1018-00005 · Penterra Pharmaceuticals Corp · Labeling Drafts

draft-medication-guide-psoriasis-rev2.docx DOCUMENT Real Estate

6 / 12 ← → ✕

Contract analysis Extract to table

CALDERWOOD & HARKNESS LLP 1700 K Street NW, Suite 900 Washington, DC 20006

PRIVILEGED & CONFIDENTIAL — ATTORNEY WORK PRODUCT

DRAFT — NOT FOR SUBMISSION

PROPOSED MEDICATION GUIDE — REVISIONS FOR PSORIASIS INDICATION

Drug: VELONATIB® (velonatib hydrochloride) tablets, for oral use

NDA No. 215-847 — sNDA (Psoriasis Indication)

Revision 2 — October 20, 2022

Prepared by: Christopher Aiken, Associate Calderwood & Harkness LLP

Reviewed by: Sean Morrissey, Associate Calderwood & Harkness LLP

Matter No.: 1018-00005

INTRODUCTORY NOTE AND REDLINE CONVENTIONS

This document sets forth only the proposed additions and changes to the existing approved Medication Guide for VELONATIB® (velonatib hydrochloride) tablets, for oral use. The current approved Medication Guide was originally approved on June 14, 2019, in connection with the approval of VELONATIB for the treatment of adults with moderately to severely active rheumatoid arthritis ("RA indication"). The currently approved Medication Guide text is reproduced in its entirety below for context, with all proposed modifications clearly marked.

Redline Conventions. The following conventions are used throughout this document to distinguish proposed changes from existing approved language:

• Deletions from the currently approved Medication Guide are shown as .

• Additions to the Medication Guide in connection with the psoriasis indication are shown as .

• Attorney annotations and comments from Calderwood & Harkness LLP are set forth in bracketed notes (e.g., "[C&H Note: …]") and appear in the text solely for the guidance of Penterra Pharmaceuticals Corp. ("Penterra" or the "Client") and its regulatory and medical affairs teams. All such annotations will be removed from the final version submitted to the U.S. Food and Drug Administration ("FDA").

Incorporation of Rev. 1 Comments. This Rev. 2 incorporates comments received on Rev. 1 (dated September 28, 2022) from the following Penterra reviewers:

• Dr. Karen Hessler, Senior Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. — comments principally addressed the plain-language description of the psoriasis indication for health literacy compliance and the formatting of the dosing table.

• Dr. Tomás Becerra, Vice President, Medical Affairs — Immunology, Penterra Pharmaceuticals Corp. — comments principally addressed the clinical accuracy of the symptom list under the liver problems subsection of the side effects section and confirmed the monitoring interval language.

Parallel Drafting. This draft Medication Guide is being prepared in parallel with Draft USPI Rev. 3 (dated October 15, 2022) and is intended to be fully consistent with the proposed USPI language. Any discrepancies between this Medication Guide draft and the USPI draft should be flagged for resolution prior to submission.

⸻ FORMAL HOLD NOTICE ⸻

THIS DRAFT WAS PLACED ON FORMAL HOLD ON NOVEMBER 22, 2022, FOLLOWING THE CLARION-3 TOP-LINE RESULTS. NO FURTHER REVISIONS WILL BE MADE UNTIL THE ENGAGEMENT IS REACTIVATED BY CLIENT INSTRUCTION UNDER MATTER NO. 1018-00005. SEE END-OF-DOCUMENT NOTATIONS FOR ADDITIONAL DETAIL REGARDING THE BASIS FOR THIS HOLD.

MEDICATION GUIDE — FULL TEXT WITH TRACKED CHANGES

MEDICATION GUIDE

VELONATIB® (vel-ON-a-tib) (velonatib hydrochloride) tablets, for oral use

Pronunciation: vel-ON-a-tib

Read this Medication Guide before you start taking VELONATIB and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about VELONATIB?

VELONATIB may cause serious side effects, including:

[C&H Note: boxed Warning consumer language conforms to FDA's September 2021 class-wide JAK-inhibitor labeling update (see FDA Safety Communication dated September 1, 2021; 86 FR 54168). Language covers serious infections, malignancies, major adverse cardiovascular events (MACE), and thrombosis. No modifications are anticipated for the psoriasis sNDA. To be confirmed with FDA during review. Cross-reference USPI Section 5 and boxed Warning. No changes from the current approved Medication Guide are proposed for this section.]

1. Serious infections. VELONATIB is a medicine that affects your immune system. VELONATIB can lower the ability of your immune system to fight infections. Some people have had serious infections while taking VELONATIB, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have been hospitalized or died from these infections.

• You should not start taking VELONATIB if you have any kind of infection unless your healthcare provider tells you it is okay.

• Your healthcare provider should test you for TB before starting VELONATIB.

• Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with VELONATIB.

2. Lymphoma and other cancers. Lymphoma and other cancers, including skin cancers, have happened in people taking VELONATIB. Tell your healthcare provider if you have ever had any type of cancer.

3. Major adverse cardiovascular events. Major adverse cardiovascular events (sometimes called MACE), including heart attack, stroke, and cardiovascular death, have happened in people taking VELONATIB. This risk may be higher in people who are current or past smokers and people who have had cardiovascular problems.

• Tell your healthcare provider if you are a current or past smoker.

• Tell your healthcare provider if you have had a heart attack, other heart problems, or a stroke.

4. Blood clots. Blood clots in the veins of the legs (deep vein thrombosis, or DVT) or lungs (pulmonary embolism, or PE) can happen in people taking VELONATIB. This may be life-threatening.

• Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.

Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms of a serious side effect:

• Fever, sweating, or chills

• Muscle aches

• Cough

• Shortness of breath

• Blood in your phlegm

• Weight loss

• Warm, red, or painful skin or sores on your body

• Diarrhea or stomach pain

• Burning when you urinate or urinating more often than normal

• Feeling very tired

• New or worsening chest pain

• Sudden weakness or numbness, especially on one side of the body

• Sudden trouble speaking

• Swelling or pain in your leg or arm

• Sudden unexplained shortness of breath

What is VELONATIB?

