Gilead Receives CHMP Positive Opinion For Trodelvy® In Pre-Treated HR+/HER2- Metastatic Breast Cancer

On June 23, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Trodelvy (sacituzumab govitecan) as monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who have received endocrine-based therapy, and at least two additional systemic therapies in the advanced setting (Press release, Gilead Sciences, JUN 23, 2023, View Source;Metastatic-Breast-Cancer/default.aspx [SID1234632877]). The final European Commission decision on the additional indication for Trodelvy is anticipated later in 2023.

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"This positive opinion from the Committee confirms the clinical benefit and value of sacituzumab govitecan in pre-treated HR+/HER2- metastatic breast cancer and is a positive step toward bringing this treatment option to patients in Europe," said Dr. Javier Cortes, Head of the International Breast Cancer Center, in Madrid and Barcelona, Spain. "Too many people living with pre-treated HR+/HER2- metastatic breast cancer are without treatment options after their cancer progresses, and this positive opinion is a significant step forward for patients and their loved ones across Europe."

The CHMP positive opinion is supported by results from the Phase 3 TROPiCS-02 study, in which Trodelvy demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit of 3.2 months versus comparator single-agent chemotherapy (treatment of physician’s choice; TPC) (median OS: 14.4 months vs. 11.2 months; hazard ratio [HR]=0.79; 95% CI: 0.65-0.96; p=0.02). Trodelvy also demonstrated a 34% reduction in risk of disease progression or death (median PFS: 5.5 vs. 4.0 months; HR: 0.66; 95% CI: 0.53-0.83; p=0.0003). Three times as many people treated with Trodelvy were progression-free one year versus those treated with chemotherapy (21% vs. 7%).

"When patients with HR+/HER2- metastatic breast cancer develop resistance to endocrine-based therapies, treatment options are limited," said Bill Grossman, M.D., Ph.D., Senior Vice President, Therapeutic Area Head, Gilead Oncology. "Trodelvy has the potential to change this outlook, and we aim to build on the demonstrated benefits in second-line metastatic triple-negative breast cancer. This positive recommendation from the CHMP marks another important step toward making a difference for patients with pre-treated HR+/HER2- metastatic breast cancer in Europe."

In the TROPiCS-02 study Trodelvy also significantly improved additional secondary endpoint measures, including objective response rate and time to deterioration (TTD) assessed by the Global Health Status/Quality of Life and Fatigue scale per EORTC-QLQ-C30. No statistically significant difference in TTD in Pain Scale was observed.

The safety profile for Trodelvy is well-characterized and consistent with prior studies, with no new safety signals identified in this patient population. In TROPiCS-02, the most frequent serious adverse reactions (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), and abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). No patients treated with Trodelvy in TROPiCS-02 experienced interstitial lung disease (ILD). In the TROPiCS-02 study, the discontinuation rate due to adverse reactions was 6% for Trodelvy and 4% for patients on single-agent chemotherapy.

The ESMO (Free ESMO Whitepaper) Living Guidelines have been updated to include Trodelvy as a category I, A, magnitude of clinical benefit (MCBS) score 3, for HR+/HER2- metastatic breast cancer patients.i

Trodelvy is also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network (NCCN) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines).ii

Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Metastatic Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 34%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitor and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 40 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.

Trodelvy is also approved in the U.S. for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting and has an accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer; see below for full U.S. indication statements.

Trodelvy is also being developed for potential investigational use in other TNBC and HR+/HER2- metastatic and adjuvant breast cancer populations. It is also being investigated across a range of tumors, including metastatic urothelial cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indications for Trodelvy

In the United States, Trodelvy is indicated for the treatment of:

Adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Adult patients with unresectable locally advanced or metastatic HR+/HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
Adult patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent doses.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI.

Diarrhea: Diarrhea occurred in 64% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 64% of all patients treated with Trodelvy and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%).

In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes.

In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

Please see full Prescribing Information , including BOXED WARNING.

Sonnet BioTherapeutics Announces Presentations at the 2023 Cytokine-Based Drug Development Summit and Provides Preliminary Update on the SON-080 Study in Chemotherapy-Induced Peripheral Neuropathy

On June 23, 2023 Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) ("Sonnet" or the "Company"), a biopharmaceutical company developing innovative targeted biologic drugs, reported that John Cini, PhD, Chief Scientific Officer and Co-Founder, and Richard Kenney, MD, Chief Medical Officer, will be featured speakers at the 4th Annual Cytokine-Based Drug Development Summit in Boston, Massachusetts, June 27-29 (Press release, Sonnet BioTherapeutics, JUN 23, 2023, View Source [SID1234632876]).

