On May 26, 2022 Galera Therapeutics, Inc. (Nasdaq: GRTX), a clinical-stage biopharmaceutical company focused on developing and commercializing a pipeline of novel, proprietary therapeutics that have the potential to transform radiotherapy in cancer, reported data from its Phase 3 ROMAN trial of avasopasem for severe oral mucositis will be highlighted in an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Friday, June 3, 2022 from 2:45 p.m. – 5:45 p.m. CDT during the Head and Neck Cancer session (Press release, Galera Therapeutics, MAY 26, 2022, View Source [SID1234615084]). Topline data was announced in December 2021. Abstracts are currently available in the ASCO (Free ASCO Whitepaper) digital program.

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"We are pleased that our Phase 3 trial of avasopasem was selected for an oral presentation at ASCO (Free ASCO Whitepaper), where details of the clinically meaningful and statistically significant results will be shared," said Mel Sorensen, M.D., Galera’s President and CEO. "Our research shows that radiation oncologists and patients cite SOM as the most burdensome radiotherapy toxicity in head and neck cancer treatment, and there are currently no FDA-approved drugs to reduce the incidence or duration of SOM in solid tumors. Avasopasem has been granted Breakthrough Therapy and Fast Track Designations by the U.S. FDA for the reduction of SOM induced by radiotherapy, and we look forward to submitting a New Drug Application to the FDA by year end in order to bring this potential treatment to patients as quickly as possible."

Results from the 455-patient Phase 3 trial demonstrated a meaningful reduction in patients’ SOM burden across multiple endpoints, with statistically significant reductions on the primary endpoint of incidence of SOM and the secondary endpoint of number of days of SOM, more than halving the median number of days a patient suffered SOM. Exploratory analyses, such as time to SOM onset and SOM incidence at various landmarks of radiotherapy delivered, also demonstrated clinical benefit of avasopasem in reducing the burden of SOM. Avasopasem also appeared to be generally well tolerated compared to placebo. These results are consistent with those from the positive 223-patient Phase 2b trial (Anderson, J Clin Oncol, 2019) that was the basis for Breakthrough Therapy Designation.

Additionally, Galera’s Phase 2 GRECO-2 study of rucosopasem (GC4711) in combination with stereotactic body radiation therapy in pancreatic cancer will be presented at the ASCO (Free ASCO Whitepaper) Annual Meeting in a Trials in Progress poster session on Saturday, June 4, 2022, from 8:00 a.m. – 11:00 a.m. CDT. The primary endpoint of this trial is overall survival.

About Severe Oral Mucositis (SOM)
Approximately 42,000 patients with head and neck cancer undergo standard-of-care radiotherapy every year in the U.S. and are at risk of experiencing SOM. In patients with head and neck cancer, radiotherapy is a mainstay of treatment. Approximately 70 percent of patients receiving radiotherapy for head and neck cancer develop SOM, defined by the inability to eat solid food or drink liquids. The impact on patients who develop SOM is substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration are required. SOM can adversely affect cancer treatment outcomes by causing interruptions in radiotherapy, which may compromise the otherwise good prognosis for tumor control in many of these patients. There is currently no drug approved to prevent or treat SOM for these patients.

About Avasopasem
Avasopasem manganese (avasopasem, or GC4419) is a selective small molecule dismutase mimetic in development for the reduction of radiation-induced severe oral mucositis (SOM) in patients with locally advanced head and neck cancer (HNC) and for the reduction of radiation-induced esophagitis in patients with lung cancer. The FDA has granted Fast Track and Breakthrough Therapy designations to avasopasem for the reduction of SOM induced by radiotherapy, with or without systemic therapy.

On May 26, 2022 Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease (SCD), prostate cancer and other rare hematologic diseases and cancers, reported that it will hold a virtual R&D Day today to provide a comprehensive update on its pipeline and strategic vision (Press release, Forma Therapeutics, MAY 26, 2022, View Source [SID1234615083]).

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The R&D event is taking place today at 8:00 a.m. ET. A live webcast will be available in the "News & Investors" section of Forma’s website.

"We are pleased to share insights into Forma’s unique commitment to patients and expansion of etavopivat development into transfusion-dependent populations that have tremendous unmet need across sickle cell disease, thalassemia and MDS," said Frank Lee, president and chief executive officer of Forma.

"In our early stage research pipeline, we are excited to introduce a USP1 program that targets a novel DNA damage repair pathway relevant to a broad range of tumor types." said David Cook, chief scientific officer of Forma. "We are also capitalizing on our knowledge of the emerging science of red blood cell health by exploring areas beyond hematologic disease."