VELONATIB is a prescription medicine called a Janus kinase (JAK) inhibitor. VELONATIB is used to treat:

•

[C&H Note: The RA indication language is reproduced without change. A new bullet has been added for the psoriasis indication. The plain-language description of the psoriasis indication was drafted to be consistent with proposed USPI Section 1.2 ("Treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy"). Consumer-facing language was reviewed with Penterra Medical Affairs (Dr. Becerra) for clinical accuracy and health literacy standards. Dr. Hessler provided comments in Rev. 1 review requesting that the phrase "who may benefit from" replace the originally proposed phrase "who are candidates for," on the basis that the latter phrasing may not be readily understood by patients with limited health literacy. This revision was adopted in Rev. 2. FDA may provide additional comments on consumer wording during review. The reading level of this section should be verified to comply with FDA Guidance for Industry, "Useful Written Consumer Medication Information" (July 2006) and 21 C.F.R. Part 208.]

It is not known if VELONATIB is safe and effective in children under 18 years of age.

[C&H Note: Pediatric limitation statement remains unchanged. FDA issued a Written Request under the Pediatric Research Equity Act (PREA) for studies in adolescents ages 12–17 with psoriasis. Penterra obtained a deferral of the pediatric studies, which was granted on July 28, 2022, with a deadline of 18 months post-adult approval. If pediatric data become available before approval of the psoriasis sNDA, this section may need to be updated to reflect the results of those studies. This matter should be tracked by Penterra Regulatory Affairs in coordination with Calderwood & Harkness.]

Who should not take VELONATIB?

Do not take VELONATIB if you are allergic to velonatib hydrochloride or any of the ingredients in VELONATIB.

See "What are the ingredients in VELONATIB?" at the end of this Medication Guide for a complete list of ingredients.

[C&H Note: No changes from the current approved Medication Guide are proposed for this section. No new contraindications were identified for the psoriasis population based on the available data from the CLARION-1 (Phase II dose-ranging, N = 324) and CLARION-2 (Phase III pivotal, N = 612) clinical trials. This section will be reassessed upon availability of CLARION-3R data to confirm that no new contraindications have emerged.]

What should I tell my healthcare provider before taking VELONATIB?

Before taking VELONATIB, tell your healthcare provider about all of your medical conditions, including if you:

• have an infection, are being treated for an infection, or have had an infection that keeps coming back.

• have or have had tuberculosis (TB), or have been in close contact with someone who has TB.

• have any liver problems.

• have any kidney problems.

• have ever had any type of cancer.

• have ever had blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism).

• have heart problems, including heart attack, other cardiovascular disease, or risk factors for cardiovascular disease (such as high blood pressure, high cholesterol, diabetes, or smoking).

• are planning to have surgery.

• have recently received or are scheduled to receive a vaccine (immunization). People who take VELONATIB should not receive live vaccines. Ask your healthcare provider if you are not sure what type of vaccine you are receiving.

• are pregnant or plan to become pregnant. VELONATIB may harm your unborn baby. You should use effective birth control (contraception) during treatment with VELONATIB and for at least 4 weeks after your last dose.

• are breastfeeding or plan to breastfeed. It is not known if VELONATIB passes into your breast milk. You and your healthcare provider should decide if you will take VELONATIB or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VELONATIB and other medicines may affect each other and cause side effects. Especially tell your healthcare provider if you take:

• other medicines that affect your immune system, including other JAK inhibitors

• biologic medicines (such as TNF blockers, interleukin inhibitors, or other biologic agents)

• other immunosuppressants (such as azathioprine, cyclosporine, or tacrolimus)

Do not start any new medicines without first talking with your healthcare provider.

[C&H Note: No changes from the current approved Medication Guide are proposed for this section at this time. The existing language regarding biologics and immunosuppressants is broadly applicable across rheumatology and dermatology patient populations. Calderwood & Harkness and Penterra Medical Affairs should discuss whether it would be advisable to add a specific reference to prior psoriasis therapies — for example, phototherapy history or prior biologic use for psoriasis — given that the target psoriasis population will include patients who have cycled through multiple prior therapies. Dr. Becerra has indicated that this may be clinically useful but could add unnecessary complexity to the Medication Guide. This point should also be discussed with the Callendar Baines Group (Penterra's consumer communications consultant) to assess whether additional language would affect health literacy scores for the document. Defer resolution to the post-CLARION-3R reactivation phase.]

How should I take VELONATIB?

• Take VELONATIB exactly as your healthcare provider tells you to take it.

[C&H Note: The psoriasis dose of 10 mg once daily (QD) is based on the Phase II dose-ranging data from the CLARION-1 trial. In CLARION-1, the 5 mg QD dose did not achieve statistical significance for the co-primary endpoint of PASI-75 at Week 12 (5 mg: 28.4% vs. placebo: 18.2%, p = 0.093; 10 mg: 52.7% vs. placebo: 18.2%, p < 0.001). FDA concurred at the Type B Pre-sNDA meeting held on May 4, 2022 (Meeting ID: FDA-2022-M-1743) that 10 mg QD is the appropriate dose for the psoriasis indication. The restructured dosing format (table) replaces the prior single-line dosing statement to accommodate both indications in a clear, patient-friendly format. This format was revised in Rev. 2 at the request of Dr. Hessler to align with the tabular format used in the proposed USPI Dosage and Administration section. Language must remain consistent with the proposed USPI Section 2.]

• Take VELONATIB with or without food.

• Swallow VELONATIB tablets whole. Do not crush, split, or chew the tablets.

• If you miss a dose of VELONATIB, take it as soon as you remember, unless it is less than 12 hours until your next scheduled dose. In that case, skip the missed dose and take your next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.

• If you take too much VELONATIB, call your healthcare provider or go to the nearest hospital emergency room right away.

Your healthcare provider should do blood tests before you start VELONATIB and while you take VELONATIB. Your healthcare provider may change your dose, temporarily stop, or permanently stop your treatment with VELONATIB based on results of your blood tests.

[C&H Note: The proposed enhancement to the laboratory monitoring language in this section is designed to provide a brief cross-reference to the more detailed hepatotoxicity monitoring language proposed under the side effects section (see below). This approach maintains the simplicity of the "How should I take" section while directing psoriasis patients to the relevant monitoring details. Final language will be conformed to the approved USPI upon finalization.]

What should I avoid while taking VELONATIB?

• Avoid receiving live vaccines during treatment with VELONATIB. Talk to your healthcare provider before receiving any vaccines. Some vaccines may not work as well during treatment with VELONATIB.

• Avoid taking VELONATIB together with biologic medicines used to treat rheumatoid arthritis, psoriasis, or other conditions. Using VELONATIB with these medicines may increase your risk of infection.

[C&H Note: No changes from the current approved Medication Guide are proposed for this section. The existing language regarding live vaccines and immunosuppressant combinations is broadly applicable and does not require modification for the psoriasis population.]

