drug Administration. All annotations should be resolved and removed prior to finalization of the prescribing information for sNDA submission.
Additional Note: This draft labeling has been prepared in coordination with Callendar Baines Group LLC ("CBG") (regulatory and clinical consultancy) and is subject to review by Whitfield & Grange LLP ("W&G") (patent counsel) for intellectual property implications. Sections 1 and 14, in particular, have been flagged for W&G review in connection with the provisional patent application covering the method-of-treatment for psoriasis.
Distribution: Limited to the following recipients only:
•  Penterra Pharmaceuticals Corp. — Regulatory Affairs (Dr. Karen Hessler, SVP; designated team members)
•  Penterra Pharmaceuticals Corp. — Medical Affairs (Dr. Tomás Becerra, VP — Immunology; designated team members)
•  Penterra Pharmaceuticals Corp. — Legal (Lisa Moritani, Esq., General Counsel; designated team members)
•  Calderwood & Harkness LLP — C&H team (Joel Strauss, Sean Morrissey, Christopher Aiken)
•  Callendar Baines Group LLC — CBG team (Dr. Priya Sundaram, Dr. Neil Oxborough)
•  Whitfield & Grange LLP — W&G (Dr. Eleanor Cassidy, Brian Takata) — Sections 1 and 14 only for patent review purposes
No further distribution, copying, or forwarding of this document is authorized without the express written consent of Calderwood & Harkness LLP and Penterra Pharmaceuticals Corp. Legal Department.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VELONATIB® safely and effectively. See full prescribing information for VELONATIB®.
VELONATIB® (velonatib hydrochloride) tablets, for oral use
Initial U.S. Approval: 2019 (June 14, 2019, NDA 215-847)
RECENT MAJOR CHANGES
[C&H Note: The following recent major changes are to be listed once the sNDA is approved by FDA. Until that time, this section should reflect only changes that have been made within the prior year to the currently approved labeling. Upon sNDA approval, the following entries will be added with the month/year of approval:]
Indications and Usage, Chronic Plaque Psoriasis (1.2) — [Month/Year]
Dosage and Administration (2) — [Month/Year]
Warnings and Precautions, Hepatotoxicity (5.5) — [Month/Year]
WARNING: SERIOUS INFECTIONS, MALIGNANCIES, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS
See full prescribing information for complete boxed warning.
SERIOUS INFECTIONS
Serious infections leading to hospitalization or death, including tuberculosis (TB) and opportunistic infections (bacterial, invasive fungal, viral, and other), have occurred in patients receiving VELONATIB. If a serious infection develops, interrupt VELONATIB until the infection is controlled.
Prior to starting VELONATIB, perform a test for latent tuberculosis; if positive, start treatment for TB prior to initiating VELONATIB. Monitor all patients for active TB during treatment, even if the initial latent TB test is negative. [See Warnings and Precautions (5.1)]
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with VELONATIB. Higher rates of all-cause mortality, including sudden cardiovascular death, have been observed with JAK inhibitors compared to TNF blockers in patients with rheumatoid arthritis. [See Warnings and Precautions (5.2)]
MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)
Higher rate of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke, has been observed with JAK inhibitors compared to TNF blockers in patients with rheumatoid arthritis. [See Warnings and Precautions (5.3)]
THROMBOSIS
Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated with VELONATIB and other JAK inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. Promptly evaluate patients with symptoms of thrombosis and treat appropriately. [See Warnings and Precautions (5.4)]
[C&H Note: The boxed Warning language set forth above conforms to the U.S. Food and Drug Administration's September 2021 class-wide JAK-inhibitor labeling update. No changes to the boxed Warning language are anticipated in connection with the psoriasis sNDA, as the safety concerns addressed in the boxed Warning are class-wide and not indication-specific. This understanding should be confirmed with FDA during the sNDA review cycle. The same boxed Warning applies to both the currently approved RA indication and the proposed psoriasis indication. If FDA requests any modifications to the boxed Warning text in connection with the sNDA, C&H will circulate a revised draft for review.]
FULL PRESCRIBING INFORMATION: TABLE OF CONTENTS
Right-click to update Table of Contents
WARNING: SERIOUS INFECTIONS, MALIGNANCIES, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS
1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis (RA)
1.2 Chronic Plaque Psoriasis [PROPOSED]
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Dosage Modifications
2.3 Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
5.2 Malignancies
5.3 Major Adverse Cardiovascular Events (MACE)
5.4 Thrombosis
5.5 Hepatotoxicity
5.6 Gastrointestinal Perforations
5.7 Laboratory Abnormalities
5.8 Immunosuppression
5.9 Hypersensitivity
5.10 Interstitial Lung Disease
5.11 Embryo-Fetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience (Rheumatoid Arthritis)
6.2 Clinical Trial Experience (Psoriasis) [PROPOSED — NEW SUBSECTION]
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
9 DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Rheumatoid Arthritis
14.2 Chronic Plaque Psoriasis [PROPOSED — NEW SUBSECTION]
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
MEDICATION GUIDE
[C&H Note: Sections containing proposed psoriasis-related changes or new content are: Sections 1, 2, 5, 6, 8, 14, 17, and the Medication Guide. These sections are highlighted throughout this annotated draft. Page references in the Table of Contents will be populated in the final clean version prepared for sNDA submission.]
FULL PRESCRIBING INFORMATION
WARNING: SERIOUS INFECTIONS, MALIGNANCIES, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS
Serious Infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving VELONATIB. The most common serious infections reported with VELONATIB included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, cytomegalovirus, BK virus, and other opportunistic infections have been reported with VELONATIB. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressive agents such as methotrexate or corticosteroids.