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Presentation details:
June 27, 1:00 – 4:00 pm
John Cini will co-lead a workshop entitled, "Examining Cytokine Biology to Develop a Specific &
Effective Drug"

June 29, 2:40 – 3:10 pm
Richard Kenney will deliver a talk entitled, "A Tale of Two Forms of IL-12: The Benefits of Extending PK"

CIPN Study (SB211) Preliminary Update
In the SB211 study, patients are being randomized to one of three treatment groups that receive 20 µg SON-080, 60 µg SON-080, or a matching placebo in a blinded fashion, three times a week for 12 weeks. As of June 22, 2023, seven patients have been enrolled. While the groups remain blinded, doses have been tolerated well with some mild-to-moderate transient injection site reactions. As the protocol requires a total of nine patients to be dosed for at least two weeks before a safety review by the Data Safety Monitoring Board (DSMB), we expect the DSMB to meet during the third quarter of 2023. Following the completion of the DSMB review, we anticipate announcing the initial safety data.

Kyowa Kirin Received Partial Change Approval of Antineoplastic Mitomycin C Agent in Japan

On June 23, 2023 Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE:4151, President and CEO: Masashi Miyamoto) reported that the company has received approval from the Ministry of Health, Labour and Welfare ("MHLW") for partial change of its antineoplastic mitomycin C agents (Mitomycin Injection 2 mg and Mitomycin Injection 10 mg) for the purpose of changing to a manufactured product in-licensed from Intas Pharmaceuticals Ltd. (Intas) (Press release, Kyowa Hakko Kirin, JUN 23, 2023, View Source [SID1234632875]).

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Kyowa Kirin voluntarily recalled its mitomycin C agent from October 2019 due to the discovery of facts that could affect the assurance of sterility in the API manufacturing process. Since then, Kyowa Kirin has been taking all possible actions to resume the supply of this product. In September 2022, Kyowa Kirin submitted an application to seek approval of Intaslicensed mitomycin C agent for use as an antineoplastic agent in Japan. Currently, the supply is under preparation and will be started when it is ready.

Apart from above, the topical ophthalmic mitomycin C agent (MITOMYCIN 2 mg for Ophthalmic Topical Use) had been approved by MHLW on December 23, 2022 and has been listed on the NHI (National Health Insurance) drug price list on May 24, 2023. Currently Kyowa Kirin is making preparation for its launch.

The Kyowa Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

HiFiBiO Therapeutics Announces First Patient First Visit for the Evaluation of HFB200301 in Combination with Tislelizumab in Patients with DIS® Selected Advanced Solid Tumors

On June 23, 2023 HiFiBiO Therapeutics, a multinational clinical-stage biotherapeutics company, reported that the first patient has been dosed with HiFiBiO’s HFB200301, a first-in-class agonistic anti-TNFR2 monoclonal antibody, in combination with tislelizumab, an investigational anti-PD-1 immune checkpoint inhibitor, for the treatment of advanced solid tumor indications preselected by HiFiBiO’s proprietary Drug Intelligence Science (DIS) platform (Press release, HiFiBiO Therapeutics, JUN 23, 2023, View Source [SID1234632874]).

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This open-label, multi-center, Phase 1a/b study of HFB200301 and tislelizumab (NCT05238883) investigates the safety and tolerability of this combination therapy. Data from the trial will inform the combination dose and dosing regimen, further indication selection, and biomarker strategy.

"Having the first patient dosed with HFB200301 and tislelizumab combination therapy is a significant milestone for HiFiBiO." commented Liang Schweizer, PhD, Founder, CEO, and Chairperson of HiFiBiO Therapeutics, "This marks a major step toward further understanding the therapeutic activity of HFB200301 and how we can best deliver safe and effective treatment strategies for cancer patients where other therapeutic options have failed."

Under the terms of a previous clinical supply agreement, Novartis will supply tislelizumab for use in combination with HFB200301 and HiFiBiO Therapeutics will maintain control of the HFB200301 program, including global R&D and commercial rights.