What are the possible side effects of VELONATIB?

VELONATIB may cause serious side effects, including:

• Serious infections. See "What is the most important information I should know about VELONATIB?"

• Cancer and immune system problems. See "What is the most important information I should know about VELONATIB?"

• Major adverse cardiovascular events (MACE). See "What is the most important information I should know about VELONATIB?"

• Blood clots (thrombosis). See "What is the most important information I should know about VELONATIB?"

• Tears (perforation) in the stomach or intestines. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits. Some people taking VELONATIB may develop tears in the stomach or intestinal wall. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.

• Changes in certain laboratory results. Your healthcare provider should do blood tests before you start taking VELONATIB and while you take it to check for the following:

• changes in the number of certain blood cells (lymphocytes, neutrophils, and red blood cells). Low blood cell counts may mean you have a higher chance of getting an infection or may mean you have anemia. Your healthcare provider may stop your VELONATIB treatment if certain blood cells drop to a low level.

• changes in cholesterol levels. Your healthcare provider should check your cholesterol levels approximately 12 weeks after you start taking VELONATIB and as needed after that.

• Liver problems.

[C&H Note: Enhanced hepatotoxicity monitoring language mirrors proposed USPI Section 5.5 addition. FDA specifically flagged the need for enhanced hepatotoxicity monitoring language in the psoriasis label at the Type B Pre-sNDA meeting (May 4, 2022), citing JAK-1 class effects and preliminary safety signals observed across the JAK-inhibitor class. Data placeholders for ALT elevation incidence rates (percentage of patients with velonatib versus percentage of patients with placebo) are included in the USPI Section 5.5; however, consistent with FDA practice for Medication Guides, the consumer-facing language does not include specific percentages but instead references the monitoring schedule. Final language will conform to the approved USPI once finalized.]

[C&H Note: The Callendar Baines Group (Dr. Priya Sundaram and Dr. Neil Oxborough) has been requested to coordinate integrated safety data tables from CLARION-2 and CLARION-3 (when available) to support the specific monitoring intervals referenced in this section. The 4-to-8-week post-initiation monitoring recommendation is based on the hepatotoxicity signal observed across the JAK-1 class of drugs and is consistent with preliminary CLARION-2 safety data showing ALT elevations > 3× ULN in 2.1% (velonatib 10 mg) versus 0.5% (placebo) over the first 16 weeks, with the majority of events occurring within the first 8 weeks of treatment. This monitoring interval was refined from "4 to 6 weeks" in Rev. 1 to "4 to 8 weeks" in Rev. 2 following Dr. Becerra's review comment that the broader interval is more consistent with the CLARION-2 data distribution and with proposed USPI Section 5.5.]

The common side effects of VELONATIB include:

• upper respiratory tract infections (common cold, sinus infections)

• nausea

• headache

• elevated cholesterol levels

[C&H Note — PLACEHOLDER: Pending completion of the integrated safety analysis from the CLARION-2 and CLARION-3 datasets, the common side effects list may need to be supplemented with any adverse reactions that occurred at a frequency of ≥ 2% in the psoriasis treatment group (velonatib 10 mg QD) and more frequently than in the placebo group, but that are not already listed for the RA population. Examples of adverse reactions that have been observed at notable frequency in the psoriasis trials but are not currently listed include acne (2.8% velonatib 10 mg vs. 0.7% placebo in CLARION-2), herpes zoster (2.4% velonatib 10 mg vs. 0.3% placebo in CLARION-2), and nasopharyngitis (5.2% velonatib 10 mg vs. 3.9% placebo in CLARION-2). This section is a PLACEHOLDER pending final integrated data. The common side effects section will be populated upon engagement reactivation and CLARION-3R data availability. All proposed additions will be reviewed for consistency with USPI Section 6 (Adverse Reactions).]

These are not all the possible side effects of VELONATIB.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store VELONATIB?

• Store VELONATIB at room temperature between 68°F to 77°F (20°C to 25°C).

• Keep VELONATIB in the original bottle.

• Keep the bottle tightly closed.

• Keep VELONATIB away from moisture and light.

• Safely throw away any medicine that is out of date or no longer needed.

Keep VELONATIB and all medicines out of the reach of children.

[C&H Note: No changes from the current approved Medication Guide are proposed for this section.]

General information about the safe and effective use of VELONATIB

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VELONATIB for a condition for which it was not prescribed. Do not give VELONATIB to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VELONATIB that is written for health professionals.

[C&H Note: No changes from the current approved Medication Guide are proposed for this section.]

What are the ingredients in VELONATIB?

Active ingredient: velonatib hydrochloride

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, iron oxide yellow (5 mg tablets), iron oxide red (10 mg tablets).

[C&H Note: No changes to the formulation are proposed for the psoriasis indication. The same dosage forms (5 mg and 10 mg oral tablets) are used for both the RA and psoriasis indications. The 10 mg tablet prescribed for psoriasis patients is the same as the currently marketed 10 mg tablet that is available (though not the standard dose) for the RA indication. Janet Ling, Vice President, Quality & CMC, Penterra Pharmaceuticals Corp., confirmed via email on September 22, 2022 that no Chemistry, Manufacturing, and Controls (CMC) changes are required for the sNDA. No supplementary inactive ingredient disclosures are necessary.]

Manufactured for: Penterra Pharmaceuticals Corp. 900 Commons Way, Suite 400 Dralvecen, NJ 08807

NDA No. 215-847

Current Medication Guide Revision Date: June 2021

This Medication Guide has been approved by the U.S. Food and Drug Administration.

[C&H Note: The revised date and FDA approval statement will be updated upon sNDA approval. For submission purposes, the draft will carry the proposed revision date as a placeholder. The current approved Medication Guide revision date of June 2021 reflects the most recent update to the Medication Guide in connection with the FDA class-wide JAK-inhibitor labeling update.]

— END OF DRAFT MEDICATION GUIDE UPDATE — REV. 2 —

Date: October 20, 2022

END-OF-DOCUMENT NOTATIONS

Status: DRAFT — ON HOLD as of November 22, 2022

Reason for Hold: The CLARION-3 Phase III confirmatory study failed to meet its co-primary endpoint of PASI-90 at Week 16 (p = 0.174) per top-line results announced by Penterra Pharmaceuticals Corp. on November 17, 2022. The CLARION-3 trial enrolled 687 patients with moderate-to-severe chronic plaque psoriasis randomized 2:1 to velonatib 10 mg QD versus placebo. The co-primary endpoint of PASI-90 at Week 16 did not reach statistical significance, although the co-primary endpoint of PASI-75 at Week 16 was nominally significant (p = 0.003). Under the pre-specified statistical analysis plan, both co-primary endpoints were required to be met for the study to be considered positive. Accordingly, the sNDA filing is not viable on the current data package (CLARION-1 + CLARION-2 + CLARION-3).

