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PHARMACOVIGILANCE AGREEMENT

Relating to Compound PPC-4187 (Penteracitinib)

by and between

PENTERRA PHARMACEUTICALS CORP.

and

MERIDIAN BIO THERAPEUTICS LIMITED

Executed: October 2, 2023

Effective Date: October 20, 2023

CONFIDENTIAL TREATMENT REQUESTED — This document and the information contained herein are confidential and proprietary. Unauthorized reproduction, distribution, or disclosure is strictly prohibited.

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RECITALS

WHEREAS, Penterra Pharmaceuticals Corp., a corporation organized and existing under the laws of the State of Delaware, United States of America, with its principal place of business and headquarters located at 400 Pharma Drive, Suite 800, Princeton, New Jersey 08540 ("Penterra" or "Licensor"), and Meridian Bio Therapeutics Limited, a limited company organized and existing under the laws of the Hong Kong Special Administrative Region of the People's Republic of China (Company Registration No. 2847631), with its principal place of business and headquarters located at 18/F, Blossom Tower, 88 Queen's Road Central, Hong Kong SAR ("Meridian" or "Licensee"), have entered into that certain Exclusive License Agreement dated October 2, 2023 (the "License Agreement") relating to the development, manufacture, and commercialization of the proprietary small-molecule compound designated PPC-4187 (proposed International Nonproprietary Name: Penteracitinib), a selective Janus kinase 1 (JAK1) inhibitor for the treatment of moderate-to-severe atopic dermatitis and such other indications as may be approved under the License Agreement;

WHEREAS, under the License Agreement, Penterra has granted to Meridian an exclusive license to develop and commercialize PPC-4187 in the Licensed Territory (as defined in Schedule D to the License Agreement), comprising the People's Republic of China (including Hong Kong Special Administrative Region and Macau Special Administrative Region), Japan, the Republic of Korea, Australia, New Zealand, Singapore, Thailand, Malaysia, Indonesia, the Philippines, Vietnam, and Taiwan (collectively, the "Territory");

WHEREAS, Penterra retains all rights to PPC-4187 outside the Territory, including without limitation in the United States, Canada, the European Union and European Economic Area, the United Kingdom, Latin America, the Middle East, Africa, and all other countries and jurisdictions not included in the Territory (the "Retained Territory");

WHEREAS, PPC-4187 has completed Phase IIb clinical development under Penterra-sponsored Study PPC-4187-201 (a randomized, double-blind, placebo-controlled, dose-ranging study enrolling 420 patients with moderate-to-severe atopic dermatitis, with topline results announced in June 2023 demonstrating statistically significant improvements in EASI-75 response rates at the 50 mg daily dose), and PPC-4187 will be entering Phase III clinical development in both the Territory and in Penterra's Retained Territory in accordance with the Development Plan set forth in Schedule E to the License Agreement;

WHEREAS, the Parties recognize that the safe and effective development and commercialization of PPC-4187 on a global basis requires the establishment of clear, comprehensive, and robust procedures for the exchange of safety information, adverse event reporting, signal detection, periodic safety reporting, and risk management in accordance with all applicable laws, regulations, and guidelines promulgated by relevant regulatory authorities worldwide, including the guidelines established by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), including without limitation ICH E2A, ICH E2B(R3), ICH E2C(R2), ICH E2D, and ICH E2E;

WHEREAS, the paramount objective of this Agreement is the protection of patient safety through the timely, complete, and accurate collection, assessment, exchange, and reporting of safety information concerning PPC-4187, regardless of the source of such information, the jurisdiction in which the relevant event occurs, or the party with primary regulatory responsibility for such jurisdiction; and

WHEREAS, this Agreement is entered into pursuant to Section 8.6 of the License Agreement, which requires the Parties to execute a pharmacovigilance agreement or safety data exchange agreement within thirty (30) days of the Effective Date of the License Agreement, governing the exchange of safety information between the Parties in connection with PPC-4187;

NOW, THEREFORE, in consideration of the mutual covenants and agreements set forth herein, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties agree as follows:

ARTICLE 1 — DEFINITIONS

Capitalized terms used in this Agreement and not otherwise defined herein shall have the meanings ascribed to them in the License Agreement. The following terms shall have the meanings set forth below for purposes of this Agreement:

1.1 "Adverse Drug Reaction" or "ADR" means any noxious, unintended response to PPC-4187 at any dose used for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function, consistent with the definition set forth in ICH E2A. For pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose shall be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between PPC-4187 and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.

1.2 "Adverse Event" or "AE" means any untoward medical occurrence in a patient or clinical investigation subject administered PPC-4187, which does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of PPC-4187, whether or not considered related to the medicinal product, consistent with the definition set forth in ICH E2A.

1.3 "Affiliate" shall have the meaning ascribed to such term in Section 1.2 of the License Agreement. For the avoidance of doubt, Meridian's Affiliates include, without limitation: (a) Meridian Pharma (Shanghai) Co., Ltd., a wholly foreign-owned enterprise organized under the laws of the People's Republic of China ("Meridian Shanghai"); (b) Meridian Japan K.K., a kabushiki kaisha organized under the laws of Japan with its registered office in Tokyo ("Meridian Japan"); (c) Meridian Korea Inc., a corporation organized under the laws of the Republic of Korea with its registered office in Seoul ("Meridian Korea"); (d) Meridian Bio Australia Pty Ltd, a proprietary company limited by shares organized under the laws of the Commonwealth of Australia with its registered office in Sydney ("Meridian Australia"); and (e) any other subsidiary, controlled entity, or Affiliate established by Meridian from time to time in accordance with the License Agreement.

1.4 "Applicable Laws" means all laws, statutes, regulations, rules, orders, decrees, ordinances, guidance documents, and guidelines of any Regulatory Authority that are applicable to the safety reporting and pharmacovigilance obligations under this Agreement, as in effect from time to time, including without limitation: (a) in the United States, the regulations of the U.S. Food and Drug Administration ("FDA") at 21 C.F.R. Parts 312 (Investigational New Drug Application) and 314 (Applications for FDA Approval to Market a New Drug), and FDA guidances relating to safety reporting; (b) in the People's Republic of China, the regulations, rules, and guidelines of the National Medical Products Administration ("NMPA"), including the Provisions for Adverse Drug Reaction Monitoring and Reporting and the Drug Administration Law; (c) in Japan, the regulations and guidelines of the Pharmaceuticals and Medical Devices Agency ("PMDA") and the Ministry of Health, Labour and Welfare, including the Pharmaceutical and Medical Device Act (PMD Act) and applicable PMDA notifications; (d) in the Republic of Korea, the regulations and guidelines of the Ministry of Food and Drug Safety ("MFDS"); (e) in Australia, the regulations and guidelines of the Therapeutic Goods Administration ("TGA"), including the Therapeutic Goods Act 1989; (f) in the remaining Territory countries and jurisdictions, the applicable regulations of the respective national regulatory authorities, including those governing ASEAN pharmaceutical regulatory harmonization; and (g) all ICH guidelines as adopted or referenced by any of the foregoing Regulatory Authorities.

1.5 "Compound" or "Licensed Product" means PPC-4187 (Penteracitinib), a selective JAK1 inhibitor, in its currently developed 25 mg and 50 mg film-coated tablet formulations, or any other formulation, dosage form, or dosage strength of PPC-4187 that may be developed by or on behalf of either Party under the License Agreement.

1.6 "CIOMS Form" means the Council for International Organizations of Medical Sciences form (CIOMS I form) used for the reporting and exchange of Individual Case Safety Reports, or any successor form adopted by CIOMS for such purpose.

1.7 "Day" means a calendar day, unless explicitly stated otherwise in this Agreement. References to "business days" mean days on which commercial banks are open for general business in both New York, New York, United States, and Hong Kong SAR.

1.8 "Effective Date" means October 20, 2023, which is the Effective Date of the License Agreement as defined therein.

1.9 "Expedited Report" means any safety report that is required by Applicable Laws or by the terms of this Agreement to be submitted to a Regulatory Authority or exchanged between the Parties within a regulatory timeline that is shorter than the timeline applicable to periodic safety reporting, including without limitation reports of SUSARs, fatal or life-threatening SAEs, and other events subject to accelerated reporting requirements under the laws or regulations of any relevant jurisdiction.

1.10 "Global Safety Database" or "GSD" means the single, centralized pharmacovigilance database for PPC-4187 maintained by Penterra in its capacity as Database Holder, which database contains all Individual Case Safety Reports and other safety data relating to PPC-4187 from all sources worldwide, including data from clinical trials, post-marketing surveillance, spontaneous reports, and literature.

1.11 "ICH" means the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (formerly the International Conference on Harmonisation), including all current and future guidelines, guidances, and technical requirements adopted by ICH.

1.12 "Individual Case Safety Report" or "ICSR" means a report of an individual adverse event or adverse drug reaction associated with PPC-4187, formatted and transmitted in accordance with ICH E2B(R3) (the ICH guideline on electronic transmission of individual case safety reports) and containing, at a minimum, the four elements of a valid case: an identifiable reporter, an identifiable patient, at least one suspected adverse reaction, and identification of the suspect product.

1.13 "License Agreement" means the Exclusive License Agreement by and between Penterra Pharmaceuticals Corp. and Meridian Bio Therapeutics Limited, dated October 2, 2023, and effective as of October 20, 2023, as such agreement may be amended, supplemented, or otherwise modified from time to time in accordance with its terms.

1.14 "PSUR" means a Periodic Safety Update Report, prepared in accordance with ICH E2C(R2), providing an update of the worldwide safety experience of PPC-4187 at defined time points during the post-authorization period.

1.15 "PBRER" means a Periodic Benefit-Risk Evaluation Report, prepared in accordance with ICH E2C(R2), which represents the current format and content recommended by ICH for periodic reporting of safety data and benefit-risk assessment, and which, for the purposes of this Agreement, shall be deemed to include PSURs to the extent that specific Regulatory Authorities continue to require PSURs by that designation.

1.16 "Reference Safety Information" or "RSI" means the safety information contained in the applicable reference document used by the Parties to determine the expectedness of an adverse drug reaction for the purpose of SUSAR classification. During the clinical development phase, the RSI shall be the safety information section of the current Investigator's Brochure for PPC-4187 maintained by Penterra. Following the first marketing authorization for PPC-4187 in any jurisdiction, the RSI shall be the Company Core Safety Information (CCSI) contained in the Company Core Data Sheet (CDS) maintained by Penterra.

1.17 "Regulatory Authority" means any national, supra-national, regional, state, or local governmental or regulatory authority, department, bureau, commission, council, agency, court, or other instrumentality responsible for the regulation, approval, or oversight of pharmaceutical or biopharmaceutical products in any jurisdiction, including without limitation: (a) the FDA in the United States; (b) the NMPA in the People's Republic of China; (c) the PMDA in Japan; (d) the MFDS in the Republic of Korea; (e) the TGA in Australia; (f) Medsafe in New Zealand; (g) the Health Sciences Authority (HSA) in Singapore; (h) the Thai FDA in Thailand; (i) the National Pharmaceutical Regulatory Agency (NPRA) in Malaysia; (j) BPOM in Indonesia; (k) the Philippine FDA in the Philippines; (l) the Drug Administration of Vietnam (DAV) in Vietnam; and (m) the Taiwan Food and Drug Administration (TFDA) in Taiwan.

1.18 "Retained Territory" means all countries, territories, and jurisdictions worldwide that are not included in the Licensed Territory as defined in Schedule D to the License Agreement, including without limitation the United States, Canada, the European Union and the European Economic Area, the United Kingdom, all countries in Latin America, the Middle East, and Africa, and all other countries and jurisdictions not expressly listed in the definition of Territory.

1.19 "Safety Data Exchange Agreement" or "SDEA" means this Pharmacovigilance Agreement, including all Annexes hereto, as may be amended from time to time in accordance with Article 22.2.

1.20 "Serious Adverse Event" or "SAE" means any adverse event that, at any dose: (a) results in death; (b) is life-threatening (i.e., the patient was at risk of death at the time of the event; this does not refer to an event that hypothetically might have caused death if it were more severe); (c) requires inpatient hospitalization or prolongation of existing hospitalization; (d) results in persistent or significant disability or incapacity; (e) is a congenital anomaly or birth defect; or (f) is an important medical event that, based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. This definition is consistent with ICH E2A.

