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Evogene Reports Third Quarter 2023 Financial Results

On November 15, 2023 Evogene Ltd. (Nasdaq: EVGN, TASE: EVGN), a leading computational biology company aiming to revolutionize the development of life-science-based products utilizing cutting-edge computational biology technologies across multiple market segments, reported its financial results for the third quarter period ended September 30, 2023 (Press release, Evogene, NOV 15, 2023, View Source [SID1234637703]).

Mr. Ofer Haviv, Evogene’s President and Chief Executive Officer, stated: "The events in Israel since October 7, 2023, have brought about significant changes to our nation; we find ourselves at a time of profound reflection. Our hearts go out to all those directly and indirectly impacted by these evil acts. I want to emphasize that these hardships only deepen our resolve to succeed and thrive. Despite these challenges, Evogene and our subsidiaries continue to operate, unwavering in our commitment to innovation and progress. Our strategic focus remains steady, and our dedicated team works tirelessly to achieve our objectives for 2023 and set the course for 2024.

In these uncertain times, it’s crucial to underscore the financial stability of the Evogene Group. As of the end of the third quarter, the group had a consolidated cash position of approximately $37.2 million, with contributions from Lavie Bio – $7.1 million, Biomica – $14.6 million, and Evogene (together with Casterra, AgPlenus, and Canonic) – $15.5 million. It’s important to note that this figure doesn’t include any amount due to the purchase orders received by Casterra in the last few months and that Lavie Bio’s cash balance is set to increase by an additional $2.5 million in January 2024 as part of a commercial agreement with Corteva.

Furthermore, we anticipate additional orders for Casterra’s castor seeds and new collaborations to generate cash flow for the group, further enhancing our financial stability."

Mr. Haviv continued: "As previously stated, this year we invested in establishing collaborations directly between Evogene and industry leaders, aiming to leverage our AI tech-engines for product development. We are very excited with the initial fruits of these efforts, as demonstrated by the recently reported collaboration with Colors Farm and Ben Gurion University – to pioneer crustacean gene editing technology aiming to enhance crustacean traits. The collaboration is powered by a grant from the Israel Innovation Authority and will utilize Evogene’s GeneRator AI tech-engine."

Mr. Haviv added: "We are very proud of the achievements of our subsidiaries in the last few months. I want to emphasize that as part of their competitive advantage, all the subsidiaries use Evogene’s AI tech-engines, under exclusive license, to direct and accelerate their product development."

Biomica Ltd. – develops microbiome-based therapeutics, leveraging Evogene’s MicroBoost AI tech-engine.

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– Biomica’s leading product candidate, BMC128, for treating cancer patients, is now in a phase 1 clinical trial. The trial is conducted in Israel and started at the Rambam Health Care Campus. It aims to evaluate BMC128’s safety and tolerability alongside Bristol Myers Squibb’s Opdivo immunotherapy. In August, Biomica opened a second site at The Davidoff Cancer Center to allow the recruitment of additional potential patients. The trial is planned to include 10-12 patients; currently, 7 have enrolled.

– Biomica is advancing in preparing for a pre-IND meeting for BMC128, expected to occur in the first quarter of 2024.

Lavie Bio Ltd. – develops and commercializes microbiome-based ag-biological products, utilizing Evogene’s MicroBoost AI tech-engine.

– In July, Lavie Bio announced a licensing agreement with Corteva. The agreement grants Corteva exclusive rights to develop further and commercialize two of Lavie Bio’s lead bio-fungicide product candidates – LAV311 and LAV312 – targeting fruit-rots. Lavie Bio is entitled to an initial payment of approximately $5 million in 2 installments: the first payment of $2.5 million was received in September 2023, and the second payment is expected in the first quarter of 2024. It will also be eligible for additional future milestone payments and royalties from Corteva’s sales of these future products.

– Last week, Lavie Bio announced a significant progress in its bio-fungicide program with LAV321, designed to combat downy mildew and late blight diseases. Field trials conducted in 2023 across Europe and the United States have yielded impressive results, establishing LAV321 as a potent solution against fungal diseases. Next year, LAV321 is expected to be tested in field trials by several multinational companies, for some of which it will be the second year of validation.

AgPlenus Ltd. – aims to develop and commercialize next-generation crop protection products, utilizing Evogene’s ChemPass AI tech-engine.

– As previously disclosed, there is a growing interest in AgPlenus’ lead target protein APTH1 and the small molecules that bind to this protein as candidates for a novel herbicide with a broad weed control spectrum. AgPlenus expects this interest to lead to a collaboration with a leading industry player.