Client Decision: Penterra has elected to pursue a redesigned confirmatory study, designated CLARION-3R, with the following modifications from the CLARION-3 protocol:

• Revised primary endpoint: PASI-75 at Week 16 (single primary endpoint, eliminating the co-primary endpoint structure)

• Increased target enrollment: N = 950 (compared to N = 687 in CLARION-3)

• Inclusion of a secondary key endpoint of PASI-90 at Week 16 with hierarchical testing

• Projected first patient enrolled: Q2 2023

• Projected top-line data availability: H2 2024

Anticipated Reactivation of This Engagement: This draft Medication Guide will be reactivated upon availability of CLARION-3R top-line data and receipt of client instruction to resume engagement under Matter No. 1018-00005. Calderwood & Harkness will maintain all work product on file in the interim.

Items Required Upon Reactivation: Upon reactivation, this draft will require the following updates and reviews before it can proceed to submission-ready form:

1. Incorporation of CLARION-3R safety data, including any adverse reactions observed at ≥ 2% and greater than placebo that are not currently listed in the common side effects section;

2. Review against any intervening FDA guidance or regulatory actions affecting JAK-inhibitor class labeling, including any updates to the September 2021 class-wide labeling requirements;

3. Reconciliation with the updated USPI (which will itself require revision to incorporate CLARION-3R data);

4. Re-review by Penterra Regulatory Affairs (Dr. Karen Hessler or designee) and Medical Affairs (Dr. Tomás Becerra or designee);

5. Updated health literacy assessment by Callendar Baines Group;

6. Confirmation from Janet Ling (VP, Quality & CMC) that no CMC changes have occurred in the interim that would affect the ingredients section.

APPENDIX: SUMMARY OF CHANGES FROM REV. 1 TO REV. 2

The following table documents each substantive revision made between Rev. 1 and Rev. 2 of this draft Medication Guide update.

Reviewer Sign-Off Log

CALDERWOOD & HARKNESS LLP PRIVILEGED & CONFIDENTIAL — ATTORNEY WORK PRODUCT Matter No. 1018-00005

Condition	Dose
Rheumatoid arthritis	5 mg by mouth once daily
Chronic plaque psoriasis	10 mg by mouth once daily
Section	Rev. 1 (September 28, 2022)	Rev. 2 (October 20, 2022)	Source of Change
"What is VELONATIB?" — Psoriasis indication language	Initial draft language: "adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy."	Revised to: "adults with moderate-to-severe chronic plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or ultraviolet (UV) light treatment (phototherapy)." Parenthetical explanations added for health literacy.	Dr. Karen Hessler — comment that "candidates for" is clinical jargon not readily understood by lay patients; requested plain-language alternative and parenthetical definitions of "systemic therapy" and "phototherapy."
"How should I take VELONATIB?" — Dosing format	Dosing information for RA and psoriasis presented as sequential bullet points in running text.	Reformatted as a two-row table (Condition / Dose) for clarity and consistency with proposed USPI Dosage and Administration section.	Dr. Karen Hessler — comment requesting alignment with tabular format in proposed USPI Section 2.
"What are the possible side effects?" — Liver problems: symptom list	Symptom list included: "tiredness, loss of appetite, stomach pain, dark urine, or yellowing of your skin or eyes."	Revised to: "unexplained tiredness, loss of appetite, pain in the upper right area of your stomach (abdomen), dark urine, or yellowing of your skin or the whites of your eyes (jaundice)." Added "unexplained" qualifier to tiredness; specified "upper right area" for anatomical precision; added "(abdomen)" and "(jaundice)" parentheticals.	Dr. Tomás Becerra — comment that the symptom descriptions should be more clinically specific to distinguish hepatotoxicity-related symptoms from common complaints; requested parenthetical terms for patient comprehension.
"What are the possible side effects?" — Liver monitoring interval	Monitoring interval specified as "4 to 6 weeks after starting."	Revised to "4 to 8 weeks after starting" to be consistent with proposed USPI Section 5.5 and the distribution of hepatotoxicity events in CLARION-2 data.	Dr. Tomás Becerra — comment that the 4-to-6-week window was narrower than supported by the CLARION-2 data and inconsistent with proposed USPI Section 5.5 language; recommended 4-to-8-week interval.
"What are the possible side effects?" — Common side effects placeholder	No annotation regarding pending CLARION-3 safety data.	Added annotation noting that the common side effects list is a placeholder pending integrated safety analysis from CLARION-2 and CLARION-3 datasets; identified preliminary adverse reactions of interest (acne, herpes zoster, nasopharyngitis).	Calderwood & Harkness — internal decision to add placeholder annotation following client correspondence regarding anticipated CLARION-3 top-line timeline.
Introductory Note	Noted Rev. 1 as initial draft.	Added description of Rev. 1 reviewer comments incorporated (Dr. Hessler and Dr. Becerra); added parallel drafting note referencing USPI Rev. 3 (October 15, 2022).	Calderwood & Harkness — standard practice for multi-revision tracking.
Role	Name	Rev. 1 Review Date	Rev. 2 Review Date	Status
Preparer	Christopher Aiken, Associate, Calderwood & Harkness LLP	September 28, 2022	October 20, 2022	Complete
Reviewer	Sean Morrissey, Associate, Calderwood & Harkness LLP	October 3, 2022	October 24, 2022	Complete
Client Reviewer — Regulatory	Dr. Karen Hessler, SVP Regulatory Affairs, Penterra	October 10, 2022 (Rev. 1 comments received)	Pending — ON HOLD	On Hold
Client Reviewer — Medical Affairs	Dr. Tomás Becerra, VP Medical Affairs — Immunology, Penterra	October 12, 2022 (Rev. 1 comments received)	Pending — ON HOLD	On Hold
Partner Review	Not yet assigned	—	—	Pending Reactivation