1.21 "Signal" means information arising from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention (including PPC-4187) and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action, consistent with the definition adopted by the Council for International Organizations of Medical Sciences (CIOMS) Working Group VIII.

1.22 "Sublicensee" means any Third Party to whom Meridian grants a sublicense under and in accordance with the terms and conditions of the License Agreement for the development, manufacture, or commercialization of PPC-4187 in all or any part of the Territory.

1.23 "SUSAR" means a Suspected Unexpected Serious Adverse Reaction, being a serious adverse drug reaction, the nature, severity, specificity, or outcome of which is not consistent with the applicable Reference Safety Information.

1.24 "Territory" means the Licensed Territory as defined in Schedule D to the License Agreement, consisting of the following countries and jurisdictions: (a) the People's Republic of China (including Hong Kong Special Administrative Region and Macau Special Administrative Region); (b) Japan; (c) the Republic of Korea; (d) Australia; (e) New Zealand; (f) Singapore; (g) Thailand; (h) Malaysia; (i) Indonesia; (j) the Philippines; (k) Vietnam; and (l) Taiwan.

1.25 All other capitalized terms used but not defined in this Agreement shall have the meanings ascribed to them in the License Agreement, which definitions are hereby incorporated by reference into this Agreement.

ARTICLE 2 — SCOPE AND PURPOSE

2.1 Scope. This Agreement governs the exchange of safety information between Penterra and Meridian (and their respective Affiliates, agents, contractors, and Sublicensees) relating to PPC-4187 (Penteracitinib) in all jurisdictions worldwide, including both the Territory and the Retained Territory. The obligations set forth in this Agreement apply to safety information arising from any and all sources, including clinical trials, post-marketing surveillance, spontaneous reports from healthcare professionals, patients, and consumers, safety data derived from scientific and medical literature, and any other source of safety information relating to PPC-4187. The scope of this Agreement extends to all activities conducted by or on behalf of either Party, its Affiliates, or its Sublicensees in connection with PPC-4187, regardless of the stage of development or commercialization.

2.2 Purpose. The purpose of this Agreement is to establish the procedures, responsibilities, and timelines necessary to ensure: (a) the timely and complete exchange of all safety data relating to PPC-4187 between the Parties; (b) compliance by each Party with all Applicable Laws and ICH guidelines governing the reporting and management of safety information in all jurisdictions in which PPC-4187 is being developed, marketed, or otherwise made available; (c) coordinated signal detection, signal evaluation, and benefit-risk assessment on a global basis; (d) the maintenance of a single, comprehensive Global Safety Database containing all safety data for PPC-4187 from all sources and jurisdictions worldwide; and (e) the overarching protection of the safety and welfare of patients and clinical trial subjects who receive PPC-4187.

2.3 Product Scope. This Agreement applies to all formulations, dosage forms, and dosage strengths of PPC-4187 (Penteracitinib), including the currently developed 25 mg and 50 mg film-coated tablet formulations, and any additional formulation, dosage form, or dosage strength that may be developed by or on behalf of either Party or its Affiliates or Sublicensees under the License Agreement during the term of this Agreement. In the event that either Party develops a new formulation or dosage strength of PPC-4187, the Parties shall promptly amend this Agreement or its Annexes as necessary to address any additional pharmacovigilance considerations arising from such new formulation or dosage strength.

2.4 Activities Covered. The pharmacovigilance activities and safety data exchange procedures set forth in this Agreement cover and apply to all of the following:

(a) clinical trials of PPC-4187, including Phase III clinical trials to be conducted in the Territory in accordance with the Development Plan set forth in Schedule E to the License Agreement, Phase III and any other clinical trials conducted by Penterra in the Retained Territory, and any other interventional or non-interventional studies involving PPC-4187;

(b) post-marketing surveillance activities, including spontaneous adverse event reporting, post-marketing observational studies, patient registries, and Phase IV clinical trials;

(c) safety reports derived from scientific and medical literature, whether published in English or in any other language;

(d) safety reports received from healthcare professionals, patients, caregivers, consumers, and any other reporters, regardless of the channel of receipt;

(e) safety information arising from special situations, including but not limited to pregnancy and lactation exposure, overdose, lack of efficacy or therapeutic failure, medication errors, misuse, abuse, off-label use, occupational exposure, and drug interactions; and

(f) any other source of safety data relating to PPC-4187 as may be identified from time to time.

2.5 Relationship to License Agreement. This Agreement is entered into pursuant to and supplementary to the License Agreement. In the event of any conflict or inconsistency between the terms and conditions of this Agreement and the terms and conditions of the License Agreement, the License Agreement shall prevail and control; provided, however, that with respect to pharmacovigilance-specific operational procedures expressly set forth in this Agreement (including the timelines for safety data exchange specified in Article 5, the roles and responsibilities specified in Articles 3 and 6, and the JSRC procedures specified in Article 9), the terms of this Agreement shall govern and control to the extent such terms address matters not specifically addressed in the License Agreement or provide more detailed or specific operational procedures than those set forth in the License Agreement.

ARTICLE 3 — ROLES AND RESPONSIBILITIES

3.1 Penterra (Licensor) Responsibilities. Penterra shall have the following pharmacovigilance roles and responsibilities under this Agreement:

3.1.1 Penterra shall maintain and host the Global Safety Database (GSD) for PPC-4187 at Penterra's pharmacovigilance facilities in Princeton, New Jersey, or at such other validated location as Penterra may designate from time to time. Penterra shall ensure that the GSD is maintained in a validated, regulatory-compliant pharmacovigilance database system in accordance with Article 4, and shall bear responsibility for the operational integrity, security, and availability of the GSD throughout the term of this Agreement.

3.1.2 Penterra shall serve as the global Database Holder for PPC-4187, with overall responsibility for the integrity, completeness, accuracy, and reconciliation of all safety data contained in the GSD, and for the archival and retention of safety records in accordance with Article 4.6 and all Applicable Laws.

3.1.3 Penterra shall be responsible for preparing and submitting all regulatory safety reports, including Individual Case Safety Reports (ICSRs), Expedited Reports, and periodic safety reports, to Regulatory Authorities in the Retained Territory, including the U.S. Food and Drug Administration and all other Regulatory Authorities having jurisdiction over PPC-4187 in countries and jurisdictions outside the Territory.

3.1.4 Penterra shall be responsible for preparing global Periodic Safety Update Reports (PSURs) and Periodic Benefit-Risk Evaluation Reports (PBRERs) for PPC-4187 in accordance with ICH E2C(R2) and shall share drafts of such reports with Meridian for review and the provision of Territory-specific input, in accordance with Article 7.

3.1.5 Penterra shall maintain and update the Reference Safety Information for PPC-4187, including the safety information section of the Investigator's Brochure during the clinical development phase and the Company Core Data Sheet (CDS) and Company Core Safety Information (CCSI) following the first marketing authorization for PPC-4187 in any jurisdiction. Penterra shall promptly provide Meridian with updated versions of the RSI upon each revision.

3.1.6 Penterra shall lead global signal detection and signal evaluation activities for PPC-4187, using data from the GSD and such other sources as Penterra deems appropriate. Penterra shall chair the Joint Safety Review Committee established under Article 9 and shall coordinate global signal management activities through the JSRC.

3.1.7 Penterra shall promptly notify Meridian of any safety-related regulatory actions, communications, or decisions received from or issued by Regulatory Authorities in the Retained Territory, including without limitation any safety-related labeling changes, clinical holds, Dear Healthcare Provider letters, field safety notices, risk evaluation and mitigation strategy (REMS) requirements, product recalls, market withdrawals, and requests for additional safety studies or data.

3.2 Meridian (Licensee) Responsibilities. Meridian shall have the following pharmacovigilance roles and responsibilities under this Agreement:

3.2.1 Meridian shall collect, process, assess, and report all adverse events and adverse drug reactions arising from clinical trials (including Meridian-sponsored Phase III trials conducted in the Territory in accordance with the Development Plan) and post-marketing use of PPC-4187 in the Territory. Meridian shall ensure that its adverse event collection and processing systems are capable of identifying, documenting, assessing, and tracking all safety information arising from the Territory in a timely and compliant manner.

3.2.2 Meridian shall be responsible for preparing and submitting all Individual Case Safety Reports, Expedited Reports, and other safety-related regulatory submissions to all Regulatory Authorities in the Territory, including the NMPA (China), PMDA (Japan), MFDS (Republic of Korea), TGA (Australia), and all other Territory Regulatory Authorities, in full compliance with the local regulatory requirements and timelines applicable in each Territory jurisdiction.

3.2.3 Meridian shall transmit all safety data collected or received in connection with PPC-4187 in the Territory to Penterra for inclusion in the GSD, in accordance with the timelines, formats, and procedures specified in Article 5 and its associated Annexes. Meridian acknowledges that the timely and complete transmission of safety data to Penterra is essential for the maintenance of a comprehensive GSD and for compliance with Penterra's regulatory reporting obligations in the Retained Territory.

3.2.4 Meridian shall provide Territory-specific input for global PSURs and PBRERs prepared by Penterra, including local post-marketing data, territory-specific adverse event data, safety-related regulatory updates, and local literature monitoring results, in accordance with Article 7.

3.2.5 Meridian shall establish and maintain pharmacovigilance systems and qualified personnel in each Territory country and jurisdiction in which PPC-4187 is developed or marketed, as required by Applicable Laws. Without limitation, Meridian shall designate and maintain a qualified person responsible for pharmacovigilance (QPPV or equivalent) in each Territory country where such a designation is required by the relevant Regulatory Authority, and shall ensure that its pharmacovigilance systems meet the requirements of all applicable regulatory inspections.

3.2.6 Meridian shall ensure that all sublicense agreements entered into with Sublicensees in the Territory contain pharmacovigilance obligations that are no less protective than the obligations of Meridian under this Agreement, and that such sublicense agreements require Sublicensees to comply with the safety data exchange procedures, reporting timelines, and quality standards established by this Agreement.

3.2.7 Meridian shall ensure that its clinical trial insurance and product liability insurance coverage, whether obtained through Jade Dragon Insurance Limited or any equivalent insurer of comparable creditworthiness and financial strength, provides adequate coverage for pharmacovigilance-related activities, including the costs associated with adverse event reporting, safety-related regulatory actions, product recalls, and any claims arising from adverse events in the Territory.

3.2.8 Meridian shall promptly notify Penterra of any safety-related regulatory actions, communications, or decisions received from or issued by Regulatory Authorities in the Territory, including without limitation any safety-related labeling changes, clinical holds, post-marketing safety commitments, risk management requirements, product recalls, market withdrawals, field safety corrective actions, and requests for additional safety studies or data.

3.3 Shared Responsibilities. The Parties shall share the following pharmacovigilance responsibilities:

3.3.1 The Parties shall cooperate in good faith in signal detection, signal evaluation, benefit-risk assessment, and the development and implementation of risk management measures for PPC-4187, including through participation in the Joint Safety Review Committee and through the timely exchange of relevant safety data and analyses.

3.3.2 Each Party shall provide the other Party with prompt notification of any product recalls, market withdrawals, field safety corrective actions, or safety-related labeling changes affecting PPC-4187 in its respective territory of responsibility, and shall consult with the other Party in advance of implementing such actions to the extent practicable and consistent with patient safety and regulatory requirements.

3.3.3 Each Party shall designate qualified representatives to participate in the Joint Safety Review Committee established under Article 9 and shall ensure that its representatives are appropriately empowered to make decisions on behalf of such Party regarding pharmacovigilance matters within the scope of the JSRC's mandate.

3.3.4 Each Party shall maintain adequate pharmacovigilance staffing, systems, and standard operating procedures to fulfill its obligations under this Agreement, and shall ensure that its personnel involved in pharmacovigilance activities receive appropriate training in accordance with Article 16.

ARTICLE 4 — GLOBAL SAFETY DATABASE

4.1 Database Holder. Penterra shall be the sole holder and maintainer of the Global Safety Database (GSD) for PPC-4187. As Database Holder, Penterra shall have overall responsibility for the design, validation, operation, integrity, security, and maintenance of the GSD, and for ensuring that the GSD contains a complete and accurate record of all safety data relating to PPC-4187 from all sources and jurisdictions worldwide. The designation of Penterra as Database Holder reflects Penterra's position as the global rights holder and originator of PPC-4187 and is consistent with regulatory expectations for a single centralized pharmacovigilance database for a globally developed pharmaceutical product.