Etavopivat (oral PKR activator) Program in SCD, thalassemia and MDS:

In addition to ongoing enrollment in the Phase II/III Hibiscus Study in SCD, Forma will outline ongoing and anticipated future development plans:

A Phase II trial is enrolling patients in three cohorts: SCD with chronic transfusion, and both transfusion-dependent and non-transfusion-dependent thalassemia. Etavopivat has the potential to address RBC health, hemolytic anemia and/or ineffective erythropoiesis in these populations, leading to reduction of transfusion burden and associated iron overload and improvement of anemia.

A Phase II trial in lower risk MDS is planned to commence in the second half of 2022. Dr. Michael Savona of Vanderbilt University will review the significant unmet need in lower-risk MDS and the potential for etavopivat to provide a well-tolerated oral treatment that may be able to improve the ability of bone marrow to produce healthier RBCs.

Analyses from the completed Phase I trial in SCD show benefit in both pain events reported in the trial and vaso-occlusive crises (VOC’s) occurring on treatment.

Enrollment in the Phase II/III Hibiscus Study in SCD is on track for the first interim analysis (IA1) in late 2022.

FT-7051 (oral CBP/p300 inhibitor) in prostate cancer:

Forma’s Phase I trial continues to enroll men with metastatic castration-resistant prostate cancer (mCRPC).

As of May 12, 2022, 25 patients have enrolled in the Phase I dose escalation trial, assessing the predicted efficacious exposure range supported by target engagement.

The trial population is heavily pre-treated, with a high AR-v7 positivity rate and mutation burden.

Future trial enrollment to include less heavily pre-treated patients and alternative dosing schedule to address adverse events, with updated results expected in the first half of 2023.

Research Pipeline/RBC Health:

Forma’s ongoing research efforts are focused on novel mechanisms of action in oncology and expansion in red blood cell health and hematologic diseases:

Forma’s research pipeline is led by the USP1 program (FT-3171), targeting a novel DNA damage repair pathway with potential to address multiple tumor types in both poly ADP ribose polymerase inhibitor (PARPi)-sensitive and resistant settings.

FT-3171 IND filing is expected in the first half of 2023.

Ongoing pre-clinical research is targeting areas of expansion for RBC health, novel mechanisms that may be complementary to etavopivat in rare hematology, and targeted oncology.

On May 26, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported detailed results from multiple cohorts of the phase 1b COSMIC-021 trial of cabozantinib (CABOMETYX) as a monotherapy and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors (Press release, Exelixis, MAY 26, 2022, View Source [SID1234615081]). Data from urothelial carcinoma (UC) cohorts 3, 4 and 5 and from non-small cell lung cancer (NSCLC) cohorts 7 and 20 will be presented during oral abstract sessions at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held June 3-7.

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UC Cohorts 3, 4 and 5 (abstract 4504):

UC results will be presented by Sumanta Pal, M.D., Clinical Professor, City of Hope, and the principal investigator for the COSMIC-021 study beginning at 2:45 p.m. CT on Friday, June 3 during the Oral Abstract Session: Genitourinary Cancer – Kidney and Bladder. In these cohorts, enrolled patients had inoperable locally advanced or metastatic UC with transitional cell histology and Eastern Cooperative Oncology Group Performance Status of 0-1. Cohort 3 had not received prior systemic therapy for advanced/metastatic disease and was ineligible for cisplatin-based chemotherapy, cohort 4 had not received prior systemic therapy for advanced/metastatic disease and was eligible for cisplatin-based chemotherapy and cohort 5 had received one prior immune checkpoint inhibitor (ICI) and no prior vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients in all three cohorts received cabozantinib in combination with atezolizumab.

At a median follow-up of 27.9 months for cohort 3, 19.1 months for cohort 4 and 32.9 months for cohort 5, the primary endpoint of objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator was 20%, 30% and 10%, respectively. Cabozantinib in combination with atezolizumab demonstrated encouraging clinical activity for other endpoints and a manageable safety profile across all three cohorts. See other efficacy outcomes, the most common treatment-related adverse events (AEs) and discontinuation rates in Table 1 below.