CALDERWOOD & HARKNESS LLP 1700 K Street NW, Suite 900 Washington, DC 20006
PRIVILEGED & CONFIDENTIAL — ATTORNEY WORK PRODUCT
DRAFT — NOT FOR SUBMISSION
PROPOSED MEDICATION GUIDE — REVISIONS FOR PSORIASIS INDICATION
Drug: VELONATIB® (velonatib hydrochloride) tablets, for oral use
NDA No. 215-847 — sNDA (Psoriasis Indication)
Revision 2 — October 20, 2022
Prepared by: Christopher Aiken, Associate Calderwood & Harkness LLP
Reviewed by: Sean Morrissey, Associate Calderwood & Harkness LLP
Matter No.: 1018-00005
INTRODUCTORY NOTE AND REDLINE CONVENTIONS
This document sets forth only the proposed additions and changes to the existing approved Medication Guide for VELONATIB® (velonatib hydrochloride) tablets, for oral use. The current approved Medication Guide was originally approved on June 14, 2019, in connection with the approval of VELONATIB for the treatment of adults with moderately to severely active rheumatoid arthritis ("RA indication"). The currently approved Medication Guide text is reproduced in its entirety below for context, with all proposed modifications clearly marked.
Redline Conventions. The following conventions are used throughout this document to distinguish proposed changes from existing approved language:
•  Deletions from the currently approved Medication Guide are shown as .
•  Additions to the Medication Guide in connection with the psoriasis indication are shown as .
•  Attorney annotations and comments from Calderwood & Harkness LLP are set forth in bracketed notes (e.g., "[C&H Note: …]") and appear in the text solely for the guidance of Penterra Pharmaceuticals Corp. ("Penterra" or the "Client") and its regulatory and medical affairs teams. All such annotations will be removed from the final version submitted to the U.S. Food and Drug Administration ("FDA").
Incorporation of Rev. 1 Comments. This Rev. 2 incorporates comments received on Rev. 1 (dated September 28, 2022) from the following Penterra reviewers:
•  Dr. Karen Hessler, Senior Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. — comments principally addressed the plain-language description of the psoriasis indication for health literacy compliance and the formatting of the dosing table.
•  Dr. Tomás Becerra, Vice President, Medical Affairs — Immunology, Penterra Pharmaceuticals Corp. — comments principally addressed the clinical accuracy of the symptom list under the liver problems subsection of the side effects section and confirmed the monitoring interval language.
Parallel Drafting. This draft Medication Guide is being prepared in parallel with Draft USPI Rev. 3 (dated October 15, 2022) and is intended to be fully consistent with the proposed USPI language. Any discrepancies between this Medication Guide draft and the USPI draft should be flagged for resolution prior to submission.
⸻ FORMAL HOLD NOTICE ⸻
THIS DRAFT WAS PLACED ON FORMAL HOLD ON NOVEMBER 22, 2022, FOLLOWING THE CLARION-3 TOP-LINE RESULTS. NO FURTHER REVISIONS WILL BE MADE UNTIL THE ENGAGEMENT IS REACTIVATED BY CLIENT INSTRUCTION UNDER MATTER NO. 1018-00005. SEE END-OF-DOCUMENT NOTATIONS FOR ADDITIONAL DETAIL REGARDING THE BASIS FOR THIS HOLD.
MEDICATION GUIDE — FULL TEXT WITH TRACKED CHANGES
MEDICATION GUIDE
VELONATIB® (vel-ON-a-tib) (velonatib hydrochloride) tablets, for oral use
Pronunciation: vel-ON-a-tib
Read this Medication Guide before you start taking VELONATIB and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about VELONATIB?
VELONATIB may cause serious side effects, including:
[C&H Note: boxed Warning consumer language conforms to FDA's September 2021 class-wide JAK-inhibitor labeling update (see FDA Safety Communication dated September 1, 2021; 86 FR 54168). Language covers serious infections, malignancies, major adverse cardiovascular events (MACE), and thrombosis. No modifications are anticipated for the psoriasis sNDA. To be confirmed with FDA during review. Cross-reference USPI Section 5 and boxed Warning. No changes from the current approved Medication Guide are proposed for this section.]
1. Serious infections. VELONATIB is a medicine that affects your immune system. VELONATIB can lower the ability of your immune system to fight infections. Some people have had serious infections while taking VELONATIB, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have been hospitalized or died from these infections.
•  You should not start taking VELONATIB if you have any kind of infection unless your healthcare provider tells you it is okay.
•  Your healthcare provider should test you for TB before starting VELONATIB.
•  Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with VELONATIB.
2. Lymphoma and other cancers. Lymphoma and other cancers, including skin cancers, have happened in people taking VELONATIB. Tell your healthcare provider if you have ever had any type of cancer.
3. Major adverse cardiovascular events. Major adverse cardiovascular events (sometimes called MACE), including heart attack, stroke, and cardiovascular death, have happened in people taking VELONATIB. This risk may be higher in people who are current or past smokers and people who have had cardiovascular problems.
•  Tell your healthcare provider if you are a current or past smoker.
•  Tell your healthcare provider if you have had a heart attack, other heart problems, or a stroke.
4. Blood clots. Blood clots in the veins of the legs (deep vein thrombosis, or DVT) or lungs (pulmonary embolism, or PE) can happen in people taking VELONATIB. This may be life-threatening.
•  Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.
Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms of a serious side effect:
•  Fever, sweating, or chills
•  Muscle aches
•  Cough
•  Shortness of breath
•  Blood in your phlegm
•  Weight loss
•  Warm, red, or painful skin or sores on your body
•  Diarrhea or stomach pain
•  Burning when you urinate or urinating more often than normal
•  Feeling very tired
•  New or worsening chest pain
•  Sudden weakness or numbness, especially on one side of the body
•  Sudden trouble speaking
•  Swelling or pain in your leg or arm
•  Sudden unexplained shortness of breath
What is VELONATIB?
VELONATIB is a prescription medicine called a Janus kinase (JAK) inhibitor. VELONATIB is used to treat:
•   
[C&H Note: The RA indication language is reproduced without change. A new bullet has been added for the psoriasis indication. The plain-language description of the psoriasis indication was drafted to be consistent with proposed USPI Section 1.2 ("Treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy"). Consumer-facing language was reviewed with Penterra Medical Affairs (Dr. Becerra) for clinical accuracy and health literacy standards. Dr. Hessler provided comments in Rev. 1 review requesting that the phrase "who may benefit from" replace the originally proposed phrase "who are candidates for," on the basis that the latter phrasing may not be readily understood by patients with limited health literacy. This revision was adopted in Rev. 2. FDA may provide additional comments on consumer wording during review. The reading level of this section should be verified to comply with FDA Guidance for Industry, "Useful Written Consumer Medication Information" (July 2006) and 21 C.F.R. Part 208.]