Avoid use of VELONATIB in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating VELONATIB in patients:
•  with chronic or recurrent infection;
•  who have been exposed to tuberculosis;
•  with a history of a serious or an opportunistic infection;
•  who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
•  with underlying conditions that may predispose them to infection.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with VELONATIB, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. [See Warnings and Precautions (5.1)]
Malignancies
Lymphoma and other malignancies have been observed in patients treated with VELONATIB. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients comparing another JAK inhibitor to TNF blockers, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. [See Warnings and Precautions (5.2)]
Major Adverse Cardiovascular Events (MACE)
In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue VELONATIB in patients that have experienced a myocardial infarction or stroke. [See Warnings and Precautions (5.3)]
Thrombosis
Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated with VELONATIB and other JAK inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of overall thrombosis, DVT, and PE was observed with the JAK inhibitor. Avoid VELONATIB in patients that may be at increased risk. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately. [See Warnings and Precautions (5.4)]
1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis (RA)
VELONATIB is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
Limitation of Use: Use of VELONATIB in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.
[C&H Note: No changes from the current approved label for Section 1.1. The language set forth above is verbatim from the approved USPI effective as of the most recent labeling supplement (September 2021 class-wide update).]
1.2 Chronic Plaque Psoriasis [PROPOSED]
VELONATIB is indicated for the treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.
[C&H Note — Limitation-of-Use Statement Under Consideration: The team is currently evaluating whether to include a limitation-of-use statement in Section 1.2 reading substantially as follows: "VELONATIB has not been studied in combination with biologic therapies for psoriasis." This issue was raised by FDA during the Type B Pre-sNDA meeting (Meeting ID: FDA-2022-M-1743, held May 4, 2022), at Item 3 of the FDA agenda. FDA noted that no clinical data exist regarding the concomitant use of VELONATIB with biologic agents indicated for psoriasis (e.g., IL-17 inhibitors, IL-23 inhibitors, TNF inhibitors) and suggested that a limitation-of-use statement may be appropriate. The team should discuss this question with Dr. Tomás Becerra (VP Medical Affairs — Immunology) and Dr. Priya Sundaram (CBG) to assess: (a) whether a limitation-of-use statement is warranted from a medical/scientific standpoint; (b) whether such a statement would be commercially disadvantageous by discouraging potential combination use that might otherwise be explored in clinical practice; and (c) whether a limitation-of-use statement can be tailored to be as narrow as possible while addressing FDA's concern. If the team determines that a limitation-of-use statement should be included, C&H will prepare proposed language for internal review. This item is tracked as Open Item #1.]
[C&H Note — Patent Coordination: Whitfield & Grange LLP (Dr. Eleanor Cassidy / Brian Takata) has been asked to review the indication statement language in Section 1.2 for consistency with the claims set forth in the provisional patent application (U.S. Prov. App. No. 63/XXX,XXX, filed August 2022) covering the method-of-treatment for psoriasis. The specific concern is to confirm that the patient population description ("adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy") does not inadvertently narrow the scope of the patent claims or create prosecution history estoppel issues. See email coordination between S. Morrissey (C&H) and B. Takata (W&G) dated October 3, 2022. W&G review is targeted for completion by October 12, 2022. This item is tracked as Open Item #2.]
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of VELONATIB is set forth in the table below based on indication:
Prior to initiating VELONATIB, the following evaluations and testing should be performed:
•  Testing for latent and active tuberculosis [see Warnings and Precautions (5.1)]
•  Complete blood count, including absolute lymphocyte count, absolute neutrophil count, and hemoglobin [see Warnings and Precautions (5.7)]
•  Liver function tests [see Warnings and Precautions (5.5)]
•  Viral hepatitis screening in accordance with clinical guidelines
•  Lipid parameters approximately 12 weeks following initiation of VELONATIB therapy [see Warnings and Precautions (5.7)]
[C&H Note — Psoriasis Dosing Rationale: The recommended dosage for the chronic plaque psoriasis indication is 10 mg orally once daily. This dosing recommendation is based on the dose-ranging data generated in the CLARION-1 Phase II trial (Study PSO-201). CLARION-1 enrolled 287 patients with moderate-to-severe chronic plaque psoriasis and was completed in September 2020. In CLARION-1, the 5 mg dose arm did not meet statistical significance for the primary endpoint of PASI-75 at Week 12. In contrast, the 10 mg dose achieved a PASI-75 response rate of 68.2% at Week 12 compared to 12.4% for placebo (p < 0.001). Based on these results, and following the dose-selection analysis presented at the FDA Type B Pre-sNDA meeting held on May 4, 2022 (Meeting ID: FDA-2022-M-1743), FDA concurred that 10 mg once daily is the appropriate dose to study in the Phase III CLARION program and to propose for the psoriasis indication.]
[C&H Note — Patent Coordination: W&G (Dr. Cassidy / Brian Takata) should confirm that specifying 10 mg once daily as the recommended dosage for psoriasis does not conflict with the method-of-treatment patent claims in the provisional application (U.S. Prov. App. No. 63/XXX,XXX). The provisional application may cover a broader dosing range (e.g., 5 mg to 20 mg), and specifying a single dose in the label should be reviewed for any potential impact on claim interpretation or scope. This item is tracked as Open Item #3.]
2.2 Dosage Modifications
The following table provides the recommended dose modification criteria for VELONATIB based on laboratory abnormalities:
Hepatic Impairment:
•  Mild hepatic impairment (Child-Pugh A): No dosage adjustment required.
•  Moderate hepatic impairment (Child-Pugh B): No dosage adjustment required.