"People with advanced bladder cancer face a poor prognosis, meaning new treatment options are needed, both in the first-line setting and after disease progression," said Dr. Pal. "Building on previous positive results in bladder cancer from cohort 2 of COSMIC-021, the findings that the combination of cabozantinib and atezolizumab benefited multiple bladder cancer populations are encouraging for these patients and their physicians. These results, together with the newest findings from multiple COSMIC-021 lung cohorts also being presented at ASCO (Free ASCO Whitepaper), underscore the broad potential of this combination regimen for patients with advanced cancers who require additional treatment options."

NSCLC Cohorts 7 and 20 (abstract 9005):

Results for cohorts 7 and 20 will be presented by Joel Neal, M.D., Ph.D., Associate Professor of Medicine (Oncology), Stanford School of Medicine, beginning at 1:00 p.m. CT on Friday, June 3 during the Oral Abstract Session: Lung Cancer – Non-Small Cell Metastatic. Eligible patients had stage IV non-squamous NSCLC and had progressed on one prior ICI, with no more than two lines of prior systemic anticancer therapy, but not VEGFR-TKI therapy. Patients received either cabozantinib in combination with atezolizumab (cohort 7) or cabozantinib alone (cohort 20).

At a median follow-up of 24.7 months for cohort 7 and 21.5 months for cohort 20, the primary endpoint of ORR per RECIST version 1.1 by investigator was 19% and 6%, respectively. A manageable safety profile was seen in both cohorts. Other efficacy outcomes, the most common treatment-emergent AEs and discontinuation rates are shown in Table 2 below. In cohort 7, clinical activity was observed with cabozantinib in combination with atezolizumab irrespective of PD-L1 expression.

"We are pleased to present these promising findings of cabozantinib in combination with atezolizumab at ASCO (Free ASCO Whitepaper) 2022, reinforcing our longstanding commitment to advancing therapies that improve outcomes for those with advanced solid tumors," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "We look forward to continuing research for these cancers, including through our ongoing phase 3 CONTACT-01 pivotal trial of cabozantinib in combination with atezolizumab in non-small cell lung cancer. Beyond cabozantinib, we launched the phase 1b STELLAR-001 and STELLAR-002 trials of our next-generation TKI, XL092, in combination with immunotherapies in genitourinary cancers, and we are also studying our next-generation tissue factor-targeting antibody-drug conjugate, XB002, in advanced solid tumors, including lung and bladder cancers."

Includes 8 patients who initiated therapy with cabozantinib plus atezolizumab after experiencing disease progression.

About COSMIC-021

COSMIC-021 is a multicenter, phase 1b, open-label study that enrolled a total of 914 patients. The trial was divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced renal cell carcinoma (RCC) with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra), after prior platinum-based therapy. Ultimately, all 12 patients who enrolled in this stage of the trial had advanced RCC. The dose-escalation phase of the study determined the recommended dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every three weeks).

In the expansion phase, the trial enrolled a total of 902 patients across 23 cohorts in 12 tumor types: RCC, UC, NSCLC, metastatic castration-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer and differentiated thyroid cancer (DTC).

Four of the cohorts were exploratory single-agent cohorts: two in advanced UC or NSCLC, one in advanced CRPC evaluating cabozantinib as a single-agent, and one in advanced CRPC evaluating single-agent atezolizumab.

Exelixis is the study sponsor of COSMIC-021. Both Ipsen Pharma SAS (Ipsen) and Takeda Pharmaceutical Company Limited (Takeda) have opted in to participate in the trial and are contributing to the funding for this study under the terms of the companies’ respective collaboration agreements with Exelixis. Roche is providing atezolizumab for the trial.

More information about COSMIC-021 is available at ClinicalTrials.gov.

About UC

UC is the most common type of bladder cancer, accounting for 90% of all cases.1 Bladder cancer is the sixth most common cancer in the U.S., with more than 81,000 new cases expected to be diagnosed in 2022.2 Bladder cancer occurs mainly in older people and is more common in men.3 Over half of cases are found at early stages, when the five-year survival rate is 96%. The five-year survival rate is only 7.7%, however, for metastatic disease.4

About NSCLC

Lung cancer is the second most common type of cancer in the U.S., with more than 236,000 new cases expected to be diagnosed in 2022. The disease is the leading cause of cancer-related mortality in both men and women, causing 25% of all cancer-related deaths. The majority (84%) of lung cancer cases are NSCLC, which mainly comprise adenocarcinoma, squamous cell carcinoma and large cell carcinoma.5,6 The five-year survival rate for patients with NSCLC is 26%, but that rate falls to just 7% for those with advanced or metastatic disease.7 More than half of lung cancer cases are diagnosed at an advanced stage, and more options are needed for these patients.8

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX is not indicated as a treatment for metastatic UC or NSCLC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

On May 26, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported results from a phase 2, investigator-sponsored trial of cabozantinib (CABOMETYX) in combination with pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) (Press release, Exelixis, MAY 26, 2022, View Source [SID1234615080]). The data will be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting during Oral Abstract Session: Head and Neck Cancer on Friday, June 3 beginning at 2:45 p.m. CT.