It is not known if VELONATIB is safe and effective in children under 18 years of age.
[C&H Note: Pediatric limitation statement remains unchanged. FDA issued a Written Request under the Pediatric Research Equity Act (PREA) for studies in adolescents ages 12–17 with psoriasis. Penterra obtained a deferral of the pediatric studies, which was granted on July 28, 2022, with a deadline of 18 months post-adult approval. If pediatric data become available before approval of the psoriasis sNDA, this section may need to be updated to reflect the results of those studies. This matter should be tracked by Penterra Regulatory Affairs in coordination with Calderwood & Harkness.]
Who should not take VELONATIB?
Do not take VELONATIB if you are allergic to velonatib hydrochloride or any of the ingredients in VELONATIB.
See "What are the ingredients in VELONATIB?" at the end of this Medication Guide for a complete list of ingredients.
[C&H Note: No changes from the current approved Medication Guide are proposed for this section. No new contraindications were identified for the psoriasis population based on the available data from the CLARION-1 (Phase II dose-ranging, N = 324) and CLARION-2 (Phase III pivotal, N = 612) clinical trials. This section will be reassessed upon availability of CLARION-3R data to confirm that no new contraindications have emerged.]
What should I tell my healthcare provider before taking VELONATIB?
Before taking VELONATIB, tell your healthcare provider about all of your medical conditions, including if you:
•  have an infection, are being treated for an infection, or have had an infection that keeps coming back.
•  have or have had tuberculosis (TB), or have been in close contact with someone who has TB.
•  have any liver problems.
•  have any kidney problems.
•  have ever had any type of cancer.
•  have ever had blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism).
•  have heart problems, including heart attack, other cardiovascular disease, or risk factors for cardiovascular disease (such as high blood pressure, high cholesterol, diabetes, or smoking).
•  are planning to have surgery.
•  have recently received or are scheduled to receive a vaccine (immunization). People who take VELONATIB should not receive live vaccines. Ask your healthcare provider if you are not sure what type of vaccine you are receiving.
•  are pregnant or plan to become pregnant. VELONATIB may harm your unborn baby. You should use effective birth control (contraception) during treatment with VELONATIB and for at least 4 weeks after your last dose.
•  are breastfeeding or plan to breastfeed. It is not known if VELONATIB passes into your breast milk. You and your healthcare provider should decide if you will take VELONATIB or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VELONATIB and other medicines may affect each other and cause side effects. Especially tell your healthcare provider if you take:
•  other medicines that affect your immune system, including other JAK inhibitors
•  biologic medicines (such as TNF blockers, interleukin inhibitors, or other biologic agents)
•  other immunosuppressants (such as azathioprine, cyclosporine, or tacrolimus)
Do not start any new medicines without first talking with your healthcare provider.
[C&H Note: No changes from the current approved Medication Guide are proposed for this section at this time. The existing language regarding biologics and immunosuppressants is broadly applicable across rheumatology and dermatology patient populations. Calderwood & Harkness and Penterra Medical Affairs should discuss whether it would be advisable to add a specific reference to prior psoriasis therapies — for example, phototherapy history or prior biologic use for psoriasis — given that the target psoriasis population will include patients who have cycled through multiple prior therapies. Dr. Becerra has indicated that this may be clinically useful but could add unnecessary complexity to the Medication Guide. This point should also be discussed with the Callendar Baines Group (Penterra's consumer communications consultant) to assess whether additional language would affect health literacy scores for the document. Defer resolution to the post-CLARION-3R reactivation phase.]
How should I take VELONATIB?
•  Take VELONATIB exactly as your healthcare provider tells you to take it.
[C&H Note: The psoriasis dose of 10 mg once daily (QD) is based on the Phase II dose-ranging data from the CLARION-1 trial. In CLARION-1, the 5 mg QD dose did not achieve statistical significance for the co-primary endpoint of PASI-75 at Week 12 (5 mg: 28.4% vs. placebo: 18.2%, p = 0.093; 10 mg: 52.7% vs. placebo: 18.2%, p < 0.001). FDA concurred at the Type B Pre-sNDA meeting held on May 4, 2022 (Meeting ID: FDA-2022-M-1743) that 10 mg QD is the appropriate dose for the psoriasis indication. The restructured dosing format (table) replaces the prior single-line dosing statement to accommodate both indications in a clear, patient-friendly format. This format was revised in Rev. 2 at the request of Dr. Hessler to align with the tabular format used in the proposed USPI Dosage and Administration section. Language must remain consistent with the proposed USPI Section 2.]
•  Take VELONATIB with or without food.
•  Swallow VELONATIB tablets whole. Do not crush, split, or chew the tablets.
•  If you miss a dose of VELONATIB, take it as soon as you remember, unless it is less than 12 hours until your next scheduled dose. In that case, skip the missed dose and take your next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.
•  If you take too much VELONATIB, call your healthcare provider or go to the nearest hospital emergency room right away.
Your healthcare provider should do blood tests before you start VELONATIB and while you take VELONATIB. Your healthcare provider may change your dose, temporarily stop, or permanently stop your treatment with VELONATIB based on results of your blood tests.
[C&H Note: The proposed enhancement to the laboratory monitoring language in this section is designed to provide a brief cross-reference to the more detailed hepatotoxicity monitoring language proposed under the side effects section (see below). This approach maintains the simplicity of the "How should I take" section while directing psoriasis patients to the relevant monitoring details. Final language will be conformed to the approved USPI upon finalization.]
What should I avoid while taking VELONATIB?
•  Avoid receiving live vaccines during treatment with VELONATIB. Talk to your healthcare provider before receiving any vaccines. Some vaccines may not work as well during treatment with VELONATIB.
•  Avoid taking VELONATIB together with biologic medicines used to treat rheumatoid arthritis, psoriasis, or other conditions. Using VELONATIB with these medicines may increase your risk of infection.