Casterra Ag Ltd. – provides an integrated end-to-end solution for large-scale castor bean cultivation, utilizing Evogene’s GeneRator AI tech-engine.

– In September, Casterra delivered its first shipment of high-yield, high-oil castor seeds from Brazil and Zambia to an African region, generating recognized revenue of approximately $0.9 million in this quarter.

– In recent months, Casterra made substantial steps in expanding its overseas seed production capabilities through subcontractors. As the complexity of this operation is high, it requires additional resources and extensive physical attendance of Casterra’s professionals at the production sites overseas. Casterra is currently investing efforts in expanding its workforce to support this operation and, in parallel, looking for additional seed production subcontractors to manage risks.

Canonic Ltd. – provides tailored medical cannabis products to optimize consumer well-being, utilizing Evogene’s GeneRator AI tech-engine.

– The Israeli medical cannabis market is characterized by a vast spectrum of products, either grown locally or imported. Capturing the patients’ attention is challenging, leading to prices dropping even for premium products. To address this challenge, Canonic is focusing its marketing efforts on the frequent launching of new products in limited batches. During the third quarter, Canonic launched two new products, Tango and Two Aces, and this week, an additional product, SouthSide, was launched.

– During the last quarter, Canonic engaged with a new Israeli cultivator, EverGreen; four elite strains are currently being cultivated.

Mr. Haviv concluded: "All the subsidiaries are advancing their business targets, and as a shareholder, Evogene is very proud of this progress. Looking forward, when evaluating the needs of our wholly owned subsidiaries and their commercial potential, we intend to invest more efforts and resources in Casterra – since we see significant potential in the bio-diesel market, which castor oil can support, while reducing our investment in Canonic – due to the challenging market conditions of the medical cannabis sector."

Key Financial Highlights:

As of September 30, 2023, Evogene had consolidated cash, cash equivalents, and short-term bank deposits amounted to approximately $37.2 million. This included $14.6 million for Biomica, $7.1 million for Lavie Bio, and $15.5 million collectively for Evogene, Casterra, Canonic, and AgPlenus. The injection of funds from the last round of investment in July strengthens Evogene’s financial position and provides it with the resources needed to execute future plans effectively.

The $15.5 million reflected in the cash balance of Evogene, together with Casterra, Canonic, and AgPlenus, does not include any amount due to the purchase orders received by Casterra in the last few months, which were partially supplied during the third quarter of 2023, and the $7.1 million reflected in the cash balance of Lavie Bio does not include the $2.5 million, which represents the second half of the upfront payment from the licensing agreement with Corteva, that is expected to be received at the beginning of 2024.

During the third quarter, the consolidated cash usage was approximately $4.8 million or approximately $3.2 million, excluding Lavie Bio, Biomica, and $1.2 million of advanced payments to Casterra’s subcontractors for castor seed production.

Financial Performance:

Revenues for the third quarter of 2023 were approximately $3.8 million compared to approximately $0.5 million in the same period the previous year. The revenue increase was primarily due to revenues recognized by Lavie Bio per the licensing agreement with Corteva and due to revenues recognized by Casterra for the supply of castor seeds during the third quarter of 2023.

R&D expenses for the third quarter of 2023, which are reported net of non-refundable grants received, were approximately $5.1 million and remained stable compared to approximately $5.0 million in the same period in the previous year.

Sales and marketing expenses were approximately $850 thousand for the third quarter of 2023 and slightly decreased as compared to approximately $895 thousand in the same period the previous year. The main contributor to this expense decrease was a reduction in personnel expenses at Canonic.

General and administrative expenses were approximately $1.5 million in the third quarter of 2023 and remained stable compared to approximately $1.6 million in the same period in the previous year.

Operating loss for the third quarter of 2023 was approximately $4.2 million compared to an operating loss of approximately $7.1 million in the same period in the previous year. The decrease in operating loss is mainly due to the increased revenues mentioned above.

Financing income net for the third quarter of 2023 was approximately $320 thousand compared to the financing expenses net of approximately $61 thousand in the same period in the previous year. This difference was mainly due to an increase in interest income during the third quarter of 2023 compared to the same period in the previous year.

Net loss for the third quarter of 2023 was approximately $3.9 million compared to a net loss of approximately $7.2 million in the same period in the previous year. The decrease in the net loss is mainly due to the increased revenues recognized in the third quarter of 2023.