•  Severe hepatic impairment (Child-Pugh C): VELONATIB is not recommended.
Renal Impairment:
•  Mild or moderate renal impairment (estimated creatinine clearance 30–89 mL/min): No dosage adjustment required.
•  Severe renal impairment (estimated creatinine clearance 15–29 mL/min): Reduce dose to 5 mg once daily for the RA indication. [PROPOSED: Reduce dose to 5 mg once daily for the psoriasis indication.]
•  End-stage renal disease on dialysis: VELONATIB is not recommended.
Lymphopenia:
•  If absolute lymphocyte count (ALC) is less than 500 cells/mm³, treatment is not recommended. If ALC falls below 500 cells/mm³ during treatment, interrupt VELONATIB until ALC returns to above this value.
Neutropenia:
•  If absolute neutrophil count (ANC) is less than 1000 cells/mm³, treatment is not recommended. If ANC falls below 1000 cells/mm³ during treatment, interrupt VELONATIB until ANC returns to above this value.
Anemia:
•  If hemoglobin is less than 8 g/dL, treatment is not recommended. If hemoglobin falls below 8 g/dL during treatment, interrupt VELONATIB until hemoglobin returns to above this value.
[C&H Note: The dosage modification criteria set forth above are unchanged from the current approved RA label. C&H recommends confirming with CBG (Dr. Sundaram) and Dr. Hessler whether any psoriasis-specific dose modification guidance is needed based on safety data from the CLARION-2 and CLARION-3 trials. In particular, given the enhanced hepatotoxicity monitoring language proposed in Section 5.5 (reflecting ALT elevations observed in the psoriasis clinical program), the team should consider whether specific hepatic transaminase thresholds triggering dose interruption or discontinuation should be added to this section. If the CLARION protocols included pre-specified dose modification or discontinuation rules for transaminase elevations, those rules should be evaluated for inclusion here.]
2.3 Administration.  VELONATIB tablets should be taken orally once daily, with or without food. Tablets should be swallowed whole. Do not crush, split, or chew the tablets.
[C&H Note: No changes from the current approved label for Section 2.3.]
3 DOSAGE FORMS AND STRENGTHS
VELONATIB is available as film-coated tablets for oral administration in the following strengths:
•  5 mg: White, round, film-coated tablet debossed with "VN" on one side and "5" on the other side.
•  10 mg: Light blue, round, film-coated tablet debossed with "VN" on one side and "10" on the other side.
[C&H Note: No changes from the current approved label for Section 3. The 10 mg tablet is already approved for the RA indication and no formulation changes are anticipated for use in the psoriasis indication. Janet Ling (VP, Quality & CMC, Penterra) should confirm that no formulation, manufacturing, or appearance changes are needed for the 10 mg tablet in connection with the psoriasis indication. If the same tablet is used for both indications (as expected), no CMC supplement is required for Section 3.]
4 CONTRAINDICATIONS
None.
[C&H Note: The current approved label does not list any contraindications for VELONATIB. C&H recommends confirming with Dr. Hessler and CBG whether any psoriasis-specific contraindications should be proposed based on the CLARION program safety data. If no psoriasis-specific contraindications have been identified, this section will remain unchanged. Note that FDA may request addition of contraindications during the sNDA review if safety signals are identified that were not previously characterized.]
5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving VELONATIB. The most common serious infections reported with VELONATIB included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus have been reported. Some patients have presented with disseminated rather than localized disease.
Avoid use of VELONATIB in patients with an active, serious infection, including localized infections. If a serious infection develops during treatment, interrupt VELONATIB until the infection is controlled. Consider the risks and benefits of treatment prior to initiating VELONATIB in patients with chronic or recurrent infection, with a history of a serious or an opportunistic infection, who have been exposed to tuberculosis, who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, or with underlying conditions that may predispose them to infection.
Tuberculosis
Evaluate and test patients for latent or active tuberculosis before and during administration of VELONATIB. Prior to initiating VELONATIB, patients should be tested for latent tuberculosis using a tuberculin skin test or an interferon-gamma release assay. If latent tuberculosis is diagnosed, start treatment for latent tuberculosis prior to initiating VELONATIB. Anti-tuberculosis therapy should also be considered prior to initiation of VELONATIB in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection.
Closely monitor patients for the development of signs and symptoms of tuberculosis during and after treatment with VELONATIB, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was observed in clinical trials with VELONATIB. If a patient develops herpes zoster, interrupt VELONATIB until the episode has resolved.
The impact of VELONATIB on chronic viral hepatitis reactivation is unknown. Patients who are carriers of hepatitis B or hepatitis C should be screened and monitored for hepatitis virus reactivation following current clinical guidelines.
[C&H Note: No changes from the current approved label for Section 5.1. The existing language applies to both the RA and psoriasis indications. Infection rates in the CLARION psoriasis trials will be reported in Section 6.2 (Adverse Reactions — Psoriasis) upon data availability.]
5.2 Malignancies.  Lymphoma and other malignancies have been observed in patients treated with VELONATIB. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.
Consider the risks and benefits of VELONATIB treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing VELONATIB in patients who develop a malignancy. Non-melanoma skin cancers have been reported in patients treated with VELONATIB. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
[C&H Note: No changes from the current approved label for Section 5.2. This language conforms to the September 2021 FDA class-wide JAK-inhibitor labeling update and applies to all approved and proposed indications.]
5.3 Major Adverse Cardiovascular Events (MACE)
In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.
Consider the risks and benefits of VELONATIB treatment prior to initiating or continuing therapy in patients with cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue VELONATIB in patients who have experienced a myocardial infarction or stroke.