[C&H Note: No changes from the current approved Medication Guide are proposed for this section. The existing language regarding live vaccines and immunosuppressant combinations is broadly applicable and does not require modification for the psoriasis population.]
What are the possible side effects of VELONATIB?
VELONATIB may cause serious side effects, including:
•  Serious infections. See "What is the most important information I should know about VELONATIB?"
•  Cancer and immune system problems. See "What is the most important information I should know about VELONATIB?"
•  Major adverse cardiovascular events (MACE). See "What is the most important information I should know about VELONATIB?"
•  Blood clots (thrombosis). See "What is the most important information I should know about VELONATIB?"
•  Tears (perforation) in the stomach or intestines. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits. Some people taking VELONATIB may develop tears in the stomach or intestinal wall. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.
•  Changes in certain laboratory results. Your healthcare provider should do blood tests before you start taking VELONATIB and while you take it to check for the following:
•  changes in the number of certain blood cells (lymphocytes, neutrophils, and red blood cells). Low blood cell counts may mean you have a higher chance of getting an infection or may mean you have anemia. Your healthcare provider may stop your VELONATIB treatment if certain blood cells drop to a low level.
•  changes in cholesterol levels. Your healthcare provider should check your cholesterol levels approximately 12 weeks after you start taking VELONATIB and as needed after that.
•  Liver problems.  
[C&H Note: Enhanced hepatotoxicity monitoring language mirrors proposed USPI Section 5.5 addition. FDA specifically flagged the need for enhanced hepatotoxicity monitoring language in the psoriasis label at the Type B Pre-sNDA meeting (May 4, 2022), citing JAK-1 class effects and preliminary safety signals observed across the JAK-inhibitor class. Data placeholders for ALT elevation incidence rates (percentage of patients with velonatib versus percentage of patients with placebo) are included in the USPI Section 5.5; however, consistent with FDA practice for Medication Guides, the consumer-facing language does not include specific percentages but instead references the monitoring schedule. Final language will conform to the approved USPI once finalized.]
[C&H Note: The Callendar Baines Group (Dr. Priya Sundaram and Dr. Neil Oxborough) has been requested to coordinate integrated safety data tables from CLARION-2 and CLARION-3 (when available) to support the specific monitoring intervals referenced in this section. The 4-to-8-week post-initiation monitoring recommendation is based on the hepatotoxicity signal observed across the JAK-1 class of drugs and is consistent with preliminary CLARION-2 safety data showing ALT elevations > 3× ULN in 2.1% (velonatib 10 mg) versus 0.5% (placebo) over the first 16 weeks, with the majority of events occurring within the first 8 weeks of treatment. This monitoring interval was refined from "4 to 6 weeks" in Rev. 1 to "4 to 8 weeks" in Rev. 2 following Dr. Becerra's review comment that the broader interval is more consistent with the CLARION-2 data distribution and with proposed USPI Section 5.5.]
The common side effects of VELONATIB include:
•  upper respiratory tract infections (common cold, sinus infections)
•  nausea
•  headache
•  elevated cholesterol levels
[C&H Note — PLACEHOLDER: Pending completion of the integrated safety analysis from the CLARION-2 and CLARION-3 datasets, the common side effects list may need to be supplemented with any adverse reactions that occurred at a frequency of ≥ 2% in the psoriasis treatment group (velonatib 10 mg QD) and more frequently than in the placebo group, but that are not already listed for the RA population. Examples of adverse reactions that have been observed at notable frequency in the psoriasis trials but are not currently listed include acne (2.8% velonatib 10 mg vs. 0.7% placebo in CLARION-2), herpes zoster (2.4% velonatib 10 mg vs. 0.3% placebo in CLARION-2), and nasopharyngitis (5.2% velonatib 10 mg vs. 3.9% placebo in CLARION-2). This section is a PLACEHOLDER pending final integrated data. The common side effects section will be populated upon engagement reactivation and CLARION-3R data availability. All proposed additions will be reviewed for consistency with USPI Section 6 (Adverse Reactions).]
These are not all the possible side effects of VELONATIB.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store VELONATIB?
•  Store VELONATIB at room temperature between 68°F to 77°F (20°C to 25°C).
•  Keep VELONATIB in the original bottle.
•  Keep the bottle tightly closed.
•  Keep VELONATIB away from moisture and light.
•  Safely throw away any medicine that is out of date or no longer needed.
Keep VELONATIB and all medicines out of the reach of children.
[C&H Note: No changes from the current approved Medication Guide are proposed for this section.]
General information about the safe and effective use of VELONATIB
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VELONATIB for a condition for which it was not prescribed. Do not give VELONATIB to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VELONATIB that is written for health professionals.
[C&H Note: No changes from the current approved Medication Guide are proposed for this section.]
What are the ingredients in VELONATIB?
Active ingredient: velonatib hydrochloride
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, iron oxide yellow (5 mg tablets), iron oxide red (10 mg tablets).
[C&H Note: No changes to the formulation are proposed for the psoriasis indication. The same dosage forms (5 mg and 10 mg oral tablets) are used for both the RA and psoriasis indications. The 10 mg tablet prescribed for psoriasis patients is the same as the currently marketed 10 mg tablet that is available (though not the standard dose) for the RA indication. Janet Ling, Vice President, Quality & CMC, Penterra Pharmaceuticals Corp., confirmed via email on September 22, 2022 that no Chemistry, Manufacturing, and Controls (CMC) changes are required for the sNDA. No supplementary inactive ingredient disclosures are necessary.]
Manufactured for: Penterra Pharmaceuticals Corp. 900 Commons Way, Suite 400 Dralvecen, NJ 08807
NDA No. 215-847
Current Medication Guide Revision Date: June 2021
This Medication Guide has been approved by the U.S. Food and Drug Administration.
[C&H Note: The revised date and FDA approval statement will be updated upon sNDA approval. For submission purposes, the draft will carry the proposed revision date as a placeholder. The current approved Medication Guide revision date of June 2021 reflects the most recent update to the Medication Guide in connection with the FDA class-wide JAK-inhibitor labeling update.]
— END OF DRAFT MEDICATION GUIDE UPDATE — REV. 2 —
Date: October 20, 2022
END-OF-DOCUMENT NOTATIONS