Evaxion Presents Proof-of-Principle for Its Unique AI Model Predicting Responses to Cancer Immunotherapy

On November 15, 2023 Evaxion Biotech A/S (NASDAQ: EVAX) ("Evaxion" or the "Company"), a clinical-stage TechBio company specializing in developing AI-Immunology powered vaccines, reported for the first time its AI model designed to predict patient responses to cancer immunotherapy at the Biomarkers & Precision Oncology Europe conference in Berlin, Germany (Press release, Evaxion Biotech, NOV 15, 2023, View Source [SID1234637702]).

The broad use of immunotherapy drugs called checkpoint inhibitors has significantly advanced cancer treatment. However, their effectiveness is limited, with success rates at approximately 15% for most cancers. This inherent challenge emphasizes the critical need for a reliable approach to identify the patients who will benefit from standard-of-care cancer immunotherapy. This can improve patient outcomes and reduce healthcare costs.

"When I joined Evaxion, I was inspired by the wealth of opportunities to improve the lives of patients facing life-threatening diseases. Building upon Evaxion’s core competencies, we have developed an AI model that shows promising results in predicting patients at risk of advancing into progressive disease while undergoing checkpoint inhibitor therapy, enabling earlier intervention with alternative treatments," commented Christian Kanstrup, Evaxion’s Chief Executive Officer.

Christian continued, "We set out to improve patient outcomes and address the growing healthcare burden by developing our first checkpoint inhibitor response predictor model. The model relies on our unique AI-Immunology platform, builds upon our existing core competencies and is part of the "Responder" leg of our corporate strategy. Today’s presentation marks our first step on our journey towards this goal, and we will develop a commercial offering where collaboration and partnerships will be instrumental in achieving our vision for a more cost-effective and efficient healthcare system as well as improving patient outcomes."

CNS Pharmaceuticals Reports Third Quarter 2023 Financial Results and Reiterates Company is on Track to Achieve Milestones for Berubicin Potentially Pivotal Study Before Year End

On November 15, 2023 CNS Pharmaceuticals, Inc. (NASDAQ: CNSP) ("CNS" or the "Company"), a biopharmaceutical company specializing in the development of novel treatments for primary and metastatic cancers in the brain and central nervous system, reported its financial results for the quarter ended September 30, 2023 and reiterated upcoming milestones (Press release, CNS Pharmaceuticals, NOV 15, 2023, View Source [SID1234637701]).

"Over the course of 2023, we have demonstrated solid execution and rapid progression of enrollment in our ongoing potentially pivotal study of Berubicin. We are preparing for the most significant milestones for patients, the Company and our stockholders in just a few short weeks, with interm data expected in December 2023," commented John Climaco, CEO of CNS Pharmaceuticals. "With topline data from our interim analysis expected in the coming weeks, we are poised to determine whether or not the independent Data Safety Monitoring Board recommends continuing the study. We are hopeful that by the end of this study Berubicin will ultimately demonstrate life-saving value as a second-line treatment for patients with recurrent glioblastoma. We look forward to an exciting remainder of the year and building value for all stakeholders in the near and long-term."

Recent Clinical Achievements

• Achieved enrollment of 239 patients; The Company has opened 45 clinical trial sites of the 60 sites selected across the U.S., Italy, France, Spain, and Switzerland.

• Presented updated results from ongoing potentially pivotal study of Berubicin in adult patients with recurrent GBM after failure of standard first line therapy at the 2023 SNO/ASCO CNS Cancer Conference.

Upcoming Expected Milestones

• Report topline results of interim analysis expected in December 2023. Enrollment will continue during the interim analysis.

• Complete enrollment in December 2023.

For more information about this trial, visit clinicaltrials.gov and reference identifier NCT04762069.

The FDA has granted CNS Pharmaceuticals Fast Track Designation for Berubicin which enables more frequent interactions with the agency for guidance on expediting the development and review process. Additionally, the Company has received Orphan Drug Designation from the FDA, which may provide seven years of marketing exclusivity upon approval of an NDA.

Summary of Financial Results for the Third Quarter 2023

The net loss for the three months ended September 30, 2023 was approximately $4.5 million compared to approximately $3.4 million for the comparable period in 2022. The change in net loss is attributable to an increase in research organization (CRO) expenses and patient treatment costs related to continued progress with the Company’s clinical trial for Berubicin, a credit to research and development expense in the prior year period for the funds collected from WPD Pharmaceuticals related to their purchase of Berubicin drug product for their clinical trials, as well as increases in legal and professional fees and other expenses.

The Company reported research and development expenses of $3.4 million for the three months ended September 30, 2023 compared to approximately $2.2 million for the comparable period in 2022. The increase in research and development expenses during the period was mainly attributed to increasing enrollment and the timing of CRO expenses related to continued progress with the Company’s clinical trial for Berubicin.