4.2 Database Format. The GSD shall be maintained in a validated pharmacovigilance database system that is compliant with ICH E2B(R3) standards and capable of: (a) receiving, storing, and retrieving Individual Case Safety Reports in ICH E2B(R3) format; (b) generating electronic ICSRs in ICH E2B(R3) XML format for regulatory submission to any Regulatory Authority worldwide; (c) supporting the generation of aggregate safety reports, line listings, and summary tabulations for PSUR/PBRER preparation, signal detection, and ad hoc safety analyses; (d) maintaining a complete audit trail of all data entries, modifications, and deletions; and (e) supporting periodic reconciliation of data between the GSD and any local pharmacovigilance databases maintained by Meridian or its Affiliates. Penterra shall ensure that the GSD undergoes periodic revalidation and that all software updates or system changes are implemented in accordance with applicable Good Pharmacovigilance Practices (GVP) and computerized systems validation requirements.

4.3 Data Entry Responsibility. Penterra shall be responsible for entering all ICSRs received from Meridian into the GSD. Meridian shall provide all ICSR data to Penterra in ICH E2B(R3)-compatible format, using the data fields and transmission protocols specified in Annex 2. In the event that Meridian is unable to transmit data in E2B(R3)-compatible electronic format due to technical constraints or system limitations, Meridian shall provide the data in CIOMS I form format (as a PDF or equivalent electronic document), and Penterra shall be responsible for entering such data into the GSD. The Parties shall work cooperatively to establish and maintain electronic gateway connectivity for automated or semi-automated ICSR transmission as soon as practicable following the Effective Date.

4.4 Data Access. Penterra shall provide Meridian with read-only access to the GSD for all ICSRs and safety data relating to PPC-4187 cases originating from the Territory, including both Territory-sourced cases and follow-up information for such cases. Meridian shall also be entitled to receive, upon reasonable written request, aggregated global safety data from the GSD to the extent necessary for Meridian's regulatory submissions in the Territory, including but not limited to data required for local PSUR/PBRER preparation, clinical trial application updates, marketing authorization applications, and responses to Regulatory Authority inquiries. Penterra shall respond to such data requests within fifteen (15) business days, or such shorter period as may be required by the applicable regulatory timeline. Meridian's access to the GSD shall be subject to Penterra's data security policies and reasonable access controls, and Meridian shall ensure that GSD access credentials are assigned only to authorized Meridian pharmacovigilance personnel.

4.5 Data Reconciliation. The Parties shall conduct a formal reconciliation of safety data between the GSD maintained by Penterra and any local pharmacovigilance databases maintained by Meridian or its Affiliates on a quarterly basis. Each reconciliation shall be completed within thirty (30) calendar days following the end of each calendar quarter (i.e., by January 30, April 30, July 30, and October 30 of each year, with the first reconciliation to be completed by January 30, 2024). Reconciliation reports shall be exchanged between the Parties and shall identify any discrepancies in case counts, case details, seriousness or expectedness assessments, or other data elements, together with proposed corrective actions. The detailed procedures for data reconciliation, including matching criteria, discrepancy resolution processes, and escalation mechanisms, are set forth in Annex 4.

4.6 Data Retention. All safety records and data relating to PPC-4187, including ICSRs, source documents, correspondence, and regulatory submissions, shall be retained by each Party for a minimum of fifteen (15) years following the date on which the last marketing authorization for PPC-4187 in any jurisdiction worldwide expires, is withdrawn, or is otherwise terminated, or for such longer period as may be required by Applicable Laws or by the terms of the License Agreement. During the retention period, each Party shall ensure that its safety records are stored securely and are readily retrievable for regulatory inspection, audit, or other legitimate purpose.

4.7 Costs. Penterra shall bear all costs and expenses associated with the establishment, maintenance, operation, and validation of the GSD, including hosting, software licensing, personnel, and system infrastructure costs. Meridian shall bear all costs and expenses associated with: (a) the establishment and maintenance of its local pharmacovigilance database systems and infrastructure; (b) the processing, assessment, and coding of ICSRs originating from the Territory; (c) the transmission of safety data to Penterra in accordance with this Agreement; and (d) the preparation and submission of regulatory safety reports to Territory Regulatory Authorities. Except as expressly set forth in this Section 4.7, each Party shall bear its own costs incurred in connection with its pharmacovigilance obligations under this Agreement.

ARTICLE 5 — INDIVIDUAL CASE SAFETY REPORTS (ICSRs) — EXCHANGE TIMELINES

5.1 Serious Adverse Events (SAEs) — Expedited Exchange. The Parties shall exchange ICSRs for Serious Adverse Events in accordance with the following timelines:

5.1.1 Fatal or Life-Threatening SAEs. For any Serious Adverse Event that results in death or is life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR (containing at minimum the four elements of a valid case) to the other Party within twenty-four (24) hours of Day 0 (as defined in Section 5.7). If a complete ICSR cannot be prepared within this timeframe, an initial notification containing all available information shall be transmitted within twenty-four (24) hours, to be followed by a complete ICSR as soon as practicable but in no event later than the timeframe specified in Section 5.1.2.

5.1.2 All Other SAEs. For all Serious Adverse Events not falling within Section 5.1.1 (i.e., SAEs that do not result in death and are not life-threatening), the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within three (3) calendar days of Day 0.

5.1.3 Follow-Up Information. Follow-up information for all Serious Adverse Events, including updated medical information, laboratory results, outcome data, causality assessments, and any other supplemental or corrective information, shall be transmitted by the reporting Party to the other Party within three (3) calendar days of receipt of such follow-up information.

5.2 Suspected Unexpected Serious Adverse Reactions (SUSARs). The Parties shall exchange ICSRs for SUSARs and comply with the following regulatory reporting timelines:

5.2.1 Fatal or Life-Threatening SUSARs. For any SUSAR that is fatal or life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within twenty-four (24) hours of Day 0. The responsible Party (as determined under Article 6) shall submit the Expedited Report to the applicable Regulatory Authority within seven (7) calendar days of Day 0, consistent with ICH E2A and ICH E2D requirements. The responsible Party shall submit follow-up information to the Regulatory Authority within an additional eight (8) calendar days (i.e., within fifteen (15) calendar days of Day 0 in total).

5.2.2 All Other SUSARs. For all SUSARs that are not fatal or life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within three (3) calendar days of Day 0. The responsible Party shall submit the Expedited Report to the applicable Regulatory Authority within fifteen (15) calendar days of Day 0.

5.3 Non-Serious Adverse Events. The Parties shall exchange data for Non-Serious Adverse Events as follows:

5.3.1 Non-serious AEs originating from clinical trials and spontaneous reports shall be exchanged between the Parties in batched format on a monthly basis, with each batch to be transmitted within fifteen (15) calendar days following the end of the calendar month in which the events were received and processed by the reporting Party. Each monthly batch shall be accompanied by a summary listing identifying all cases included in the batch, organized by case number, report date, event term (coded using MedDRA), and seriousness/expectedness classification.

5.3.2 Notwithstanding Section 5.3.1, any Non-Serious Adverse Event that is subject to expedited reporting requirements under any Territory-specific regulation or any Retained Territory regulation shall be exchanged between the Parties within the shorter of: (a) the applicable regulatory reporting timeline; or (b) five (5) calendar days of Day 0. The Parties shall maintain an updated list of Territory-specific and Retained Territory-specific expedited reporting requirements that apply to Non-Serious AEs, and shall review and update such list at each quarterly JSRC meeting.

5.4 Special Situations Reports. Reports involving any of the following special situations shall be transmitted by the Party first becoming aware of the event to the other Party within three (3) calendar days of Day 0, regardless of the seriousness of the event:

(a) exposure to PPC-4187 during pregnancy or lactation (including paternal exposure);

(b) overdose (whether intentional or accidental), with or without an associated adverse event;

(c) lack of efficacy or therapeutic failure (particularly in situations where such lack of efficacy could be life-threatening or could result in serious consequences for the patient);

(d) medication errors, including dispensing errors, prescribing errors, and administration errors, with or without an associated adverse event;

(e) misuse, abuse, or off-label use of PPC-4187;

(f) occupational exposure to PPC-4187 (e.g., exposure of healthcare workers, caregivers, or manufacturing personnel);

(g) suspected transmission of an infectious agent via PPC-4187;

(h) drug-drug interactions or drug-food interactions involving PPC-4187 that result in or may result in adverse consequences; and

(i) any other situation deemed by either Party or by a Regulatory Authority to warrant reporting as a special situation.

5.5 Format. All ICSRs exchanged between the Parties shall be transmitted in CIOMS I form format (or the local equivalent form acceptable to the relevant Regulatory Authority) and, where technically feasible and where electronic gateway connectivity has been established between the Parties, in ICH E2B(R3) XML electronic format. The specific data fields required for each ICSR and the format specifications for electronic transmission are set forth in Annex 2. In all cases, ICSRs shall contain a complete narrative summary of the case, coded adverse event terms using the current version of the Medical Dictionary for Regulatory Activities (MedDRA), and a causality assessment.

5.6 Transmission Method. ICSRs and other safety data shall be transmitted between the Parties via one or more of the following methods: (a) secure, encrypted email to the designated pharmacovigilance contact points identified in Annex 1; (b) validated electronic gateway for E2B(R3) XML transmission, once such gateway has been established and validated by the Parties; or (c) such other secure transmission method as the Parties may mutually agree upon in writing. All transmissions containing patient-identifiable data, including initial and follow-up ICSRs, shall be encrypted using industry-standard encryption protocols (minimum AES-256 or equivalent) to ensure the confidentiality and security of personal health information during transmission.

5.7 Day Zero Rules. For the purposes of this Agreement, "Day 0" (the date of first awareness) shall be defined as the date on which any employee, agent, contractor, or representative of the Party (including any employee or representative of the Party's Affiliates or Sublicensees) who is engaged in pharmacovigilance, medical affairs, clinical operations, regulatory affairs, quality assurance, medical information, commercial operations, or any other function first receives information (whether in written, oral, electronic, or any other form) sufficient to constitute a valid ICSR (i.e., containing at a minimum the four elements of a valid case: an identifiable reporter, an identifiable patient, at least one suspected adverse reaction, and identification of the suspect product as PPC-4187 or Penteracitinib). For the avoidance of doubt, Day 0 is determined based on the date of first awareness by any person within the organization (not solely pharmacovigilance personnel), and the reporting Party shall have in place internal procedures to ensure prompt escalation of safety information from all functions to the pharmacovigilance department. Day 0 for the receiving Party (i.e., the Party to whom the ICSR is transmitted) shall be the date on which such Party receives the ICSR or notification from the reporting Party.

ARTICLE 6 — REGULATORY REPORTING RESPONSIBILITIES

6.1 Penterra's Reporting Obligations (Retained Territory).

6.1.1 Penterra shall be solely responsible for the preparation and submission of all regulatory safety reports, including ICSRs, Expedited Reports (IND safety reports under 21 C.F.R. § 312.32, NDA safety reports under 21 C.F.R. § 314.80, and equivalent reports under the regulations of other Retained Territory countries), and periodic safety reports, to the FDA and to all other Regulatory Authorities in the Retained Territory. Penterra shall ensure that all such regulatory submissions are made in compliance with the applicable timelines and formatting requirements established by the relevant Regulatory Authority.

6.1.2 Penterra shall be responsible for SUSAR reporting to all ethics committees and investigators participating in Penterra-sponsored clinical trials of PPC-4187 in the Retained Territory, in accordance with ICH E6(R2) (Good Clinical Practice), 21 C.F.R. Part 312, and all other Applicable Laws governing investigator notification in the Retained Territory.