Status: DRAFT — ON HOLD as of November 22, 2022
Reason for Hold: The CLARION-3 Phase III confirmatory study failed to meet its co-primary endpoint of PASI-90 at Week 16 (p = 0.174) per top-line results announced by Penterra Pharmaceuticals Corp. on November 17, 2022. The CLARION-3 trial enrolled 687 patients with moderate-to-severe chronic plaque psoriasis randomized 2:1 to velonatib 10 mg QD versus placebo. The co-primary endpoint of PASI-90 at Week 16 did not reach statistical significance, although the co-primary endpoint of PASI-75 at Week 16 was nominally significant (p = 0.003). Under the pre-specified statistical analysis plan, both co-primary endpoints were required to be met for the study to be considered positive. Accordingly, the sNDA filing is not viable on the current data package (CLARION-1 + CLARION-2 + CLARION-3).
Client Decision: Penterra has elected to pursue a redesigned confirmatory study, designated CLARION-3R, with the following modifications from the CLARION-3 protocol:
•  Revised primary endpoint: PASI-75 at Week 16 (single primary endpoint, eliminating the co-primary endpoint structure)
•  Increased target enrollment: N = 950 (compared to N = 687 in CLARION-3)
•  Inclusion of a secondary key endpoint of PASI-90 at Week 16 with hierarchical testing
•  Projected first patient enrolled: Q2 2023
•  Projected top-line data availability: H2 2024
Anticipated Reactivation of This Engagement: This draft Medication Guide will be reactivated upon availability of CLARION-3R top-line data and receipt of client instruction to resume engagement under Matter No. 1018-00005. Calderwood & Harkness will maintain all work product on file in the interim.
Items Required Upon Reactivation: Upon reactivation, this draft will require the following updates and reviews before it can proceed to submission-ready form:
1.  Incorporation of CLARION-3R safety data, including any adverse reactions observed at ≥ 2% and greater than placebo that are not currently listed in the common side effects section;
2.  Review against any intervening FDA guidance or regulatory actions affecting JAK-inhibitor class labeling, including any updates to the September 2021 class-wide labeling requirements;
3.  Reconciliation with the updated USPI (which will itself require revision to incorporate CLARION-3R data);
4.  Re-review by Penterra Regulatory Affairs (Dr. Karen Hessler or designee) and Medical Affairs (Dr. Tomás Becerra or designee);
5.  Updated health literacy assessment by Callendar Baines Group;
6.  Confirmation from Janet Ling (VP, Quality & CMC) that no CMC changes have occurred in the interim that would affect the ingredients section.
APPENDIX: SUMMARY OF CHANGES FROM REV. 1 TO REV. 2
The following table documents each substantive revision made between Rev. 1 and Rev. 2 of this draft Medication Guide update.
Reviewer Sign-Off Log
CALDERWOOD & HARKNESS LLP PRIVILEGED & CONFIDENTIAL — ATTORNEY WORK PRODUCT Matter No. 1018-00005
Condition | Dose
Rheumatoid arthritis | 5 mg by mouth once daily
Chronic plaque psoriasis | 10 mg by mouth once daily
Section | Rev. 1 (September 28, 2022) | Rev. 2 (October 20, 2022) | Source of Change
"What is VELONATIB?" — Psoriasis indication language | Initial draft language: "adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy." | Revised to: "adults with moderate-to-severe chronic plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or ultraviolet (UV) light treatment (phototherapy)." Parenthetical explanations added for health literacy. | Dr. Karen Hessler — comment that "candidates for" is clinical jargon not readily understood by lay patients; requested plain-language alternative and parenthetical definitions of "systemic therapy" and "phototherapy."
"How should I take VELONATIB?" — Dosing format | Dosing information for RA and psoriasis presented as sequential bullet points in running text. | Reformatted as a two-row table (Condition / Dose) for clarity and consistency with proposed USPI Dosage and Administration section. | Dr. Karen Hessler — comment requesting alignment with tabular format in proposed USPI Section 2.
"What are the possible side effects?" — Liver problems: symptom list | Symptom list included: "tiredness, loss of appetite, stomach pain, dark urine, or yellowing of your skin or eyes." | Revised to: "unexplained tiredness, loss of appetite, pain in the upper right area of your stomach (abdomen), dark urine, or yellowing of your skin or the whites of your eyes (jaundice)." Added "unexplained" qualifier to tiredness; specified "upper right area" for anatomical precision; added "(abdomen)" and "(jaundice)" parentheticals. | Dr. Tomás Becerra — comment that the symptom descriptions should be more clinically specific to distinguish hepatotoxicity-related symptoms from common complaints; requested parenthetical terms for patient comprehension.
"What are the possible side effects?" — Liver monitoring interval | Monitoring interval specified as "4 to 6 weeks after starting." | Revised to "4 to 8 weeks after starting" to be consistent with proposed USPI Section 5.5 and the distribution of hepatotoxicity events in CLARION-2 data. | Dr. Tomás Becerra — comment that the 4-to-6-week window was narrower than supported by the CLARION-2 data and inconsistent with proposed USPI Section 5.5 language; recommended 4-to-8-week interval.
"What are the possible side effects?" — Common side effects placeholder | No annotation regarding pending CLARION-3 safety data. | Added annotation noting that the common side effects list is a placeholder pending integrated safety analysis from CLARION-2 and CLARION-3 datasets; identified preliminary adverse reactions of interest (acne, herpes zoster, nasopharyngitis). | Calderwood & Harkness — internal decision to add placeholder annotation following client correspondence regarding anticipated CLARION-3 top-line timeline.
Introductory Note | Noted Rev. 1 as initial draft. | Added description of Rev. 1 reviewer comments incorporated (Dr. Hessler and Dr. Becerra); added parallel drafting note referencing USPI Rev. 3 (October 15, 2022). | Calderwood & Harkness — standard practice for multi-revision tracking.
Role | Name | Rev. 1 Review Date | Rev. 2 Review Date | Status
Preparer | Christopher Aiken, Associate, Calderwood & Harkness LLP | September 28, 2022 | October 20, 2022 | Complete
Reviewer | Sean Morrissey, Associate, Calderwood & Harkness LLP | October 3, 2022 | October 24, 2022 | Complete
Client Reviewer — Regulatory | Dr. Karen Hessler, SVP Regulatory Affairs, Penterra | October 10, 2022 (Rev. 1 comments received) | Pending — ON HOLD | On Hold
Client Reviewer — Medical Affairs | Dr. Tomás Becerra, VP Medical Affairs — Immunology, Penterra | October 12, 2022 (Rev. 1 comments received) | Pending — ON HOLD | On Hold
Partner Review | Not yet assigned | — | — | Pending Reactivation

CALDERWOOD & HARKNESS LLP 1700 K Street NW, Suite 900 Washington, DC 20006

INTRODUCTORY NOTE AND REDLINE CONVENTIONS

MEDICATION GUIDE

END-OF-DOCUMENT NOTATIONS

APPENDIX: SUMMARY OF CHANGES FROM REV. 1 TO REV. 2

Record

Parties

Dates

Amounts