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The trial met its primary endpoint of objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 54%. The overall clinical benefit rate was 91%. At a median follow-up of 10.6 months, the one-year progression-free survival rate was 54.0% (95% confidence interval [CI]: 31.5-72.0%), and median progression-free survival was 14.6 months. The one-year overall survival (OS) rate was 68.4% (95% CI: 45.1-83.5%; median OS: 22.3 months). For the 17 patients with a PD-L1 combined positive score (CPS) under 20, the one-year OS rate was 54.9% (95% CI: 24.5-77.5%; median OS: 14.6 months). For the 17 patients with a CPS score of 20 or more, the one-year OS rate was 83.6% (95% CI: 48.0-95.7%; median OS: 32.9 months).

"Metastatic head and neck cancer is a challenging disease to treat, particularly following disease progression after definitive therapy, meaning patients need additional options beyond radiation and chemotherapy," said Nabil F. Saba, M.D., Professor and Vice Chair, Hematology and Medical Oncology, The Lynne and Howard Halpern Chair in Head and Neck Cancer Research, Co-Director of Head and Neck Cancer Multidisciplinary Program, Winship Cancer Institute, Emory University, and primary investigator of the investigator-sponsored trial. "These results showing promising clinical activity of cabozantinib in combination with pembrolizumab are encouraging to these patients who face poor outcomes."

In this phase 2 trial, eligible patients had recurrent or metastatic HNSCC that was deemed inoperable, with measurable disease per RECIST version 1.1, a life expectancy of at least 3 months and an Eastern Cooperative Group Performance Status of 0 or 1. Of the 36 evaluable patients, 61% had cancer in the oropharynx, 16% in the nasopharynx, 11% in the larynx, 6% in the hypopharynx and 6% in the oral cavity. Eighty-nine percent of patients had received prior radiation therapy and all had received prior chemotherapy.

The most frequent adverse events (AEs) were fatigue (44.4%), diarrhea (33.3%), hypothyroidism (33.3%), constipation (30.6%), dry mouth (27.8%), anorexia (25.0%), headache (25.0%), hypertension (25.0%), hyponatremia (25.0%) and oral mucositis (25.0%). Grade 3/4 treatment-related AEs were aspartate aminotransferase (AST) increase (8.3%), hyponatremia (8.3%), gamma-glutamyl transferase increase (5.6%), lipase increase (5.6%), oral mucositis (5.6%), alanine transaminase/AST increase (2.8%), bilirubin increase (2.8%) and hypertension (2.8%). Dose reductions occurred in 47.2% of patients, and AEs leading to discontinuation occurred in 25.0% of patients.

"Treatment options for patients with metastatic head and neck squamous cell carcinoma are limited, leaving a critical unmet need for this community," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "These data support the further development of a combination regimen of cabozantinib and an immune checkpoint inhibitor in patients with metastatic head and neck carcinoma and we are pleased to share these data at ASCO (Free ASCO Whitepaper). Through our research, including our investigator-sponsored trials program, we continue to advance toward our goal of bringing new treatment options to people with difficult-to-treat cancers."

About HNSCC

HNSCC comprises head and neck cancers that begin in the squamous cells that line the mucosal surfaces of the head and neck.1 Accounting for about 90% of all head and neck cancers, HNSCC is classified by its location: it can occur in the oral cavity, oropharynx, nasal cavity and paranasal sinuses, nasopharynx, larynx or hypopharynx.1,2 Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16.3 About 50,000 new cases of HNSCC are diagnosed in the U.S. every year.1 HNSCC is more common among men and people over the age of 50.4 Depending on the site of the cancer and level of metastases, the five-year survival rate for metastatic HNSCC ranges from 4-35%.5

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX is not indicated as a treatment for recurrent or metastatic HNSCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

On May 26, 2022 Evogene Ltd. (NASDAQ: EVGN) (TASE: EVGN), a leading computational biology company targeting to revolutionize life-science product discovery and development across multiple market segments, reported its financial results for the first quarter ended March 31, 2022 (Press release, Evogene, MAY 26, 2022, View Source [SID1234615079]).