6.2 Meridian's Reporting Obligations (Licensed Territory).

6.2.1 Meridian shall be solely responsible for the preparation and submission of all regulatory safety reports, including ICSRs, Expedited Reports, and periodic safety reports, to all Regulatory Authorities in the Territory. Meridian's Territory reporting obligations include, without limitation, submissions to the NMPA in the People's Republic of China, the PMDA in Japan, the MFDS in the Republic of Korea, the TGA in Australia, Medsafe in New Zealand, the Health Sciences Authority in Singapore, the Thai FDA in Thailand, the National Pharmaceutical Regulatory Agency in Malaysia, BPOM in Indonesia, the Philippine FDA in the Philippines, the Drug Administration of Vietnam in Vietnam, and the Taiwan Food and Drug Administration in Taiwan. Meridian shall ensure that all such regulatory submissions are made in compliance with the applicable timelines, formatting requirements, and language requirements established by each relevant Regulatory Authority.

6.2.2 Meridian shall be responsible for SUSAR reporting to all ethics committees, institutional review boards, and investigators participating in Meridian-sponsored clinical trials of PPC-4187 in the Territory, in accordance with ICH E6(R2) (Good Clinical Practice) and all applicable local regulations governing investigator notification in each Territory country.

6.2.3 Meridian shall comply with all country-specific reporting timelines and requirements applicable in the Territory, including without limitation:

(i) Japan (PMDA): 7-day and 15-day expedited reporting requirements under the Pharmaceutical and Medical Device Act (PMD Act) and applicable PMDA notifications, including PMDA-mandated case reporting for infections, deaths, and other serious events requiring 7-day expedited reporting;

(ii) China (NMPA): expedited individual case reporting requirements and periodic aggregate reporting requirements under the Provisions for Adverse Drug Reaction Monitoring and Reporting and other NMPA regulations applicable to clinical trials and post-marketing surveillance;

(iii) Republic of Korea (MFDS): periodic and expedited reporting requirements under the Pharmaceutical Affairs Act and applicable MFDS regulations;

(iv) Australia (TGA): 15-day expedited reporting for serious adverse events and SUSARs, and periodic reporting requirements under the Therapeutic Goods Act 1989 and associated regulatory instruments; and

(v) All other Territory jurisdictions: compliance with the applicable reporting timelines and requirements of each Regulatory Authority, including requirements arising from ASEAN regulatory harmonization initiatives.

6.2.4 Meridian shall ensure that regulatory safety submissions in the Territory are made through the appropriate Meridian entity or authorized representative in each jurisdiction, including: (a) Meridian Japan K.K. for submissions to the PMDA; (b) Meridian Pharma (Shanghai) Co., Ltd. for submissions to the NMPA; (c) Meridian Korea Inc. for submissions to the MFDS; and (d) Meridian Bio Australia Pty Ltd for submissions to the TGA. Meridian may also, where appropriate and in accordance with Applicable Laws, utilize its regulatory counsel, including Nakamura & Takeda Law Offices (Tokyo), as its authorized representative for regulatory submissions to the PMDA.

6.3 Cross-Referencing. Each Party shall provide the other Party with copies of all safety-related regulatory submissions (including ICSRs, Expedited Reports, and correspondence relating to safety matters) filed with Regulatory Authorities in its respective territory of responsibility within five (5) business days of the date of filing. Such copies may be provided in redacted form to the extent necessary to protect patient-identifiable information that cannot be shared under applicable data protection laws, provided that such redactions do not materially impair the other Party's ability to understand the substance of the submission.

6.4 Regulatory Authority Inquiries. Each Party shall promptly notify the other Party (and in any event within two (2) business days) of any safety-related inquiry, question, request for information, deficiency notice, inspection, or other communication received from any Regulatory Authority relating to PPC-4187, regardless of the territory from which such inquiry originates. The Parties shall cooperate fully and in good faith in preparing and submitting responses to such Regulatory Authority inquiries, and each Party shall provide the other Party with copies of all correspondence with Regulatory Authorities relating to safety matters within five (5) business days of sending or receiving such correspondence.

ARTICLE 7 — PERIODIC SAFETY UPDATE REPORTS (PSURs) AND PBRERs

7.1 Global PSUR/PBRER Preparation. Penterra shall be responsible for preparing global Periodic Safety Update Reports (PSURs) and Periodic Benefit-Risk Evaluation Reports (PBRERs) for PPC-4187 in accordance with ICH E2C(R2) and all applicable regulatory requirements. Penterra shall utilize data from the GSD, together with Territory-specific data and input provided by Meridian, to prepare each global PSUR/PBRER. Each PSUR/PBRER shall contain a comprehensive analysis of the worldwide safety experience with PPC-4187, including clinical trial data, post-marketing surveillance data, and data from all other sources, together with an updated benefit-risk evaluation.

7.2 Territory-Specific Input. Meridian shall provide Penterra with Territory-specific safety data, regulatory updates, and post-marketing information for inclusion in each global PSUR/PBRER. Such Territory-specific input shall include, without limitation: (a) aggregate data on all adverse events and serious adverse events reported in the Territory during the reporting period; (b) information regarding Territory-specific regulatory actions, labeling changes, or post-marketing commitments; (c) results of Territory-specific literature monitoring (including local-language literature); (d) data from any post-marketing studies, registries, or Phase IV trials conducted in the Territory; and (e) any other information requested by Penterra or by the JSRC that is relevant to the global benefit-risk assessment. Meridian shall provide such Territory-specific input to Penterra at least sixty (60) calendar days prior to each PSUR/PBRER data lock point.

7.3 Review Period. Penterra shall share the draft PSUR/PBRER with Meridian for review at least thirty (30) calendar days prior to the scheduled submission date. Meridian shall review the draft and provide written comments, corrections, and any additional Territory-specific information to Penterra within fifteen (15) calendar days of receipt of the draft. Penterra shall consider Meridian's comments in good faith and shall incorporate Meridian's Territory-specific data and corrections to the extent appropriate for the final PSUR/PBRER. Any disagreements between the Parties regarding the content of the PSUR/PBRER shall be discussed at the JSRC and, if not resolved, shall be escalated in accordance with Article 9.7.

7.4 PSUR Submission Responsibilities.

7.4.1 Penterra shall be responsible for submitting PSURs/PBRERs to all Regulatory Authorities in the Retained Territory, including the FDA (to the extent PSURs are required under U.S. regulations or as post-marketing commitments), the EMA (for any centralized procedure in the EU/EEA), and all other Retained Territory Regulatory Authorities.

7.4.2 Meridian shall be responsible for submitting PSURs/PBRERs (or the local equivalent periodic safety reports, such as the PMDA-format Periodic Safety Reports in Japan) to all Regulatory Authorities in the Territory. Meridian may adapt the global PSUR/PBRER prepared by Penterra to meet local formatting, content, or language requirements of each Territory Regulatory Authority, provided that the substance and conclusions of the global report are not materially altered without Penterra's prior written consent.

7.5 Frequency. The frequency of PSUR/PBRER preparation shall be determined by the most stringent Regulatory Authority requirement applicable globally. Unless otherwise required by a Regulatory Authority, the initial PSUR/PBRER preparation frequency shall be as follows:

(a) During clinical development: every six (6) months from the International Birth Date (IBD) of PPC-4187 or from the date of the first Investigational New Drug application (IND) filing, whichever is earlier;

(b) Upon first marketing authorization: annually from the IBD for the first two (2) years, then every three (3) years thereafter; and

The Parties shall coordinate through the JSRC to align PSUR/PBRER preparation schedules with the requirements of all applicable Regulatory Authorities worldwide.

7.6 Data Lock Points. Data lock points for each PSUR/PBRER shall be established and coordinated internationally by Penterra, in consultation with Meridian and the JSRC, to ensure consistency of the reporting period across all jurisdictions. Penterra shall notify Meridian of each data lock point at least ninety (90) calendar days in advance. Both Parties shall ensure that all safety data within their respective territories of responsibility are transmitted and entered into the GSD prior to each data lock point.

ARTICLE 8 — SIGNAL DETECTION AND RISK MANAGEMENT

8.1 Signal Detection. Penterra shall conduct signal detection activities for PPC-4187 on a global basis, using data from the GSD and such other data sources as Penterra deems appropriate, including published scientific and medical literature, pharmacoepidemiological databases, and regulatory databases. Signal detection methodologies shall include, at a minimum, regular review of individual serious adverse event reports, periodic aggregate data review, statistical disproportionality analyses (such as proportional reporting ratios and Bayesian analysis), and clinical review of cases of special interest. Meridian shall conduct supplementary signal detection activities using safety data from the Territory, focusing on Territory-specific safety issues, local epidemiological factors, and patterns of adverse event reporting that may be unique to Territory populations. Meridian shall share the results of its Territory-specific signal detection activities with Penterra and with the JSRC on a quarterly basis, or more frequently as warranted by emerging safety concerns.

8.2 Signal Notification. Any potential safety signal identified by either Party, whether through routine signal detection activities, review of individual case reports, analysis of aggregate data, review of scientific literature, or any other source, shall be communicated to the other Party in writing within three (3) business days of initial identification of the signal. The initial notification shall include a description of the signal, the data source(s) from which the signal was identified, a preliminary assessment of the strength and clinical relevance of the signal, and any supporting data available at the time of communication.

8.3 Signal Evaluation. All potential safety signals shall be evaluated jointly by the Parties through the Joint Safety Review Committee (JSRC) established under Article 9. Upon identification of a potential signal, the JSRC shall convene (either at its next scheduled meeting or at a special meeting if the urgency of the signal warrants) to review the available data and determine the appropriate course of action. Both Parties shall provide all relevant data and analyses requested by the JSRC within fifteen (15) calendar days of the JSRC's request, unless a shorter timeframe is agreed upon due to the urgency of the signal. Signal evaluation shall include, as appropriate, detailed case review, literature review, pharmacoepidemiological analysis, assessment of biological plausibility, evaluation of class effects, and consideration of the overall benefit-risk profile of PPC-4187.

8.4 Risk Evaluation and Mitigation Strategies (REMS) / Risk Management Plans (RMPs).

8.4.1 Penterra shall be responsible for the development, implementation, and maintenance of any Risk Evaluation and Mitigation Strategy (REMS) or other risk management measure required by the FDA or any other Retained Territory Regulatory Authority for PPC-4187 in the Retained Territory.

8.4.2 Meridian shall be responsible for the development, implementation, and maintenance of any Risk Management Plan (RMP) or equivalent risk management measure required by Territory Regulatory Authorities, including the NMPA, PMDA, MFDS, TGA, and all other Territory regulatory bodies, for PPC-4187 in the Territory. Meridian shall provide Penterra with copies of all RMPs and risk management measures developed for the Territory for Penterra's review and comment prior to submission to Territory Regulatory Authorities, to the extent practicable.

8.4.3 The Parties shall coordinate through the JSRC to ensure global consistency in the overall risk management approach for PPC-4187. While the specific risk management measures implemented in each territory may differ to reflect local regulatory requirements, prescribing practices, and healthcare systems, the Parties shall endeavor to maintain alignment in the core risk minimization messages and interventions to the extent consistent with patient safety and regulatory compliance.

8.5 Urgent Safety Measures. Either Party may, in its sole discretion, take urgent safety measures with respect to PPC-4187 in its respective territory of responsibility when such Party reasonably determines that urgent action is necessary to protect patient safety. Urgent safety measures may include, without limitation, suspension or termination of clinical trials, issuance of Dear Healthcare Provider letters or field safety notices, voluntary product recalls or market withdrawals, and implementation of new risk minimization measures. A Party taking urgent safety measures shall not be required to obtain the prior consent of the other Party before implementing such measures; provided, however, that the Party taking such measures shall: (a) notify the other Party of the urgent safety measures and the reasons therefor within twenty-four (24) hours of implementing such measures; and (b) consult with the other Party and with the JSRC as soon as practicable thereafter regarding the potential implications of such measures for the other Party's territory and the global benefit-risk profile of PPC-4187.