[C&H Note: No changes from the current approved label for Section 5.3. This language conforms to the September 2021 FDA class-wide JAK-inhibitor labeling update.]
5.4 Thrombosis.  Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated with VELONATIB and other JAK inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death.
In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers, a higher rate of overall thrombosis, DVT, and PE was observed with the JAK inhibitor.
Avoid VELONATIB in patients that may be at increased risk for thrombosis. If symptoms of thrombosis occur, patients should discontinue VELONATIB and be promptly evaluated and treated appropriately.
[C&H Note: No changes from the current approved label for Section 5.4. Class labeling language per September 2021 FDA update.]
5.5 Hepatotoxicity [ENHANCED FOR PSORIASIS INDICATION]
Treatment with VELONATIB was associated with increases in liver enzymes. In patients with rheumatoid arthritis, treatment with VELONATIB was associated with an increased incidence of liver enzyme elevations compared to placebo. These elevations were generally mild and transient and did not require treatment discontinuation in most cases. Evaluate hepatic enzymes prior to initiating VELONATIB and as clinically indicated thereafter.
[PROPOSED ADDITION — NEW PARAGRAPH:]
In clinical trials of VELONATIB in patients with chronic plaque psoriasis, ALT elevations greater than 3 times the upper limit of normal (> 3× ULN) were observed in [X]% of patients receiving VELONATIB 10 mg (compared to [X]% of patients receiving placebo). Cases of hepatic transaminase elevations were generally asymptomatic and reversible upon treatment interruption or discontinuation. Hepatic transaminases should be evaluated at baseline, after 4 to 8 weeks of initiating therapy, and periodically thereafter in patients treated with VELONATIB for chronic plaque psoriasis. If increases in ALT or AST are observed during routine monitoring and drug-induced liver injury is suspected, interrupt VELONATIB until this diagnosis has been excluded.
[C&H Note — Data Placeholders: The data placeholders denoted as "[X]%" in the paragraph above are to be populated with the integrated safety data from CLARION-2 (Study PSO-301, N=742, completed April 2022) and CLARION-3 (Study PSO-302, N=698) upon availability of the final safety tables. CBG (Dr. Neil Oxborough) has been asked to coordinate the generation of integrated safety data tables in consultation with Penterra biostatistics. This item is tracked as Open Item #4.]
[C&H Note — FDA Guidance: FDA specifically flagged enhanced hepatotoxicity monitoring for the psoriasis label during the Type B Pre-sNDA meeting on May 4, 2022 (Meeting ID: FDA-2022-M-1743). The FDA review team cited JAK-1 class effects and the observed hepatic signal in CLARION-2 interim safety data as the basis for their recommendation. The proposed monitoring frequency (baseline, 4 to 8 weeks, then periodically) was discussed at the meeting and aligns with FDA's verbal guidance. Dr. Hessler should confirm that this monitoring frequency is consistent with the hepatic monitoring schedule implemented in the CLARION-2 and CLARION-3 clinical trial protocols. If the clinical trial protocols specified a different monitoring cadence, the team should consider whether the USPI monitoring recommendation should mirror the protocol or follow a modified schedule considered more practical for real-world clinical practice.]
[C&H Note — Medication Guide Alignment: This enhancement to Section 5.5 will need to be mirrored in the Medication Guide. See Draft Medication Guide Update, Rev. 2, dated October 20, 2022, prepared by Christopher Aiken (C&H). The Medication Guide should include patient-friendly language explaining that liver function tests will be performed before and during treatment, and that patients should report symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fatigue, dark urine, jaundice) to their healthcare provider.]
5.6 Gastrointestinal Perforations
Events of gastrointestinal perforations have been reported in clinical trials with VELONATIB, although the role of JAK inhibition in these events is not known. VELONATIB should be used with caution in patients who may be at increased risk for gastrointestinal perforations (e.g., patients with a history of diverticulitis or taking concomitant NSAIDs or corticosteroids). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
[C&H Note: No changes from the current approved label for Section 5.6.]
5.7 Laboratory Abnormalities
Lipid Elevations
Treatment with VELONATIB was associated with increases in lipid parameters, including total cholesterol, LDL cholesterol, and HDL cholesterol. Assess lipid parameters approximately 12 weeks following initiation of VELONATIB therapy. Manage patients according to clinical guidelines for the management of hyperlipidemia.
Lymphocyte Abnormalities
Treatment with VELONATIB was associated with increases in lymphocyte counts in some patients. Lymphocyte counts should be monitored at baseline and every 3 months thereafter. If confirmed absolute lymphocyte count is below 500 cells/mm³, treatment with VELONATIB should be interrupted until the value has recovered.
Neutropenia
Treatment with VELONATIB was associated with an increased incidence of neutropenia. Neutrophil counts should be monitored at baseline, after 4 to 8 weeks of initiation of therapy, and every 3 months thereafter. If the absolute neutrophil count falls below 1000 cells/mm³, treatment with VELONATIB should be interrupted until the value has recovered.
Anemia
Treatment with VELONATIB was associated with decreases in hemoglobin levels. Hemoglobin should be monitored at baseline, after 4 to 8 weeks of initiation of therapy, and every 3 months thereafter. If hemoglobin falls below 8 g/dL, treatment with VELONATIB should be interrupted until the value has recovered.
[C&H Note: No changes from the current approved label for Section 5.7 at this time. However, psoriasis-specific laboratory abnormality rates (including lipid elevations, lymphocyte counts, neutrophil counts, hemoglobin, and CPK elevations) should be added once the CLARION-3 final data are available and the integrated safety tables have been generated. A placeholder for psoriasis-specific laboratory abnormality data will be included in Section 6.2. CBG and Penterra biostatistics to coordinate.]