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Mr. Ofer Haviv, Evogene’s President and Chief Executive Officer, stated, "Our subsidiaries continue to advance and we see many of them now at an inflection point, meeting critical milestones and the inherent value of our subsidiaries is becoming increasingly obvious.

"Evogene’s overarching goal is to revolutionize the development process of new and novel life-science based products, via our cutting-edge technologies. Our three tech-engines, relying on our computational predictive biology platform, are the driving force behind our activities, and they serve as the underlying competitive advantage of each our subsidiaries. Our goal is to maximize the value we can capture from our technology, through the end-products developed by its use. We have built a business ecosystem around each of our tech engines, primarily in the form of separate subsidiaries, each of which empowers multiple product development, and in addition, through strategic collaborations. We believe that over the long-term, significant value will be generated through our equity stake in the subsidiaries and royalties generated from end-products developed in the framework of collaborations."

"During the quarter, we took a number of steps to strengthen our management team, including appointing Yaron Eldad as our new Chief Financial Officer, bringing significant financial experience, and I welcome him to the Evogene family. We also promoted Sassi Masliah as Executive Vice President, responsible for relationship management with our subsidiaries, and Liat Foigel Wejgman as VP Human Resources. I believe that for a disruptive company at the crossroads of life science and leading-edge technologies, it is critical that we attract and retain the best people."

"We continue to maintain a strong cash position of approximately $45 million as of March 31, 2022. While this gives us a long runway, even in the current challenging market environment, we continue to work to diversify funding sources at the subsidiary level. We aim to partner with value-adding companies and investors at the subsidiary level, who can better value and appreciate the potential from the products that our subsidiaries are developing. We believe this will allow us to demonstrate in a very public way the subsidiaries’ very significant untapped value," Mr. Haviv concluded.

Recent Milestones and Achievements:

Biomica Ltd.

As previously announced, during 2021, Biomica achieved positive results from a series of pre-clinical studies for BMC333, indicating reduction of intestinal tissue damage resulting from inflammatory bowel disease (IBD), a serious disease with a potential $20 billion market opportunity[1]. These results provided the evidential groundwork to proceed to the scale up development process of BMC333.

In April 2022, Biomica announced an agreement with Sheba Medical Center, a global top 10 ranked hospital by Newsweek, for joint microbiome clinical research. The goal is to conduct deep sequencing and high-resolution microbiome analysis of samples obtained from patients with IBD. Biomica expects this analysis will be highly complementary to the company’s previous work on IBD and will enable the development of new drug candidates for these diseases. The upcoming milestone for 2022 is to initiate scale-up for GMP production of BMC333 as preparation for clinical trials.

Biomica also recently received clearance from the Israeli Ministry of Health to proceed to a first-in-human phase I study, which is set to be held at the Rambam Healthcare Campus in Israel. This milestone follows the completion of a series of pre-clinical trials with BMC128 given in combination with Immune Checkpoint Inhibitors immunotherapy, indicating significant improvement in anti-tumor activity. Biomica is currently advancing towards the initiation of the study. The milestone for 2022 would be initial readout from this proof of concept, first-in-human study.

Canonic Ltd.

During October 2021, Canonic began initial commercial sales of its first products from the MetaYield program in Israel. The products, named G200 and G150, are cannabis inflorescence marketed under the T20/C4 and T15/C3 categories, respectively[2]. The milestone for 2022 is the commercial launch of second-generation MetaYield products in Israel.

In January 2022, Canonic shipped a first batch of its unique cannabis varieties to a potential cultivation sub-contractor in Portugal. The goal is to test those varieties under European growing conditions as well as to enter into commercial agreements with local growers and manufacturers in Europe to meet the milestone of commercialization in Europe in 2023.

For the Precise program, during 2020-2021, Canonic conducted pre-clinical trials, identifying cannabis varieties with pain relief and anti-inflammatory properties, for which Canonic recently filed a patent application. In January 2022, Canonic announced positive results in pre-clinical studies that supported the successful identification of specific cannabis varieties with anti-inflammatory and pain relief properties. The upcoming milestone for 2022 is to gather additional clinical information to support the commercial launch of these products in 2023.

AgPlenus Ltd.

AgPlenus is currently working on expanding the data package regarding the company’s leading herbicide product candidate, APH1, as part of preparation for a potential future collaboration. The upcoming milestone for 2022 is to enter into an additional collaboration agreement in the field of herbicides.