ARTICLE 9 — JOINT SAFETY REVIEW COMMITTEE

9.1 Establishment. A Joint Safety Review Committee ("JSRC") shall be established by the Parties within thirty (30) days of the Effective Date (i.e., by no later than November 19, 2023). The JSRC shall serve as the primary governance body for pharmacovigilance matters relating to PPC-4187, providing oversight and coordinatio

PHARMACOVIGILANCE AGREEMENT
Relating to Compound PPC-4187 (Penteracitinib)
by and between
PENTERRA PHARMACEUTICALS CORP.
and
MERIDIAN BIO THERAPEUTICS LIMITED
Executed: October 2, 2023
Effective Date: October 20, 2023
CONFIDENTIAL TREATMENT REQUESTED — This document and the information contained herein are confidential and proprietary. Unauthorized reproduction, distribution, or disclosure is strictly prohibited.
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RECITALS
WHEREAS, Penterra Pharmaceuticals Corp., a corporation organized and existing under the laws of the State of Delaware, United States of America, with its principal place of business and headquarters located at 400 Pharma Drive, Suite 800, Princeton, New Jersey 08540 ("Penterra" or "Licensor"), and Meridian Bio Therapeutics Limited, a limited company organized and existing under the laws of the Hong Kong Special Administrative Region of the People's Republic of China (Company Registration No. 2847631), with its principal place of business and headquarters located at 18/F, Blossom Tower, 88 Queen's Road Central, Hong Kong SAR ("Meridian" or "Licensee"), have entered into that certain Exclusive License Agreement dated October 2, 2023 (the "License Agreement") relating to the development, manufacture, and commercialization of the proprietary small-molecule compound designated PPC-4187 (proposed International Nonproprietary Name: Penteracitinib), a selective Janus kinase 1 (JAK1) inhibitor for the treatment of moderate-to-severe atopic dermatitis and such other indications as may be approved under the License Agreement;
WHEREAS, under the License Agreement, Penterra has granted to Meridian an exclusive license to develop and commercialize PPC-4187 in the Licensed Territory (as defined in Schedule D to the License Agreement), comprising the People's Republic of China (including Hong Kong Special Administrative Region and Macau Special Administrative Region), Japan, the Republic of Korea, Australia, New Zealand, Singapore, Thailand, Malaysia, Indonesia, the Philippines, Vietnam, and Taiwan (collectively, the "Territory");
WHEREAS, Penterra retains all rights to PPC-4187 outside the Territory, including without limitation in the United States, Canada, the European Union and European Economic Area, the United Kingdom, Latin America, the Middle East, Africa, and all other countries and jurisdictions not included in the Territory (the "Retained Territory");
WHEREAS, PPC-4187 has completed Phase IIb clinical development under Penterra-sponsored Study PPC-4187-201 (a randomized, double-blind, placebo-controlled, dose-ranging study enrolling 420 patients with moderate-to-severe atopic dermatitis, with topline results announced in June 2023 demonstrating statistically significant improvements in EASI-75 response rates at the 50 mg daily dose), and PPC-4187 will be entering Phase III clinical development in both the Territory and in Penterra's Retained Territory in accordance with the Development Plan set forth in Schedule E to the License Agreement;
WHEREAS, the Parties recognize that the safe and effective development and commercialization of PPC-4187 on a global basis requires the establishment of clear, comprehensive, and robust procedures for the exchange of safety information, adverse event reporting, signal detection, periodic safety reporting, and risk management in accordance with all applicable laws, regulations, and guidelines promulgated by relevant regulatory authorities worldwide, including the guidelines established by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), including without limitation ICH E2A, ICH E2B(R3), ICH E2C(R2), ICH E2D, and ICH E2E;
WHEREAS, the paramount objective of this Agreement is the protection of patient safety through the timely, complete, and accurate collection, assessment, exchange, and reporting of safety information concerning PPC-4187, regardless of the source of such information, the jurisdiction in which the relevant event occurs, or the party with primary regulatory responsibility for such jurisdiction; and
WHEREAS, this Agreement is entered into pursuant to Section 8.6 of the License Agreement, which requires the Parties to execute a pharmacovigilance agreement or safety data exchange agreement within thirty (30) days of the Effective Date of the License Agreement, governing the exchange of safety information between the Parties in connection with PPC-4187;
NOW, THEREFORE, in consideration of the mutual covenants and agreements set forth herein, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties agree as follows:
ARTICLE 1 — DEFINITIONS
Capitalized terms used in this Agreement and not otherwise defined herein shall have the meanings ascribed to them in the License Agreement. The following terms shall have the meanings set forth below for purposes of this Agreement:
1.1 "Adverse Drug Reaction" or "ADR" means any noxious, unintended response to PPC-4187 at any dose used for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function, consistent with the definition set forth in ICH E2A. For pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose shall be considered adverse drug reactions. The phrase "responses to a medicinal product" means that a causal relationship between PPC-4187 and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.
1.2 "Adverse Event" or "AE" means any untoward medical occurrence in a patient or clinical investigation subject administered PPC-4187, which does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of PPC-4187, whether or not considered related to the medicinal product, consistent with the definition set forth in ICH E2A.
1.3 "Affiliate" shall have the meaning ascribed to such term in Section 1.2 of the License Agreement. For the avoidance of doubt, Meridian's Affiliates include, without limitation: (a) Meridian Pharma (Shanghai) Co., Ltd., a wholly foreign-owned enterprise organized under the laws of the People's Republic of China ("Meridian Shanghai"); (b) Meridian Japan K.K., a kabushiki kaisha organized under the laws of Japan with its registered office in Tokyo ("Meridian Japan"); (c) Meridian Korea Inc., a corporation organized under the laws of the Republic of Korea with its registered office in Seoul ("Meridian Korea"); (d) Meridian Bio Australia Pty Ltd, a proprietary company limited by shares organized under the laws of the Commonwealth of Australia with its registered office in Sydney ("Meridian Australia"); and (e) any other subsidiary, controlled entity, or Affiliate established by Meridian from time to time in accordance with the License Agreement.
1.4 "Applicable Laws" means all laws, statutes, regulations, rules, orders, decrees, ordinances, guidance documents, and guidelines of any Regulatory Authority that are applicable to the safety reporting and pharmacovigilance obligations under this Agreement, as in effect from time to time, including without limitation: (a) in the United States, the regulations of the U.S. Food and Drug Administration ("FDA") at 21 C.F.R. Parts 312 (Investigational New Drug Application) and 314 (Applications for FDA Approval to Market a New Drug), and FDA guidances relating to safety reporting; (b) in the People's Republic of China, the regulations, rules, and guidelines of the National Medical Products Administration ("NMPA"), including the Provisions for Adverse Drug Reaction Monitoring and Reporting and the Drug Administration Law; (c) in Japan, the regulations and guidelines of the Pharmaceuticals and Medical Devices Agency ("PMDA") and the Ministry of Health, Labour and Welfare, including the Pharmaceutical and Medical Device Act (PMD Act) and applicable PMDA notifications; (d) in the Republic of Korea, the regulations and guidelines of the Ministry of Food and Drug Safety ("MFDS"); (e) in Australia, the regulations and guidelines of the Therapeutic Goods Administration ("TGA"), including the Therapeutic Goods Act 1989; (f) in the remaining Territory countries and jurisdictions, the applicable regulations of the respective national regulatory authorities, including those governing ASEAN pharmaceutical regulatory harmonization; and (g) all ICH guidelines as adopted or referenced by any of the foregoing Regulatory Authorities.
1.5 "Compound" or "Licensed Product" means PPC-4187 (Penteracitinib), a selective JAK1 inhibitor, in its currently developed 25 mg and 50 mg film-coated tablet formulations, or any other formulation, dosage form, or dosage strength of PPC-4187 that may be developed by or on behalf of either Party under the License Agreement.
1.6 "CIOMS Form" means the Council for International Organizations of Medical Sciences form (CIOMS I form) used for the reporting and exchange of Individual Case Safety Reports, or any successor form adopted by CIOMS for such purpose.
1.7 "Day" means a calendar day, unless explicitly stated otherwise in this Agreement. References to "business days" mean days on which commercial banks are open for general business in both New York, New York, United States, and Hong Kong SAR.
1.8 "Effective Date" means October 20, 2023, which is the Effective Date of the License Agreement as defined therein.
1.9 "Expedited Report" means any safety report that is required by Applicable Laws or by the terms of this Agreement to be submitted to a Regulatory Authority or exchanged between the Parties within a regulatory timeline that is shorter than the timeline applicable to periodic safety reporting, including without limitation reports of SUSARs, fatal or life-threatening SAEs, and other events subject to accelerated reporting requirements under the laws or regulations of any relevant jurisdiction.
1.10 "Global Safety Database" or "GSD" means the single, centralized pharmacovigilance database for PPC-4187 maintained by Penterra in its capacity as Database Holder, which database contains all Individual Case Safety Reports and other safety data relating to PPC-4187 from all sources worldwide, including data from clinical trials, post-marketing surveillance, spontaneous reports, and literature.
1.11 "ICH" means the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (formerly the International Conference on Harmonisation), including all current and future guidelines, guidances, and technical requirements adopted by ICH.
1.12 "Individual Case Safety Report" or "ICSR" means a report of an individual adverse event or adverse drug reaction associated with PPC-4187, formatted and transmitted in accordance with ICH E2B(R3) (the ICH guideline on electronic transmission of individual case safety reports) and containing, at a minimum, the four elements of a valid case: an identifiable reporter, an identifiable patient, at least one suspected adverse reaction, and identification of the suspect product.
1.13 "License Agreement" means the Exclusive License Agreement by and between Penterra Pharmaceuticals Corp. and Meridian Bio Therapeutics Limited, dated October 2, 2023, and effective as of October 20, 2023, as such agreement may be amended, supplemented, or otherwise modified from time to time in accordance with its terms.
1.14 "PSUR" means a Periodic Safety Update Report, prepared in accordance with ICH E2C(R2), providing an update of the worldwide safety experience of PPC-4187 at defined time points during the post-authorization period.
1.15 "PBRER" means a Periodic Benefit-Risk Evaluation Report, prepared in accordance with ICH E2C(R2), which represents the current format and content recommended by ICH for periodic reporting of safety data and benefit-risk assessment, and which, for the purposes of this Agreement, shall be deemed to include PSURs to the extent that specific Regulatory Authorities continue to require PSURs by that designation.
1.16 "Reference Safety Information" or "RSI" means the safety information contained in the applicable reference document used by the Parties to determine the expectedness of an adverse drug reaction for the purpose of SUSAR classification. During the clinical development phase, the RSI shall be the safety information section of the current Investigator's Brochure for PPC-4187 maintained by Penterra. Following the first marketing authorization for PPC-4187 in any jurisdiction, the RSI shall be the Company Core Safety Information (CCSI) contained in the Company Core Data Sheet (CDS) maintained by Penterra.
1.17 "Regulatory Authority" means any national, supra-national, regional, state, or local governmental or regulatory authority, department, bureau, commission, council, agency, court, or other instrumentality responsible for the regulation, approval, or oversight of pharmaceutical or biopharmaceutical products in any jurisdiction, including without limitation: (a) the FDA in the United States; (b) the NMPA in the People's Republic of China; (c) the PMDA in Japan; (d) the MFDS in the Republic of Korea; (e) the TGA in Australia; (f) Medsafe in New Zealand; (g) the Health Sciences Authority (HSA) in Singapore; (h) the Thai FDA in Thailand; (i) the National Pharmaceutical Regulatory Agency (NPRA) in Malaysia; (j) BPOM in Indonesia; (k) the Philippine FDA in the Philippines; (l) the Drug Administration of Vietnam (DAV) in Vietnam; and (m) the Taiwan Food and Drug Administration (TFDA) in Taiwan.
1.18 "Retained Territory" means all countries, territories, and jurisdictions worldwide that are not included in the Licensed Territory as defined in Schedule D to the License Agreement, including without limitation the United States, Canada, the European Union and the European Economic Area, the United Kingdom, all countries in Latin America, the Middle East, and Africa, and all other countries and jurisdictions not expressly listed in the definition of Territory.
1.19 "Safety Data Exchange Agreement" or "SDEA" means this Pharmacovigilance Agreement, including all Annexes hereto, as may be amended from time to time in accordance with Article 22.2.
1.20 "Serious Adverse Event" or "SAE" means any adverse event that, at any dose: (a) results in death; (b) is life-threatening (i.e., the patient was at risk of death at the time of the event; this does not refer to an event that hypothetically might have caused death if it were more severe); (c) requires inpatient hospitalization or prolongation of existing hospitalization; (d) results in persistent or significant disability or incapacity; (e) is a congenital anomaly or birth defect; or (f) is an important medical event that, based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. This definition is consistent with ICH E2A.