5.8 Immunosuppression.  The use of VELONATIB in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. The risk of added immunosuppression when VELONATIB is coadministered with other potent immunosuppressants has not been adequately studied. Immunosuppression may increase the risk of infections and malignancies.
[C&H Note: No changes from the current approved label for Section 5.8.]
5.9 Hypersensitivity.  Hypersensitivity reactions, including angioedema, urticaria, and rash, have been reported in patients receiving VELONATIB. If a serious hypersensitivity reaction occurs, promptly discontinue VELONATIB.
[C&H Note: No changes from the current approved label for Section 5.9.]
5.10 Interstitial Lung Disease
Cases of interstitial lung disease have been reported in patients receiving VELONATIB in clinical trials and in postmarketing experience. If interstitial lung disease is suspected, promptly evaluate and treat appropriately. If the diagnosis is confirmed, consider the risks and benefits of whether to continue or discontinue VELONATIB.
[C&H Note: No changes from the current approved label for Section 5.10.]
5.11 Embryo-Fetal Toxicity
Based on findings from animal reproduction studies, VELONATIB may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of velonatib to pregnant rats and rabbits during organogenesis at exposures that were approximately 15 times (rats) and 7 times (rabbits) the maximum recommended human dose (MRHD) resulted in adverse developmental outcomes, including increased embryo-fetal lethality and structural abnormalities.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to initiating treatment with VELONATIB [see Use in Specific Populations (8.1, 8.3)].
[C&H Note: No changes from the current approved label for Section 5.11. However, the psoriasis population may skew younger and include a higher proportion of women of childbearing potential compared to the RA population. The team should review whether the existing pregnancy-related warnings are sufficiently prominent for the psoriasis population or whether any enhanced language is warranted. This issue should be discussed with Dr. Becerra (VP Medical Affairs — Immunology) and Dr. Hessler (SVP Regulatory Affairs). This item is tracked as Open Item #5.]
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•  Serious Infections [see Warnings and Precautions (5.1)]
•  Malignancies [see Warnings and Precautions (5.2)]
•  Major Adverse Cardiovascular Events [see Warnings and Precautions (5.3)]
•  Thrombosis [see Warnings and Precautions (5.4)]
•  Hepatotoxicity [see Warnings and Precautions (5.5)]
•  Gastrointestinal Perforations [see Warnings and Precautions (5.6)]
•  Laboratory Abnormalities [see Warnings and Precautions (5.7)]
•  Immunosuppression [see Warnings and Precautions (5.8)]
•  Interstitial Lung Disease [see Warnings and Precautions (5.10)]
6.1 Clinical Trial Experience (Rheumatoid Arthritis)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of VELONATIB was evaluated in patients with moderately to severely active rheumatoid arthritis in four randomized, double-blind, controlled, multicenter clinical trials. The data described below reflect exposure to VELONATIB 5 mg once daily in 2,847 patients, including 1,612 patients exposed for at least 6 months and 1,108 patients exposed for at least 12 months.
The most common adverse reactions reported in ≥ 2% of patients treated with VELONATIB 5 mg and at a higher rate than placebo were: upper respiratory tract infections, nasopharyngitis, headache, diarrhea, and herpes zoster.
[C&H Note: The detailed adverse reaction tables and narrative text for the RA clinical trial experience are retained verbatim from the current approved label and are not reproduced in full in this annotated draft for the sake of brevity. The complete text of Section 6.1 will be carried forward without modification in the final prescribing information.]
6.2 Clinical Trial Experience (Psoriasis) [PROPOSED — NEW SUBSECTION]
[C&H Note: This entire subsection is to be populated with adverse reaction data from the CLARION-2 (Study PSO-301) and CLARION-3 (Study PSO-302) clinical trials upon final data availability. CBG (Dr. Neil Oxborough) has been tasked with preparing the integrated safety data summary in coordination with Penterra biostatistics. All data placeholders in this section (denoted by "[DATA PENDING]") must be resolved before the sNDA filing. This item is tracked as Open Item #6.]
The safety of VELONATIB for the treatment of moderate-to-severe chronic plaque psoriasis was evaluated in two randomized, double-blind, controlled, multicenter clinical trials (CLARION-2 and CLARION-3). Across these two trials, a total of [DATA PENDING] patients received VELONATIB 10 mg once daily. The combined safety population included 1,440 patients randomized (742 patients in CLARION-2 and 698 patients in CLARION-3), though the treatment arms are to be broken out upon final data availability. In CLARION-3, patients received VELONATIB 10 mg once daily, adalimumab, or placebo. The data described below reflect exposure to VELONATIB 10 mg once daily for up to 16 weeks.
The most common adverse reactions reported in ≥ 2% of patients treated with VELONATIB 10 mg and at a higher rate than placebo in the psoriasis clinical trials are presented in the following table:
Table: Adverse Reactions Reported in ≥ 2% of Patients Treated with VELONATIB 10 mg and Greater Than Placebo in Psoriasis Clinical Trials (CLARION-2 and CLARION-3)
Clinically Significant Adverse Reactions
Infections: In the CLARION-2 and CLARION-3 clinical trials, [DATA PENDING]% of patients treated with VELONATIB 10 mg experienced infections compared to [DATA PENDING]% of patients treated with placebo. The most commonly reported infections were upper respiratory tract infections and nasopharyngitis. Serious infections were reported in [DATA PENDING]% of patients treated with VELONATIB 10 mg compared to [DATA PENDING]% of patients receiving placebo. Herpes zoster was reported in [DATA PENDING]% of patients treated with VELONATIB 10 mg compared to [DATA PENDING]% of patients receiving placebo [see Warnings and Precautions (5.1)].