HFB200301
HFB200301 is a first-in-class agonistic anti-TNFR2 antibody that binds potently and selectively to TNFR2, and induces the activation of CD4 T cells, CD8 T cells, and NK cells. HFB200301 demonstrates potent antitumor activity as a single agent and in combination with anti-PD-1 in animal models. HiFiBiO is applying a biomarker strategy by leveraging its DIS platform to select indications that may benefit the most from HFB200301 as a monotherapy as well as combination therapy.

Tislelizumab
Tislelizumab is an investigational humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Heron Therapeutics Announces Appointment of Ira Duarte as Chief Financial Officer

On June 23, 2023 Heron Therapeutics, Inc. (Nasdaq: HRTX), a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments to address some of the most important unmet patient needs, reported the appointment of Ira Duarte as Chief Financial Officer (Press release, Heron Therapeutics, JUN 23, 2023, View Source [SID1234632873]). Ms. Duarte has more than twenty-five years of experience in a variety of finance and accounting positions, including over a decade in the pharma industry.

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"I am excited to welcome Ira to Heron as Chief Financial Officer," said Craig Collard, Chief Executive Officer of Heron. "I had the pleasure of previously working with Ira and I look forward to her contributions as we continue to develop long-term plans aimed at maximizing the potential of Heron’s commercial portfolio."

Ms. Duarte brings significant experience and expertise in financial leadership to Heron. Prior to joining Heron, Ms. Duarte served in financial leadership roles from 2016 – 2023, most recently as Chief Financial Officer, at Veloxis Pharmaceuticals, Inc., a fully integrated specialty pharmaceutical company. Prior to that, Ms. Duarte served as the Corporate Controller at BioDelivery Sciences, Inc. from 2014 – 2016, and from 2009 – 2014 she was Senior Director of Corporate Finance for Chiesi USA, Inc. and Director of Accounting and Financial Planning for Cornerstone Therapeutics, Inc., where she was a core member of the team that guided the sale of Cornerstone Therapeutics, Inc. to Chiesi Farmaceutici S.p.A. Ms. Duarte previously held various roles from Staff to Senior Manager at Ernst & Young Global Limited. Ms. Duarte currently serves on the board of directors of TerrAscend Corporation and has since December 2022. Ms. Duarte is a Certified Public Accountant and holds a BS in Accounting from Florida Atlantic University.

"Heron is a commercial-stage company with tremendous potential for growth in the post-operative pain and oncology markets, with four products that deliver relief to thousands of people worldwide," said Ms. Duarte. "My immediate priority is to work with the accomplished management team and board of directors to identify ways to reduce our cash burn through improved operational efficacy. I am excited to join the team and believe that Heron has a bright future."

In connection with the commencement of Ms. Duarte’s employment, Heron granted Ms. Duarte an inducement award consisting of (i) a non-statutory stock option to purchase 800,000 shares of Heron common stock (Inducement Option), (ii) restricted stock units consisting of 50,000 shares of Heron common stock (Inducement RSUs), and (iii) a non-statutory stock option to purchase up to 500,000 shares of Heron common stock based upon the achievement of certain common stock price goals (Inducement PSO). The Inducement Option and Inducement PSO each have an exercise price based on the closing price per share as reported on the Nasdaq Capital Market as of June 16, 2023, the effective date of the grants and the start date of Ms. Duarte’s employment with Heron. The Inducement Option has a 10-year term with a four-year vesting schedule, with 25% of the shares subject to the option vesting on the first anniversary of the grant date and the remaining 75% vesting on a monthly basis over the next three years, subject to Ms. Duarte’s continuous service through each vesting date. The Inducement RSUs vest as to 25% of the shares subject to the Inducement RSUs on each of the first four anniversaries of the grant date, subject to Ms. Duarte’s continuous service through each such vesting date. The Inducement PSO has a 10-year term and vests as to a certain number of shares of the Company’s common stock upon achievement of certain stock price goals during Ms. Duarte’s employment with the Company and during the term of the Inducement PSO, subject to Ms. Duarte’s continuous service through each such vesting date. In accordance with Nasdaq Listing Rule 5635(c)(4), the inducement award grants were approved by Heron’s Board of Directors and Heron’s Compensation Committee of the Board of Directors and were made as a material inducement to Ms. Duarte entering into employment with Heron.