1.21 "Signal" means information arising from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention (including PPC-4187) and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action, consistent with the definition adopted by the Council for International Organizations of Medical Sciences (CIOMS) Working Group VIII.
1.22 "Sublicensee" means any Third Party to whom Meridian grants a sublicense under and in accordance with the terms and conditions of the License Agreement for the development, manufacture, or commercialization of PPC-4187 in all or any part of the Territory.
1.23 "SUSAR" means a Suspected Unexpected Serious Adverse Reaction, being a serious adverse drug reaction, the nature, severity, specificity, or outcome of which is not consistent with the applicable Reference Safety Information.
1.24 "Territory" means the Licensed Territory as defined in Schedule D to the License Agreement, consisting of the following countries and jurisdictions: (a) the People's Republic of China (including Hong Kong Special Administrative Region and Macau Special Administrative Region); (b) Japan; (c) the Republic of Korea; (d) Australia; (e) New Zealand; (f) Singapore; (g) Thailand; (h) Malaysia; (i) Indonesia; (j) the Philippines; (k) Vietnam; and (l) Taiwan.
1.25 All other capitalized terms used but not defined in this Agreement shall have the meanings ascribed to them in the License Agreement, which definitions are hereby incorporated by reference into this Agreement.
ARTICLE 2 — SCOPE AND PURPOSE
2.1 Scope. This Agreement governs the exchange of safety information between Penterra and Meridian (and their respective Affiliates, agents, contractors, and Sublicensees) relating to PPC-4187 (Penteracitinib) in all jurisdictions worldwide, including both the Territory and the Retained Territory. The obligations set forth in this Agreement apply to safety information arising from any and all sources, including clinical trials, post-marketing surveillance, spontaneous reports from healthcare professionals, patients, and consumers, safety data derived from scientific and medical literature, and any other source of safety information relating to PPC-4187. The scope of this Agreement extends to all activities conducted by or on behalf of either Party, its Affiliates, or its Sublicensees in connection with PPC-4187, regardless of the stage of development or commercialization.
2.2 Purpose. The purpose of this Agreement is to establish the procedures, responsibilities, and timelines necessary to ensure: (a) the timely and complete exchange of all safety data relating to PPC-4187 between the Parties; (b) compliance by each Party with all Applicable Laws and ICH guidelines governing the reporting and management of safety information in all jurisdictions in which PPC-4187 is being developed, marketed, or otherwise made available; (c) coordinated signal detection, signal evaluation, and benefit-risk assessment on a global basis; (d) the maintenance of a single, comprehensive Global Safety Database containing all safety data for PPC-4187 from all sources and jurisdictions worldwide; and (e) the overarching protection of the safety and welfare of patients and clinical trial subjects who receive PPC-4187.
2.3 Product Scope. This Agreement applies to all formulations, dosage forms, and dosage strengths of PPC-4187 (Penteracitinib), including the currently developed 25 mg and 50 mg film-coated tablet formulations, and any additional formulation, dosage form, or dosage strength that may be developed by or on behalf of either Party or its Affiliates or Sublicensees under the License Agreement during the term of this Agreement. In the event that either Party develops a new formulation or dosage strength of PPC-4187, the Parties shall promptly amend this Agreement or its Annexes as necessary to address any additional pharmacovigilance considerations arising from such new formulation or dosage strength.
2.4 Activities Covered. The pharmacovigilance activities and safety data exchange procedures set forth in this Agreement cover and apply to all of the following:
(a) clinical trials of PPC-4187, including Phase III clinical trials to be conducted in the Territory in accordance with the Development Plan set forth in Schedule E to the License Agreement, Phase III and any other clinical trials conducted by Penterra in the Retained Territory, and any other interventional or non-interventional studies involving PPC-4187;
(b) post-marketing surveillance activities, including spontaneous adverse event reporting, post-marketing observational studies, patient registries, and Phase IV clinical trials;
(c) safety reports derived from scientific and medical literature, whether published in English or in any other language;
(d) safety reports received from healthcare professionals, patients, caregivers, consumers, and any other reporters, regardless of the channel of receipt;
(e) safety information arising from special situations, including but not limited to pregnancy and lactation exposure, overdose, lack of efficacy or therapeutic failure, medication errors, misuse, abuse, off-label use, occupational exposure, and drug interactions; and
(f) any other source of safety data relating to PPC-4187 as may be identified from time to time.
2.5 Relationship to License Agreement. This Agreement is entered into pursuant to and supplementary to the License Agreement. In the event of any conflict or inconsistency between the terms and conditions of this Agreement and the terms and conditions of the License Agreement, the License Agreement shall prevail and control; provided, however, that with respect to pharmacovigilance-specific operational procedures expressly set forth in this Agreement (including the timelines for safety data exchange specified in Article 5, the roles and responsibilities specified in Articles 3 and 6, and the JSRC procedures specified in Article 9), the terms of this Agreement shall govern and control to the extent such terms address matters not specifically addressed in the License Agreement or provide more detailed or specific operational procedures than those set forth in the License Agreement.
ARTICLE 3 — ROLES AND RESPONSIBILITIES
3.1 Penterra (Licensor) Responsibilities. Penterra shall have the following pharmacovigilance roles and responsibilities under this Agreement:
3.1.1 Penterra shall maintain and host the Global Safety Database (GSD) for PPC-4187 at Penterra's pharmacovigilance facilities in Princeton, New Jersey, or at such other validated location as Penterra may designate from time to time. Penterra shall ensure that the GSD is maintained in a validated, regulatory-compliant pharmacovigilance database system in accordance with Article 4, and shall bear responsibility for the operational integrity, security, and availability of the GSD throughout the term of this Agreement.
3.1.2 Penterra shall serve as the global Database Holder for PPC-4187, with overall responsibility for the integrity, completeness, accuracy, and reconciliation of all safety data contained in the GSD, and for the archival and retention of safety records in accordance with Article 4.6 and all Applicable Laws.
3.1.3 Penterra shall be responsible for preparing and submitting all regulatory safety reports, including Individual Case Safety Reports (ICSRs), Expedited Reports, and periodic safety reports, to Regulatory Authorities in the Retained Territory, including the U.S. Food and Drug Administration and all other Regulatory Authorities having jurisdiction over PPC-4187 in countries and jurisdictions outside the Territory.
3.1.4 Penterra shall be responsible for preparing global Periodic Safety Update Reports (PSURs) and Periodic Benefit-Risk Evaluation Reports (PBRERs) for PPC-4187 in accordance with ICH E2C(R2) and shall share drafts of such reports with Meridian for review and the provision of Territory-specific input, in accordance with Article 7.
3.1.5 Penterra shall maintain and update the Reference Safety Information for PPC-4187, including the safety information section of the Investigator's Brochure during the clinical development phase and the Company Core Data Sheet (CDS) and Company Core Safety Information (CCSI) following the first marketing authorization for PPC-4187 in any jurisdiction. Penterra shall promptly provide Meridian with updated versions of the RSI upon each revision.
3.1.6 Penterra shall lead global signal detection and signal evaluation activities for PPC-4187, using data from the GSD and such other sources as Penterra deems appropriate. Penterra shall chair the Joint Safety Review Committee established under Article 9 and shall coordinate global signal management activities through the JSRC.
3.1.7 Penterra shall promptly notify Meridian of any safety-related regulatory actions, communications, or decisions received from or issued by Regulatory Authorities in the Retained Territory, including without limitation any safety-related labeling changes, clinical holds, Dear Healthcare Provider letters, field safety notices, risk evaluation and mitigation strategy (REMS) requirements, product recalls, market withdrawals, and requests for additional safety studies or data.
3.2 Meridian (Licensee) Responsibilities. Meridian shall have the following pharmacovigilance roles and responsibilities under this Agreement:
3.2.1 Meridian shall collect, process, assess, and report all adverse events and adverse drug reactions arising from clinical trials (including Meridian-sponsored Phase III trials conducted in the Territory in accordance with the Development Plan) and post-marketing use of PPC-4187 in the Territory. Meridian shall ensure that its adverse event collection and processing systems are capable of identifying, documenting, assessing, and tracking all safety information arising from the Territory in a timely and compliant manner.
3.2.2 Meridian shall be responsible for preparing and submitting all Individual Case Safety Reports, Expedited Reports, and other safety-related regulatory submissions to all Regulatory Authorities in the Territory, including the NMPA (China), PMDA (Japan), MFDS (Republic of Korea), TGA (Australia), and all other Territory Regulatory Authorities, in full compliance with the local regulatory requirements and timelines applicable in each Territory jurisdiction.
3.2.3 Meridian shall transmit all safety data collected or received in connection with PPC-4187 in the Territory to Penterra for inclusion in the GSD, in accordance with the timelines, formats, and procedures specified in Article 5 and its associated Annexes. Meridian acknowledges that the timely and complete transmission of safety data to Penterra is essential for the maintenance of a comprehensive GSD and for compliance with Penterra's regulatory reporting obligations in the Retained Territory.
3.2.4 Meridian shall provide Territory-specific input for global PSURs and PBRERs prepared by Penterra, including local post-marketing data, territory-specific adverse event data, safety-related regulatory updates, and local literature monitoring results, in accordance with Article 7.
3.2.5 Meridian shall establish and maintain pharmacovigilance systems and qualified personnel in each Territory country and jurisdiction in which PPC-4187 is developed or marketed, as required by Applicable Laws. Without limitation, Meridian shall designate and maintain a qualified person responsible for pharmacovigilance (QPPV or equivalent) in each Territory country where such a designation is required by the relevant Regulatory Authority, and shall ensure that its pharmacovigilance systems meet the requirements of all applicable regulatory inspections.
3.2.6 Meridian shall ensure that all sublicense agreements entered into with Sublicensees in the Territory contain pharmacovigilance obligations that are no less protective than the obligations of Meridian under this Agreement, and that such sublicense agreements require Sublicensees to comply with the safety data exchange procedures, reporting timelines, and quality standards established by this Agreement.
3.2.7 Meridian shall ensure that its clinical trial insurance and product liability insurance coverage, whether obtained through Jade Dragon Insurance Limited or any equivalent insurer of comparable creditworthiness and financial strength, provides adequate coverage for pharmacovigilance-related activities, including the costs associated with adverse event reporting, safety-related regulatory actions, product recalls, and any claims arising from adverse events in the Territory.
3.2.8 Meridian shall promptly notify Penterra of any safety-related regulatory actions, communications, or decisions received from or issued by Regulatory Authorities in the Territory, including without limitation any safety-related labeling changes, clinical holds, post-marketing safety commitments, risk management requirements, product recalls, market withdrawals, field safety corrective actions, and requests for additional safety studies or data.
3.3 Shared Responsibilities. The Parties shall share the following pharmacovigilance responsibilities:
3.3.1 The Parties shall cooperate in good faith in signal detection, signal evaluation, benefit-risk assessment, and the development and implementation of risk management measures for PPC-4187, including through participation in the Joint Safety Review Committee and through the timely exchange of relevant safety data and analyses.
3.3.2 Each Party shall provide the other Party with prompt notification of any product recalls, market withdrawals, field safety corrective actions, or safety-related labeling changes affecting PPC-4187 in its respective territory of responsibility, and shall consult with the other Party in advance of implementing such actions to the extent practicable and consistent with patient safety and regulatory requirements.
3.3.3 Each Party shall designate qualified representatives to participate in the Joint Safety Review Committee established under Article 9 and shall ensure that its representatives are appropriately empowered to make decisions on behalf of such Party regarding pharmacovigilance matters within the scope of the JSRC's mandate.
3.3.4 Each Party shall maintain adequate pharmacovigilance staffing, systems, and standard operating procedures to fulfill its obligations under this Agreement, and shall ensure that its personnel involved in pharmacovigilance activities receive appropriate training in accordance with Article 16.
ARTICLE 4 — GLOBAL SAFETY DATABASE