General and administrative expense was approximately $1.1 million for the three months ended September 30, 2023 compared to approximately $1.2 million for the comparable period in 2022.

As of September 30, 2023, the Company had cash of approximately $0.9 million. In addition, in October 2023, the Company raised an additional $2.6 million in a warrant inducement transaction and placements on the ATM facility. The Company’s current expectation is that the cash on hand and cash raised in October is sufficient to fund our operations through the end of the fourth quarter of 2023. The timing and costs of clinical trials are difficult to predict and trial plans may change in response to evolving circumstances and as such the foregoing estimates may prove to be inaccurate.

Cellectis Announces the execution of the Subsequent Investment Agreement with AstraZeneca

On November 15, 2023 Cellectis (Euronext Growth: ALCLS – NASDAQ: CLLS) reported that, following the consultation of its works council, it has now signed a binding Subsequent Investment Agreement with AstraZeneca (LSE/STO/Nasdaq: AZN) regarding the contemplated additional equity investment of $140M by AstraZeneca, which was previously announced on November 1, 2023 (Press release, Cellectis, NOV 15, 2023, View Source [SID1234637700]). The additional investment will be made by way of subscription of 10,000,000 "class A" convertible preferred shares and 18,000,000 "class B" convertible preferred shares, in each case at a price of $5.00 per share (the "Additional Investment").

The closing of the Additional Investment remains subject to (i) the approval of the extraordinary general meeting of the shareholders of Cellectis to be called in the coming days and expected to be held on or around December 22, 2023, (ii) clearance of such investment from the French Ministry of Economy according to the foreign direct investment French regulations, and (iii) other customary closing conditions. Immediately following the Additional Investment, it is anticipated that AstraZeneca would own approximately 44% of the share capital of the Company and 30% of the voting rights of the Company (based on the number of voting rights currently outstanding).

In the absence of a public offering, no prospectus will be established in France or outside of France in connection with the Additional Investment.

U.S. Food and Drug Administration Approves Augtyro™ (repotrectinib), a Next-Generation Tyrosine Kinase Inhibitor (TKI), for the Treatment of Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)

On November 15, 2023 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) approved Augtyro (repotrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, NOV 15, 2023, View Source [SID1234637699]). Administered as an oral therapy, Augtyro is a tyrosine kinase inhibitor (TKI) targeting ROS1 oncogenic fusions.

The approval is based on the TRIDENT-1 study, an open-label, single-arm, Phase 1/2 trial that evaluated Augtyro in TKI-naïve and TKI-pretreated patients. In TKI-naïve patients (n=71), the primary endpoint of objective response rate (ORR), defined as the percentage of people treated within a certain period of time whose tumor size decreased (partial response) or who no longer have signs of cancer (complete response),was 79% (95% Confidence Interval [CI]: 68 to 88). The median duration of response (mDOR) was 34.1 months. Among patients pretreated with one prior ROS1 TKI and no prior chemotherapy (n=56), the ORR was 38% (95% CI: 25 to 52) and the mDOR was 14.8 months. Among those who had measurable central nervous system (CNS) metastases at baseline, responses in intracranial lesions were observed in 7 of 8 TKI-naïve patients (n=71) and 5 of 12 of those who were TKI-pretreated (n=56).

"New treatment options continue to be needed for patients with ROS1 fusion-positive NSCLC that support important clinical goals, including achieving durable therapeutic responses," said Jessica J. Lin, MD, TRIDENT-1 primary investigator and attending physician at the Center for Thoracic Cancers at Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School.4,5,6,7 "Based on the data we have seen in the TRIDENT-1 trial, repotrectinib has the potential to become a new standard of care option for patients with locally advanced or metastatic ROS1 fusion-positive lung cancer."

Augtyro is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity. Please see Important Safety Information below.

"While progress has been made in the treatment of NSCLC over the past decade, there is still a need to address this particularly difficult-to-treat form of the disease with innovative science and a targeted approach," said Samit Hirawat, MD, executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb.6,7 "As the only approved next-generation TKI for ROS1-positive NSCLC patients, Augtyro builds on our legacy of delivering transformational therapies for patients with thoracic cancers."

"ROS1-positive NSCLC patients and their families face a stressful journey because our cancer can be difficult to treat, especially when it spreads to the brain," said Janet Freeman-Daily, co-founder and president of The ROS1ders, a patient advocacy organization. "Today’s approval brings a new treatment option for the ROS1-positive patient community, which gives us hope for more time with loved ones."