Laboratory Abnormalities: In the CLARION-2 and CLARION-3 clinical trials, elevations in ALT and AST were observed in patients receiving VELONATIB 10 mg [see Warnings and Precautions (5.5)]. Elevations in creatine phosphokinase (CPK) were also observed; CPK elevations greater than 5 times the upper limit of normal were reported in [DATA PENDING]% of patients receiving VELONATIB 10 mg compared to [DATA PENDING]% of patients receiving placebo. Changes in lipid parameters (increases in total cholesterol, LDL cholesterol, and HDL cholesterol) were observed in patients treated with VELONATIB, consistent with the lipid changes observed in the RA clinical trials [see Warnings and Precautions (5.7)].
Other Psoriasis-Specific Safety signals: [DATA PENDING — to be added if any additional psoriasis-specific safety signals are identified from the integrated safety data analysis.]
[C&H Note: The adverse reaction table and narrative text above are structured as placeholders and will be populated in full upon receipt of the CLARION-3 final Clinical Study Report and generation of the integrated safety data tables. All brackets marked "[DATA PENDING]" must be resolved prior to sNDA filing. CBG is the primary responsible party for data generation, with support from Penterra biostatistics.]
6.3 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of VELONATIB. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
[C&H Note: No changes from the current approved label for Section 6.3. If any new postmarketing adverse reactions have been identified since the last labeling supplement, they should be added here in accordance with the periodic adverse drug experience report cycle.]
7 DRUG INTERACTIONS
The following drug interactions have been identified for VELONATIB:
Strong CYP3A4 Inhibitors (e.g., ketoconazole): Coadministration of VELONATIB with strong CYP3A4 inhibitors increases velonatib plasma concentrations. If VELONATIB is used in combination with a strong CYP3A4 inhibitor, reduce the dose of VELONATIB to the extent specified in the current approved labeling.
Moderate CYP3A4 Inhibitors (e.g., fluconazole): Coadministration of VELONATIB with moderate CYP3A4 inhibitors may increase velonatib plasma concentrations. Monitor patients for adverse reactions when VELONATIB is coadministered with moderate CYP3A4 inhibitors.
Strong CYP3A4 Inducers (e.g., rifampin): Coadministration of VELONATIB with strong CYP3A4 inducers decreases velonatib plasma concentrations, which may result in reduced therapeutic effect. Avoid coadministration of VELONATIB with strong CYP3A4 inducers.
Immunosuppressive Agents: Use of VELONATIB in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. The risk of added immunosuppression has not been studied [see Warnings and Precautions (5.8)].
[C&H Note: No changes from the current approved label for Section 7. However, C&H recommends confirming with CBG whether any psoriasis-specific concomitant medication interactions require additional language. In particular, the following should be assessed:
(a) Methotrexate in psoriasis: Although the RA label already addresses concomitant use with methotrexate in the context of DMARD therapy, the psoriasis population may use methotrexate at different dose ranges or regimens. Confirm whether additional language is needed.
(b) Cyclosporine: The existing immunosuppressive agents language addresses cyclosporine. Confirm whether the existing language is sufficient for the psoriasis context.
(c) Acitretin: Acitretin is a retinoid commonly used in psoriasis. Confirm whether any PK interaction data exist for velonatib and acitretin.
(d) Phototherapy (UVB): FDA may inquire about the interaction between VELONATIB and ultraviolet B (UVB) phototherapy, as this is a common treatment modality for psoriasis. The team should consider whether to proactively address this in the labeling, or to await FDA comment. No formal drug–phototherapy interaction study has been conducted.
These items do not rise to the level of tracked Open Items but should be addressed by CBG in the ordinary course of label development.]
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy.  Risk Summary
Based on findings from animal studies, VELONATIB may cause fetal harm when administered to a pregnant woman [see Data]. In animal reproduction studies, administration of velonatib to pregnant rats and rabbits during organogenesis at exposures approximately 15 times (rats) and 7 times (rabbits) the maximum recommended human dose (MRHD) resulted in adverse developmental outcomes, including increased embryo-fetal lethality and structural abnormalities [see Data]. There are no adequate and well-controlled studies of VELONATIB in pregnant women. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Clinical Considerations
Advise females of reproductive potential to use effective contraception during treatment with VELONATIB and for at least 4 weeks after the final dose.
Pregnancy Registry: There is a pregnancy registry that monitors pregnancy outcomes in women exposed to VELONATIB during pregnancy. Healthcare providers are encouraged to register patients by calling [pregnancy registry phone number].
[C&H Note: No changes from the current approved label for Section 8.1. Given that the psoriasis population may skew younger and include a higher proportion of women of childbearing potential, the pregnancy registry information should be prominently featured. The team should confirm that the pregnancy registry remains active and that the contact information is current.]
8.2 Lactation.  Risk Summary
There are no data on the presence of velonatib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Velonatib was present in the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants from VELONATIB, advise women not to breastfeed during treatment with VELONATIB and for at least 4 weeks after the final dose.
[C&H Note: No changes from the current approved label for Section 8.2.]
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with VELONATIB.
Contraception
Females: VELONATIB may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with VELONATIB and for at least 4 weeks after the final dose.
Infertility
Based on findings in animals, VELONATIB may impair female fertility. The reversibility of the effect on fertility was not evaluated.
[C&H Note: No changes from the current approved label for Section 8.3.]
8.4 Pediatric Use
The safety and effectiveness of VELONATIB for the treatment of rheumatoid arthritis have not been established in pediatric patients.
Safety and effectiveness of VELONATIB for the treatment of chronic plaque psoriasis have not been established in pediatric patients.