In addition, together with Evogene’s ‘ChemPass AI’ team, AgPlenus is continuously working to expand computational and validation capabilities to enhance the discovery of novel pesticide compounds.

Lavie Bio Ltd.

result, the brand name of Lavie Bio’s inoculant (bio-stimulant) for spring wheat, was launched during late 2021. A few weeks ago, it was announced that Lavie Bio successfully produced and fully sold its planned production quota to U.S. customers for result.

Global wheat prices have recently increased significantly due to supply chain constraints and global shortages, which have been compounded by the war between Russia and Ukraine, the world’s first and fifth largest wheat exporters, respectively.

Current high wheat prices have made it highly economical for growers to explore ways to increase wheat production, by increasing yields. Lavie Bio’s trials showed that result potentially contributes an additional 3-4 bushels per acre via yield improvements, which could translate to additional significant profit for growers at an average of $30-40 per acre.

Looking ahead, Lavie Bio’s management is working on expanding production for the 2023 growing season, compared to its original market penetration plan. Lavie Bio is also aiming to broaden sales throughout North American markets, including Canada, in the near-term, and later, European markets. Furthermore, the aim is to expand the label to include additional crops, such as small grains and oil seed.

With regard to the pipeline advancement, following the completion of three consecutive years of vineyard trials, conducted in Europe and in the U.S., the bio-fungicide fruit rot program is continuing to progress. Upcoming milestones in 2022 aim to submit a regulatory dossier with the federal U.S. EPA and California EPA and file for regulatory approval for leading candidate LAV311, as preparation for commercialization in 2024.

Consolidated Financial Results Summary

Cash position: Evogene continues to maintain a strong financial position for its activities with approximately $44.6 million in consolidated cash, cash related accounts, bank deposits and marketable securities as of March 31, 2022. Approximately $6.6 million of Evogene’s consolidated cash is appropriated to its subsidiary, Lavie Bio. The Company does not have bank debt.

During the first quarter of 2022, the consolidated cash usage was approximately $9.3 million, or approximately $7.6 million if excluding Lavie Bio. This cash usage this quarter included $1 million of financing expenses due to the USD/NIS exchange rate differences and a decrease in marketable securities value and approximately $700 thousand of non recurring expenses, such as annual bonus payments to Evogene employees and establishing production capability for Lavie Bio. As stated at the previous quarter, the estimated cash usage for 2022 is expected to be in the range of $26-28 million, of which approximately $7.6 million will be used by Lavie Bio.

Revenues for the quarter were $237 thousand, in comparison to $333 thousand in the same period the previous year. Revenues were primarily due to sales of Canonic products and a joint research project conducted by AgPlenus.

R&D expenses for the quarter, which are reported net of non-refundable grants received, were $5.6 million, in comparison to $4.3 million in the same period the previous year. R&D expenses increased primarily due to:

Biomica’s ongoing preparations, including GMP microbe production, for the initiation of its first-in-human proof-of-concept study in the immuno-oncology program;
Lavie Bio’s activities supporting the production and commercial launch of its inoculant product, branded as result; and
Canonic’s products commercialization efforts in Israel and Europe.
Business and Development expenses were approximately $908 thousand for the first quarter of 2022, in comparison to $570 thousand in the same period the previous year. The increase in the Business and Development expenses was primarily due to recruitment of business development personnel supporting the commercialization activities of our subsidiaries.

General and Administrative expenses remained steady, and for the first quarter of 2022 were $1.6 million, in comparison to $1.5 million in the first quarter of 2021.

Operating expenses were $8.1 million in the first quarter of 2022 versus $6.3 million in the same period the previous year. Overall operating expenses increased among other reasons due to an increase in the activities described above, as well as headcount and salary increases, due to a growth in market demand for highly skilled workers.

The net loss for the quarter was $9.1 million in comparison to $7.1 million in the same period the previous year. The increase in loss is attributed mainly to the increase in operating expenses as described above and to the increase in financing expenses.

Replay Information: A replay of the conference call will be available approximately two hours following the completion of the call.

To access the replay, please dial 1-888-326-9310 toll free from the United States, or +972-3-925-5901 internationally. The replay will be accessible through May 28, 2022, and an archive of the webcast will be available on the Company’s website.

The Company presentation can be viewed here: View Source

[1] Grandview Research. Source: View Source,4.4%25%20from%202018%20to%202026.

[2] According to the product categories established by the Israeli Ministry of Health, T20/C4 category means 17%-24% THC & 1%-7% CBD and T15/C3 category means 11%-19% THC & 0.5%-5.5% CBD.