Augtyro is designed to minimize interactions that can lead to certain forms of treatment resistance in ROS1-positive metastatic NSCLC patients. It is expected to be available to patients in the U.S. in mid-December 2023. Bristol Myers Squibb thanks the patients and investigators involved in the TRIDENT-1 clinical trial program.

About TRIDENT-1

TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including non-small cell lung cancer (NSCLC). Phase 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 fusions.2 Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed.1,2 The trial excludes patients with symptomatic brain metastases, among other exclusion criteria.1 Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose.

Phase 2 of the trial has a primary endpoint of overall response rate (ORR).1,2 Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC.

In TRIDENT-1, of the 79% (95% Confidence Interval [CI]: 68 to 88) of TKI-naïve patients who responded to treatment, 6% experienced complete responses and 73% experienced partial responses.1 The median duration of response (mDOR) was 34.1 months.1 Of the 38% (95% CI: 25 to 52) of TKI-pretreated patients (n=56) who responded to treatment, 5% experienced complete responses and 32% experienced partial responses and the mDOR was 14.8 months.1 Among those who had measurable CNS metastases at baseline as assessed by BICR, responses in intracranial lesions were observed in 7 of 8 TKI-naïve patients (n=71) and in 5 of 12 of those who were TKI-pretreated (n=56).

The FDA-approved dosing for Augtyrois 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity.1

Select Safety Profile From TRIDENT-1

Permanent discontinuation of Augtyro occurred in 8% of patients.1 Augtyro dosage was interrupted due to an adverse reaction in 48% of patients, and dose reductions due to an adverse event occurred in 35% of patients.1 Serious adverse reactions occurred in 33% of patients who received Augtyro.1 Serious adverse reactions in ≥2% of patients included pneumonia (5.7%), dyspnea (3.8%), pleural effusion (3.4%) and hypoxia (3%). Fatal adverse reactions occurred in 4.2% of patients who received Augtyro, including death, pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, sudden death, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1 The most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%).1 Grade 3 dizziness occurred in 1.9% of patients. The most common and serious adverse reactions and fatal events were evaluated in 264 patients who received the Phase 2 recommended dose of Augtyro in TRIDENT-1.1

About Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States.12 The two main types of lung cancer are non-small cell and small cell.12 Non-small cell lung cancer (NSCLC) represents up to 85% of diagnoses.12 Survival rates vary depending on the stage and type of the cancer when diagnosed.13 ROS1 fusions are rare and occur in about 1-2% of patients with NSCLC.10 With a median age of 50, patients with tumors that are ROS1-positive tend to be younger than the average lung cancer patient, more often female than male and may have little to no smoking history.10ROS1-positive lung cancer tends to be aggressive and can often spread to the brain.10ROS1 tyrosine kinase inhibitor (TKI) therapy is the current standard of care for patients with a tumor harboring this gene alteration.4

INDICATION

AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

Warnings & Precautions

IMPORTANT SAFETY INFORMATION

Central Nervous System Adverse Reactions

Among the 351 patients who received AUGTYRO in the TRIDENT-1 study, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 75% with Grade 3 or 4 events occurring in 4%. Dizziness, including vertigo, occurred in 64% and Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness.
Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction and one patient (0.3%) permanently discontinued AUGTYRO due to ataxia.
Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 1.7% required dose reduction and 0.6% permanently discontinued AUGTYRO due to cognitive adverse reactions.
Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in >1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% required a dose reduction due to mood disorders.
Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in >1% of patients were somnolence (8%), insomnia (6%) and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% required a dose reduction due to sleep disorders.
The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Interstitial Lung Disease (ILD)/Pneumonitis

Among the 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.
Hepatotoxicity

Among the 351 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%.
Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.
Myalgia with Creatine Phosphokinase (CPK) Elevation

Among the 351 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.
Hyperuricemia

Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.9% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Skeletal Fractures

Among 351 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.
Embryo-Fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.
Adverse Reactions

Among 351 patients who received AUGTYRO for ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%).
In a subset of 264 patients who received AUGTYRO for ROS1-positive NSCLC, the most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%).
Drug Interactions

Effects of Other Drugs on AUGTYRO

Strong and Moderate CYP3A Inhibitors

Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.
P-gp Inhibitors

Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.
Strong and Moderate CYP3A Inducers

Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.
Effects of AUGTYRO on other Drugs

Certain CYP3A4 Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.
Contraceptives

Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females to use an effective nonhormonal contraceptive.
Please see U.S. Full Prescribing Information for AUGTYRO