4.1 Database Holder. Penterra shall be the sole holder and maintainer of the Global Safety Database (GSD) for PPC-4187. As Database Holder, Penterra shall have overall responsibility for the design, validation, operation, integrity, security, and maintenance of the GSD, and for ensuring that the GSD contains a complete and accurate record of all safety data relating to PPC-4187 from all sources and jurisdictions worldwide. The designation of Penterra as Database Holder reflects Penterra's position as the global rights holder and originator of PPC-4187 and is consistent with regulatory expectations for a single centralized pharmacovigilance database for a globally developed pharmaceutical product.
4.2 Database Format. The GSD shall be maintained in a validated pharmacovigilance database system that is compliant with ICH E2B(R3) standards and capable of: (a) receiving, storing, and retrieving Individual Case Safety Reports in ICH E2B(R3) format; (b) generating electronic ICSRs in ICH E2B(R3) XML format for regulatory submission to any Regulatory Authority worldwide; (c) supporting the generation of aggregate safety reports, line listings, and summary tabulations for PSUR/PBRER preparation, signal detection, and ad hoc safety analyses; (d) maintaining a complete audit trail of all data entries, modifications, and deletions; and (e) supporting periodic reconciliation of data between the GSD and any local pharmacovigilance databases maintained by Meridian or its Affiliates. Penterra shall ensure that the GSD undergoes periodic revalidation and that all software updates or system changes are implemented in accordance with applicable Good Pharmacovigilance Practices (GVP) and computerized systems validation requirements.
4.3 Data Entry Responsibility. Penterra shall be responsible for entering all ICSRs received from Meridian into the GSD. Meridian shall provide all ICSR data to Penterra in ICH E2B(R3)-compatible format, using the data fields and transmission protocols specified in Annex 2. In the event that Meridian is unable to transmit data in E2B(R3)-compatible electronic format due to technical constraints or system limitations, Meridian shall provide the data in CIOMS I form format (as a PDF or equivalent electronic document), and Penterra shall be responsible for entering such data into the GSD. The Parties shall work cooperatively to establish and maintain electronic gateway connectivity for automated or semi-automated ICSR transmission as soon as practicable following the Effective Date.
4.4 Data Access. Penterra shall provide Meridian with read-only access to the GSD for all ICSRs and safety data relating to PPC-4187 cases originating from the Territory, including both Territory-sourced cases and follow-up information for such cases. Meridian shall also be entitled to receive, upon reasonable written request, aggregated global safety data from the GSD to the extent necessary for Meridian's regulatory submissions in the Territory, including but not limited to data required for local PSUR/PBRER preparation, clinical trial application updates, marketing authorization applications, and responses to Regulatory Authority inquiries. Penterra shall respond to such data requests within fifteen (15) business days, or such shorter period as may be required by the applicable regulatory timeline. Meridian's access to the GSD shall be subject to Penterra's data security policies and reasonable access controls, and Meridian shall ensure that GSD access credentials are assigned only to authorized Meridian pharmacovigilance personnel.
4.5 Data Reconciliation. The Parties shall conduct a formal reconciliation of safety data between the GSD maintained by Penterra and any local pharmacovigilance databases maintained by Meridian or its Affiliates on a quarterly basis. Each reconciliation shall be completed within thirty (30) calendar days following the end of each calendar quarter (i.e., by January 30, April 30, July 30, and October 30 of each year, with the first reconciliation to be completed by January 30, 2024). Reconciliation reports shall be exchanged between the Parties and shall identify any discrepancies in case counts, case details, seriousness or expectedness assessments, or other data elements, together with proposed corrective actions. The detailed procedures for data reconciliation, including matching criteria, discrepancy resolution processes, and escalation mechanisms, are set forth in Annex 4.
4.6 Data Retention. All safety records and data relating to PPC-4187, including ICSRs, source documents, correspondence, and regulatory submissions, shall be retained by each Party for a minimum of fifteen (15) years following the date on which the last marketing authorization for PPC-4187 in any jurisdiction worldwide expires, is withdrawn, or is otherwise terminated, or for such longer period as may be required by Applicable Laws or by the terms of the License Agreement. During the retention period, each Party shall ensure that its safety records are stored securely and are readily retrievable for regulatory inspection, audit, or other legitimate purpose.
4.7 Costs. Penterra shall bear all costs and expenses associated with the establishment, maintenance, operation, and validation of the GSD, including hosting, software licensing, personnel, and system infrastructure costs. Meridian shall bear all costs and expenses associated with: (a) the establishment and maintenance of its local pharmacovigilance database systems and infrastructure; (b) the processing, assessment, and coding of ICSRs originating from the Territory; (c) the transmission of safety data to Penterra in accordance with this Agreement; and (d) the preparation and submission of regulatory safety reports to Territory Regulatory Authorities. Except as expressly set forth in this Section 4.7, each Party shall bear its own costs incurred in connection with its pharmacovigilance obligations under this Agreement.
ARTICLE 5 — INDIVIDUAL CASE SAFETY REPORTS (ICSRs) — EXCHANGE TIMELINES
5.1 Serious Adverse Events (SAEs) — Expedited Exchange. The Parties shall exchange ICSRs for Serious Adverse Events in accordance with the following timelines:
5.1.1 Fatal or Life-Threatening SAEs. For any Serious Adverse Event that results in death or is life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR (containing at minimum the four elements of a valid case) to the other Party within twenty-four (24) hours of Day 0 (as defined in Section 5.7). If a complete ICSR cannot be prepared within this timeframe, an initial notification containing all available information shall be transmitted within twenty-four (24) hours, to be followed by a complete ICSR as soon as practicable but in no event later than the timeframe specified in Section 5.1.2.
5.1.2 All Other SAEs. For all Serious Adverse Events not falling within Section 5.1.1 (i.e., SAEs that do not result in death and are not life-threatening), the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within three (3) calendar days of Day 0.
5.1.3 Follow-Up Information. Follow-up information for all Serious Adverse Events, including updated medical information, laboratory results, outcome data, causality assessments, and any other supplemental or corrective information, shall be transmitted by the reporting Party to the other Party within three (3) calendar days of receipt of such follow-up information.
5.2 Suspected Unexpected Serious Adverse Reactions (SUSARs). The Parties shall exchange ICSRs for SUSARs and comply with the following regulatory reporting timelines:
5.2.1 Fatal or Life-Threatening SUSARs. For any SUSAR that is fatal or life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within twenty-four (24) hours of Day 0. The responsible Party (as determined under Article 6) shall submit the Expedited Report to the applicable Regulatory Authority within seven (7) calendar days of Day 0, consistent with ICH E2A and ICH E2D requirements. The responsible Party shall submit follow-up information to the Regulatory Authority within an additional eight (8) calendar days (i.e., within fifteen (15) calendar days of Day 0 in total).
5.2.2 All Other SUSARs. For all SUSARs that are not fatal or life-threatening, the Party first becoming aware of the event shall transmit the initial ICSR to the other Party within three (3) calendar days of Day 0. The responsible Party shall submit the Expedited Report to the applicable Regulatory Authority within fifteen (15) calendar days of Day 0.
5.3 Non-Serious Adverse Events. The Parties shall exchange data for Non-Serious Adverse Events as follows:
5.3.1 Non-serious AEs originating from clinical trials and spontaneous reports shall be exchanged between the Parties in batched format on a monthly basis, with each batch to be transmitted within fifteen (15) calendar days following the end of the calendar month in which the events were received and processed by the reporting Party. Each monthly batch shall be accompanied by a summary listing identifying all cases included in the batch, organized by case number, report date, event term (coded using MedDRA), and seriousness/expectedness classification.
5.3.2 Notwithstanding Section 5.3.1, any Non-Serious Adverse Event that is subject to expedited reporting requirements under any Territory-specific regulation or any Retained Territory regulation shall be exchanged between the Parties within the shorter of: (a) the applicable regulatory reporting timeline; or (b) five (5) calendar days of Day 0. The Parties shall maintain an updated list of Territory-specific and Retained Territory-specific expedited reporting requirements that apply to Non-Serious AEs, and shall review and update such list at each quarterly JSRC meeting.
5.4 Special Situations Reports. Reports involving any of the following special situations shall be transmitted by the Party first becoming aware of the event to the other Party within three (3) calendar days of Day 0, regardless of the seriousness of the event:
(a) exposure to PPC-4187 during pregnancy or lactation (including paternal exposure);
(b) overdose (whether intentional or accidental), with or without an associated adverse event;
(c) lack of efficacy or therapeutic failure (particularly in situations where such lack of efficacy could be life-threatening or could result in serious consequences for the patient);
(d) medication errors, including dispensing errors, prescribing errors, and administration errors, with or without an associated adverse event;
(e) misuse, abuse, or off-label use of PPC-4187;
(f) occupational exposure to PPC-4187 (e.g., exposure of healthcare workers, caregivers, or manufacturing personnel);
(g) suspected transmission of an infectious agent via PPC-4187;
(h) drug-drug interactions or drug-food interactions involving PPC-4187 that result in or may result in adverse consequences; and
(i) any other situation deemed by either Party or by a Regulatory Authority to warrant reporting as a special situation.
5.5 Format. All ICSRs exchanged between the Parties shall be transmitted in CIOMS I form format (or the local equivalent form acceptable to the relevant Regulatory Authority) and, where technically feasible and where electronic gateway connectivity has been established between the Parties, in ICH E2B(R3) XML electronic format. The specific data fields required for each ICSR and the format specifications for electronic transmission are set forth in Annex 2. In all cases, ICSRs shall contain a complete narrative summary of the case, coded adverse event terms using the current version of the Medical Dictionary for Regulatory Activities (MedDRA), and a causality assessment.
5.6 Transmission Method. ICSRs and other safety data shall be transmitted between the Parties via one or more of the following methods: (a) secure, encrypted email to the designated pharmacovigilance contact points identified in Annex 1; (b) validated electronic gateway for E2B(R3) XML transmission, once such gateway has been established and validated by the Parties; or (c) such other secure transmission method as the Parties may mutually agree upon in writing. All transmissions containing patient-identifiable data, including initial and follow-up ICSRs, shall be encrypted using industry-standard encryption protocols (minimum AES-256 or equivalent) to ensure the confidentiality and security of personal health information during transmission.
5.7 Day Zero Rules. For the purposes of this Agreement, "Day 0" (the date of first awareness) shall be defined as the date on which any employee, agent, contractor, or representative of the Party (including any employee or representative of the Party's Affiliates or Sublicensees) who is engaged in pharmacovigilance, medical affairs, clinical operations, regulatory affairs, quality assurance, medical information, commercial operations, or any other function first receives information (whether in written, oral, electronic, or any other form) sufficient to constitute a valid ICSR (i.e., containing at a minimum the four elements of a valid case: an identifiable reporter, an identifiable patient, at least one suspected adverse reaction, and identification of the suspect product as PPC-4187 or Penteracitinib). For the avoidance of doubt, Day 0 is determined based on the date of first awareness by any person within the organization (not solely pharmacovigilance personnel), and the reporting Party shall have in place internal procedures to ensure prompt escalation of safety information from all functions to the pharmacovigilance department. Day 0 for the receiving Party (i.e., the Party to whom the ICSR is transmitted) shall be the date on which such Party receives the ICSR or notification from the reporting Party.
ARTICLE 6 — REGULATORY REPORTING RESPONSIBILITIES
6.1 Penterra's Reporting Obligations (Retained Territory).
6.1.1 Penterra shall be solely responsible for the preparation and submission of all regulatory safety reports, including ICSRs, Expedited Reports (IND safety reports under 21 C.F.R. § 312.32, NDA safety reports under 21 C.F.R. § 314.80, and equivalent reports under the regulations of other Retained Territory countries), and periodic safety reports, to the FDA and to all other Regulatory Authorities in the Retained Territory. Penterra shall ensure that all such regulatory submissions are made in compliance with the applicable timelines and formatting requirements established by the relevant Regulatory Authority.
6.1.2 Penterra shall be responsible for SUSAR reporting to all ethics committees and investigators participating in Penterra-sponsored clinical trials of PPC-4187 in the Retained Territory, in accordance with ICH E6(R2) (Good Clinical Practice), 21 C.F.R. Part 312, and all other Applicable Laws governing investigator notification in the Retained Territory.
6.2 Meridian's Reporting Obligations (Licensed Territory).