[C&H Note: The second sentence above is a proposed addition for the psoriasis indication. FDA issued a Written Request under the Pediatric Research Equity Act (PREA) for pediatric studies in psoriasis patients ages 12 to 17. Penterra received a deferral from the pediatric study requirement, which was granted on July 28, 2022, providing that pediatric study results must be submitted no later than 18 months after adult psoriasis approval. See the Pediatric Study Deferral Analysis Memorandum dated September 8, 2022, prepared by Sean Morrissey and Christopher Aiken (C&H), for a detailed analysis of the deferral terms and timeline implications. The language in this section should cross-reference the existence of the pediatric deferral requirement but should not commit to a specific timeline for completion of the pediatric studies, as this could create binding expectations. Suggested cross-reference language to be included in the final draft: "Penterra Pharmaceuticals Corp. has received a deferral for the submission of pediatric study results for VELONATIB in psoriasis patients [ages 12 to 17]." This item is tracked as Open Item #7.]
8.5 Geriatric Use
Of the total number of patients in clinical trials of VELONATIB for rheumatoid arthritis, approximately 14% were 65 years of age and older, while approximately 2% were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
[C&H Note: No changes from the current approved label for Section 8.5. The team should review CLARION-2 and CLARION-3 subgroup data for patients aged 65 and older to confirm that no differential efficacy or safety signals were observed in the psoriasis population. If subgroup data indicate any notable differences in the geriatric psoriasis population, additional language may be warranted. CBG should include geriatric subgroup analysis in the integrated safety data summary.]
8.6 Hepatic Impairment
No dosage adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. VELONATIB has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended for use in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
[C&H Note: No changes from the current approved label for Section 8.6. Cross-reference enhanced hepatotoxicity monitoring language in Section 5.5 for the psoriasis indication.]
8.7 Renal Impairment
No dosage adjustment is required in patients with mild or moderate renal impairment (estimated creatinine clearance 30–89 mL/min). In patients with severe renal impairment (estimated creatinine clearance 15–29 mL/min), the recommended dose should be reduced as specified in Section 2.2. VELONATIB has not been studied in patients with end-stage renal disease on dialysis and is not recommended for use in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
[C&H Note: No changes from the current approved label for Section 8.7.]
9 DRUG ABUSE AND DEPENDENCE
VELONATIB is not a controlled substance and has no known potential for abuse or dependence.
[C&H Note: No changes from the current approved label for Section 9.]
10 OVERDOSAGE
There is no specific antidote for overdosage with VELONATIB. In the event of an overdose, the patient should be monitored for signs and symptoms of adverse reactions and appropriate symptomatic treatment should be instituted immediately. Pharmacokinetic data suggest that velonatib is not expected to be efficiently removed by hemodialysis.
Single doses up to 100 mg and multiple doses up to 50 mg once daily for 14 days have been administered in clinical pharmacology studies without dose-limiting toxicities. There is no specific treatment for VELONATIB overdosage. In clinical trials, the highest single dose administered was 100 mg. The adverse reactions observed at the higher doses were consistent with the safety profile of VELONATIB.
[C&H Note: No changes from the current approved label for Section 10.]
11 DESCRIPTION
Velonatib hydrochloride is a selective Janus kinase 1 (JAK-1) inhibitor for oral administration. The chemical name of velonatib hydrochloride is [chemical name per approved label]. The molecular formula is [molecular formula per approved label] and the molecular weight is [molecular weight per approved label]. Velonatib hydrochloride is a white to off-white crystalline powder that is freely soluble in water and sparingly soluble in ethanol.
The structural formula is:
[Structural formula as per approved label — to be reproduced in final clean version]
VELONATIB tablets for oral administration are supplied as film-coated tablets containing velonatib hydrochloride equivalent to 5 mg or 10 mg of velonatib free base. The inactive ingredients are: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and FD&C Blue No. 2 aluminum lake (10 mg tablet only).
[C&H Note: No changes from the current approved label for Section 11. The chemical name, molecular formula, molecular weight, and structural formula will be reproduced verbatim from the approved USPI in the final clean version.]
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Velonatib is a selective inhibitor of Janus kinase 1 (JAK-1). JAK kinases are intracellular enzymes that transduce cytokine-mediated signals through the JAK-STAT pathway, which influences cellular processes of hematopoiesis and immune cell function. Velonatib preferentially inhibits signaling mediated by JAK-1, with functional selectivity over JAK-2, JAK-3, and TYK2 in cellular assays. In vitro, velonatib inhibited the phosphorylation of STAT proteins in response to cytokines that signal through JAK-1-containing receptor complexes, including IL-6, IL-2, IFN-γ, and IL-7.
[C&H Note: The mechanism of action language set forth above is the existing approved text. The team should consider whether to add psoriasis-specific MOA context to this section for the sNDA submission. Potential additions could include a brief description of the role of JAK-1/STAT signaling in psoriatic inflammation, including modulation of the IL-6 and IL-23 pathways relevant to Th17-mediated inflammation in psoriasis. This issue should be discussed with Dr. Tomás Becerra (VP Medical Affairs — Immunology). FDA may request scientific rationale language supporting the use of a JAK-1 selective inhibitor in psoriasis. If additional MOA language is included, it should be concise and supported by published literature or data from the CLARION nonclinical pharmacology program. This item is tracked as Open Item #8.]
12.2 Pharmacodynamics.  In clinical pharmacology studies, administration of velonatib resulted in dose-dependent inhibition of IL-6-induced STAT3 phosphorylation in whole blood. Maximum inhibition of STAT3 phosphorylation was observed at approximately 1 to 2 hours after dosing, which returned to near baseline by 24 hours.