6.2.1 Meridian shall be solely responsible for the preparation and submission of all regulatory safety reports, including ICSRs, Expedited Reports, and periodic safety reports, to all Regulatory Authorities in the Territory. Meridian's Territory reporting obligations include, without limitation, submissions to the NMPA in the People's Republic of China, the PMDA in Japan, the MFDS in the Republic of Korea, the TGA in Australia, Medsafe in New Zealand, the Health Sciences Authority in Singapore, the Thai FDA in Thailand, the National Pharmaceutical Regulatory Agency in Malaysia, BPOM in Indonesia, the Philippine FDA in the Philippines, the Drug Administration of Vietnam in Vietnam, and the Taiwan Food and Drug Administration in Taiwan. Meridian shall ensure that all such regulatory submissions are made in compliance with the applicable timelines, formatting requirements, and language requirements established by each relevant Regulatory Authority.
6.2.2 Meridian shall be responsible for SUSAR reporting to all ethics committees, institutional review boards, and investigators participating in Meridian-sponsored clinical trials of PPC-4187 in the Territory, in accordance with ICH E6(R2) (Good Clinical Practice) and all applicable local regulations governing investigator notification in each Territory country.
6.2.3 Meridian shall comply with all country-specific reporting timelines and requirements applicable in the Territory, including without limitation:
(i) Japan (PMDA): 7-day and 15-day expedited reporting requirements under the Pharmaceutical and Medical Device Act (PMD Act) and applicable PMDA notifications, including PMDA-mandated case reporting for infections, deaths, and other serious events requiring 7-day expedited reporting;
(ii) China (NMPA): expedited individual case reporting requirements and periodic aggregate reporting requirements under the Provisions for Adverse Drug Reaction Monitoring and Reporting and other NMPA regulations applicable to clinical trials and post-marketing surveillance;
(iii) Republic of Korea (MFDS): periodic and expedited reporting requirements under the Pharmaceutical Affairs Act and applicable MFDS regulations;
(iv) Australia (TGA): 15-day expedited reporting for serious adverse events and SUSARs, and periodic reporting requirements under the Therapeutic Goods Act 1989 and associated regulatory instruments; and
(v) All other Territory jurisdictions: compliance with the applicable reporting timelines and requirements of each Regulatory Authority, including requirements arising from ASEAN regulatory harmonization initiatives.
6.2.4 Meridian shall ensure that regulatory safety submissions in the Territory are made through the appropriate Meridian entity or authorized representative in each jurisdiction, including: (a) Meridian Japan K.K. for submissions to the PMDA; (b) Meridian Pharma (Shanghai) Co., Ltd. for submissions to the NMPA; (c) Meridian Korea Inc. for submissions to the MFDS; and (d) Meridian Bio Australia Pty Ltd for submissions to the TGA. Meridian may also, where appropriate and in accordance with Applicable Laws, utilize its regulatory counsel, including Nakamura & Takeda Law Offices (Tokyo), as its authorized representative for regulatory submissions to the PMDA.
6.3 Cross-Referencing. Each Party shall provide the other Party with copies of all safety-related regulatory submissions (including ICSRs, Expedited Reports, and correspondence relating to safety matters) filed with Regulatory Authorities in its respective territory of responsibility within five (5) business days of the date of filing. Such copies may be provided in redacted form to the extent necessary to protect patient-identifiable information that cannot be shared under applicable data protection laws, provided that such redactions do not materially impair the other Party's ability to understand the substance of the submission.
6.4 Regulatory Authority Inquiries. Each Party shall promptly notify the other Party (and in any event within two (2) business days) of any safety-related inquiry, question, request for information, deficiency notice, inspection, or other communication received from any Regulatory Authority relating to PPC-4187, regardless of the territory from which such inquiry originates. The Parties shall cooperate fully and in good faith in preparing and submitting responses to such Regulatory Authority inquiries, and each Party shall provide the other Party with copies of all correspondence with Regulatory Authorities relating to safety matters within five (5) business days of sending or receiving such correspondence.
ARTICLE 7 — PERIODIC SAFETY UPDATE REPORTS (PSURs) AND PBRERs
7.1 Global PSUR/PBRER Preparation. Penterra shall be responsible for preparing global Periodic Safety Update Reports (PSURs) and Periodic Benefit-Risk Evaluation Reports (PBRERs) for PPC-4187 in accordance with ICH E2C(R2) and all applicable regulatory requirements. Penterra shall utilize data from the GSD, together with Territory-specific data and input provided by Meridian, to prepare each global PSUR/PBRER. Each PSUR/PBRER shall contain a comprehensive analysis of the worldwide safety experience with PPC-4187, including clinical trial data, post-marketing surveillance data, and data from all other sources, together with an updated benefit-risk evaluation.
7.2 Territory-Specific Input. Meridian shall provide Penterra with Territory-specific safety data, regulatory updates, and post-marketing information for inclusion in each global PSUR/PBRER. Such Territory-specific input shall include, without limitation: (a) aggregate data on all adverse events and serious adverse events reported in the Territory during the reporting period; (b) information regarding Territory-specific regulatory actions, labeling changes, or post-marketing commitments; (c) results of Territory-specific literature monitoring (including local-language literature); (d) data from any post-marketing studies, registries, or Phase IV trials conducted in the Territory; and (e) any other information requested by Penterra or by the JSRC that is relevant to the global benefit-risk assessment. Meridian shall provide such Territory-specific input to Penterra at least sixty (60) calendar days prior to each PSUR/PBRER data lock point.
7.3 Review Period. Penterra shall share the draft PSUR/PBRER with Meridian for review at least thirty (30) calendar days prior to the scheduled submission date. Meridian shall review the draft and provide written comments, corrections, and any additional Territory-specific information to Penterra within fifteen (15) calendar days of receipt of the draft. Penterra shall consider Meridian's comments in good faith and shall incorporate Meridian's Territory-specific data and corrections to the extent appropriate for the final PSUR/PBRER. Any disagreements between the Parties regarding the content of the PSUR/PBRER shall be discussed at the JSRC and, if not resolved, shall be escalated in accordance with Article 9.7.
7.4 PSUR Submission Responsibilities.
7.4.1 Penterra shall be responsible for submitting PSURs/PBRERs to all Regulatory Authorities in the Retained Territory, including the FDA (to the extent PSURs are required under U.S. regulations or as post-marketing commitments), the EMA (for any centralized procedure in the EU/EEA), and all other Retained Territory Regulatory Authorities.
7.4.2 Meridian shall be responsible for submitting PSURs/PBRERs (or the local equivalent periodic safety reports, such as the PMDA-format Periodic Safety Reports in Japan) to all Regulatory Authorities in the Territory. Meridian may adapt the global PSUR/PBRER prepared by Penterra to meet local formatting, content, or language requirements of each Territory Regulatory Authority, provided that the substance and conclusions of the global report are not materially altered without Penterra's prior written consent.
7.5 Frequency. The frequency of PSUR/PBRER preparation shall be determined by the most stringent Regulatory Authority requirement applicable globally. Unless otherwise required by a Regulatory Authority, the initial PSUR/PBRER preparation frequency shall be as follows:
(a) During clinical development: every six (6) months from the International Birth Date (IBD) of PPC-4187 or from the date of the first Investigational New Drug application (IND) filing, whichever is earlier;
(b) Upon first marketing authorization: annually from the IBD for the first two (2) years, then every three (3) years thereafter; and
(c) As otherwise required: at any additional frequency required by any Regulatory Authority in any jurisdiction.
The Parties shall coordinate through the JSRC to align PSUR/PBRER preparation schedules with the requirements of all applicable Regulatory Authorities worldwide.
7.6 Data Lock Points. Data lock points for each PSUR/PBRER shall be established and coordinated internationally by Penterra, in consultation with Meridian and the JSRC, to ensure consistency of the reporting period across all jurisdictions. Penterra shall notify Meridian of each data lock point at least ninety (90) calendar days in advance. Both Parties shall ensure that all safety data within their respective territories of responsibility are transmitted and entered into the GSD prior to each data lock point.
ARTICLE 8 — SIGNAL DETECTION AND RISK MANAGEMENT
8.1 Signal Detection. Penterra shall conduct signal detection activities for PPC-4187 on a global basis, using data from the GSD and such other data sources as Penterra deems appropriate, including published scientific and medical literature, pharmacoepidemiological databases, and regulatory databases. Signal detection methodologies shall include, at a minimum, regular review of individual serious adverse event reports, periodic aggregate data review, statistical disproportionality analyses (such as proportional reporting ratios and Bayesian analysis), and clinical review of cases of special interest. Meridian shall conduct supplementary signal detection activities using safety data from the Territory, focusing on Territory-specific safety issues, local epidemiological factors, and patterns of adverse event reporting that may be unique to Territory populations. Meridian shall share the results of its Territory-specific signal detection activities with Penterra and with the JSRC on a quarterly basis, or more frequently as warranted by emerging safety concerns.
8.2 Signal Notification. Any potential safety signal identified by either Party, whether through routine signal detection activities, review of individual case reports, analysis of aggregate data, review of scientific literature, or any other source, shall be communicated to the other Party in writing within three (3) business days of initial identification of the signal. The initial notification shall include a description of the signal, the data source(s) from which the signal was identified, a preliminary assessment of the strength and clinical relevance of the signal, and any supporting data available at the time of communication.
8.3 Signal Evaluation. All potential safety signals shall be evaluated jointly by the Parties through the Joint Safety Review Committee (JSRC) established under Article 9. Upon identification of a potential signal, the JSRC shall convene (either at its next scheduled meeting or at a special meeting if the urgency of the signal warrants) to review the available data and determine the appropriate course of action. Both Parties shall provide all relevant data and analyses requested by the JSRC within fifteen (15) calendar days of the JSRC's request, unless a shorter timeframe is agreed upon due to the urgency of the signal. Signal evaluation shall include, as appropriate, detailed case review, literature review, pharmacoepidemiological analysis, assessment of biological plausibility, evaluation of class effects, and consideration of the overall benefit-risk profile of PPC-4187.
8.4 Risk Evaluation and Mitigation Strategies (REMS) / Risk Management Plans (RMPs).
8.4.1 Penterra shall be responsible for the development, implementation, and maintenance of any Risk Evaluation and Mitigation Strategy (REMS) or other risk management measure required by the FDA or any other Retained Territory Regulatory Authority for PPC-4187 in the Retained Territory.
8.4.2 Meridian shall be responsible for the development, implementation, and maintenance of any Risk Management Plan (RMP) or equivalent risk management measure required by Territory Regulatory Authorities, including the NMPA, PMDA, MFDS, TGA, and all other Territory regulatory bodies, for PPC-4187 in the Territory. Meridian shall provide Penterra with copies of all RMPs and risk management measures developed for the Territory for Penterra's review and comment prior to submission to Territory Regulatory Authorities, to the extent practicable.
8.4.3 The Parties shall coordinate through the JSRC to ensure global consistency in the overall risk management approach for PPC-4187. While the specific risk management measures implemented in each territory may differ to reflect local regulatory requirements, prescribing practices, and healthcare systems, the Parties shall endeavor to maintain alignment in the core risk minimization messages and interventions to the extent consistent with patient safety and regulatory compliance.
8.5 Urgent Safety Measures. Either Party may, in its sole discretion, take urgent safety measures with respect to PPC-4187 in its respective territory of responsibility when such Party reasonably determines that urgent action is necessary to protect patient safety. Urgent safety measures may include, without limitation, suspension or termination of clinical trials, issuance of Dear Healthcare Provider letters or field safety notices, voluntary product recalls or market withdrawals, and implementation of new risk minimization measures. A Party taking urgent safety measures shall not be required to obtain the prior consent of the other Party before implementing such measures; provided, however, that the Party taking such measures shall: (a) notify the other Party of the urgent safety measures and the reasons therefor within twenty-four (24) hours of implementing such measures; and (b) consult with the other Party and with the JSRC as soon as practicable thereafter regarding the potential implications of such measures for the other Party's territory and the global benefit-risk profile of PPC-4187.
ARTICLE 9 — JOINT SAFETY REVIEW COMMITTEE
9.1 Establishment. A Joint Safety Review Committee ("JSRC") shall be established by the Parties within thirty (30) days of the Effective Date (i.e., by no later than November 19, 2023). The JSRC shall serve as the primary governance body for pharmacovigilance matters relating to PPC-4187, providing oversight and coordinatio

PHARMACOVIGILANCE AGREEMENT

PENTERRA PHARMACEUTICALS CORP.

MERIDIAN BIO THERAPEUTICS LIMITED

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