No prolongation of the QTc interval was observed with VELONATIB at plasma concentrations approximately [X]-fold higher than the mean steady-state peak concentration following administration of the maximum recommended dose.
[C&H Note: No changes from the current approved label for Section 12.2.]
12.3 Pharmacokinetics.  Absorption
Following oral administration, velonatib is well absorbed with an absolute bioavailability of approximately [X]%. Peak plasma concentrations (Cmax) are reached within approximately [X] hours after dosing. Administration with a high-fat meal did not have a clinically meaningful effect on the pharmacokinetics of velonatib.
Distribution
The mean apparent volume of distribution at steady state is approximately [X] L. Velonatib is approximately [X]% bound to plasma proteins, primarily to albumin.
Elimination
The mean terminal half-life of velonatib is approximately [X] hours. Velonatib is eliminated primarily through hepatic metabolism, with approximately [X]% of the dose excreted in the urine and approximately [X]% in the feces.
metabolism
Velonatib is metabolized primarily by CYP3A4 with minor contributions from CYP2C9 and CYP2C19. The active metabolite [metabolite designation] has activity against JAK-1 with approximately [X]-fold lower potency than velonatib.
[C&H Note: No changes from the current approved label for Section 12.3. The PK parameter values set forth above use placeholders in brackets and will be populated from the approved USPI in the final clean version. C&H recommends confirming with CBG whether any PK data generated during the CLARION program (e.g., population PK analysis from CLARION-2) should be incorporated into this section. As a general matter, the pharmacokinetic profile of velonatib is not expected to differ between the RA and psoriasis populations at the same dose level. However, FDA may inquire about PK parameters at the 10 mg dose in the psoriasis population, particularly given the higher dose relative to the RA indication. If population PK data from the CLARION program support the conclusion that exposure at 10 mg QD in psoriasis patients is consistent with predictions from the existing PK model, a brief statement to that effect may be appropriate.]
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: In a 2-year carcinogenicity study in rats, velonatib was administered at oral doses of [X], [X], and [X] mg/kg/day. [Description of findings per approved label.]
Mutagenesis: Velonatib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. [Additional mutagenesis study results per approved label.]
Impairment of Fertility: In a fertility study in rats, velonatib was administered at oral doses of [X], [X], and [X] mg/kg/day. [Description of findings per approved label.]
[C&H Note: No changes from the current approved label for Section 13.1. The specific data values and study descriptions will be reproduced verbatim from the approved USPI.]
13.2 Animal Toxicology and/or Pharmacology
In repeat-dose toxicology studies, the target organs of toxicity included the immune system, hematopoietic system, and liver. [Description of findings per approved label.]
[C&H Note: No changes from the current approved label for Section 13.2.]
14 CLINICAL STUDIES
14.1 Rheumatoid Arthritis
The efficacy and safety of VELONATIB were evaluated in four randomized, double-blind, controlled clinical trials in patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to one or more DMARDs.
[C&H Note: The full text of Section 14.1, including study design descriptions, patient demographics, efficacy results tables, and supporting narrative for each of the four RA clinical trials, is retained verbatim from the current approved label and is not reproduced in full in this annotated draft. The complete text will be carried forward without modification in the final prescribing information.]
14.2 Chronic Plaque Psoriasis [PROPOSED — NEW SUBSECTION]
The efficacy and safety of VELONATIB were evaluated in [two] randomized, double-blind, controlled clinical trials (CLARION-2 and CLARION-3) in adult patients with moderate-to-severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy.
[C&H Note: The "[two]" placeholder in the introductory paragraph reflects the current expectation that both CLARION-2 and CLARION-3 will be referenced in the USPI. However, the final number of trials referenced depends on the CLARION-3 top-line results. If CLARION-3 fails to meet both co-primary endpoints, the team will need to reassess whether and how to reference the study in the USPI. In a failure scenario, the section may reference only CLARION-2 and a potential redesigned confirmatory trial (CLARION-3R). This assessment will require a separate strategy memorandum and likely consultation with FDA regarding the acceptability of the clinical evidence package. This item is tracked as Open Item #9.]
CLARION-2 (Study PSO-301).  CLARION-2 was a randomized, double-blind, placebo-controlled, multicenter clinical trial conducted at approximately 95 investigational sites in the United States, Canada, and the European Union. A total of 742 adult patients with moderate-to-severe chronic plaque psoriasis were enrolled. Eligible patients were required to have a body surface area (BSA) involvement of ≥ 10%, a Psoriasis Area and Severity Index (PASI) score of ≥ 12, and a static Physician's Global Assessment (sPGA) score of ≥ 3 (moderate or greater) at baseline. Patients were required to be candidates for systemic therapy or phototherapy.
Patients were randomized 2:1 to receive VELONATIB 10 mg orally once daily (N=494) or matching placebo (N=248) for 16 weeks. The co-primary efficacy endpoints were: (1) the proportion of patients achieving at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI-75) at Week 16, and (2) the proportion of patients achieving a static Physician's Global Assessment (sPGA) score of 0 (clear) or 1 (almost clear) at Week 16. Key secondary endpoints included the proportion of patients achieving PASI-90 at Week 16, the mean change from baseline in the Dermatology Life Quality Index (DLQI) at Week 16, and the proportion of patients achieving PASI-75 at Week 8.
Patient demographics and baseline disease characteristics were generally balanced across treatment groups. The mean age of enrolled patients was approximately 46 years, and approximately 67% were male. The mean baseline PASI score was approximately 19.4 and the mean BSA involvement was approximately 25%.
Both co-primary endpoints were met