On March 3, 2023 Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) approved an expanded indication for Verzenio (abemaciclib), in combination with endocrine therapy (ET), for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at a high risk of recurrence (Press release, Eli Lilly, MAR 3, 2023, View Source [SID1234628137]). High risk patients eligible for Verzenio can now be identified solely based on nodal status, tumor size, and tumor grade (4+ positive nodes, or 1-3 positive nodes and at least one of the following: tumors that are ≥5 cm or Grade 3).1 This expanded adjuvant indication removes the Ki-67 score requirement for patient selection.

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This label expansion is supported by four-year data from the Phase 3 monarchE trial of adjuvant Verzenio in combination with ET, which showed a deepened benefit in invasive disease-free survival (IDFS) beyond the two-year treatment course with adjuvant Verzenio. The absolute difference in IDFS between treatment groups increased over time. At four years, 85.5% of patients remained recurrence-free with Verzenio plus ET, compared to 78.6% with ET alone, an absolute difference in IDFS of 6.9%. At two years and at three years, the absolute differences between treatment groups were 3.1% and 5.0%, respectively; see Fig. 1 below. The addition of Verzenio to ET reduced the risk of recurrence by 35% compared to ET alone (HR=0.653 [95% CI: 0.567-0.753]). There were no new safety findings, and overall results are consistent with the well-established safety profile for Verzenio. These four-year monarchE data were presented at the 2022 San Antonio Breast Cancer Symposium and simultaneously published in The Lancet Oncology.2

The monarchE study enrolled 5,637 adults with high risk HR+, HER2-, node-positive EBC into two cohorts. Verzenio is now approved for use in the full Cohort 1 patient population, which comprised 91% of the study population. A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population, primarily due to patients in Cohort 1. As of the data cut-off date, while overall survival (OS) data remain immature across the entire study, an OS trend in favor of Verzenio was observed in the Cohort 1 population, but not the Cohort 2 population where more deaths were seen with Verzenio plus ET compared to ET alone (10/253 vs. 5/264). The "About the monarchE Study" section below provides more details on study design.

"Our goal in intensifying treatment for early breast cancer is to maintain remission and prevent the recurrence of cancer. The magnitude of benefit seen in the four-year data from the monarchE study reinforces my confidence in adjuvant Verzenio as the standard-of-care for high risk patients in this setting," said Erika P. Hamilton, M.D., medical oncologist, director of Breast and Gynecologic Cancer Research at Sarah Cannon Research Institute, and an investigator on the monarchE clinical trial. "The initial Verzenio FDA approval in early breast cancer was practice-changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them."

More than 300,000 people are expected to be diagnosed with breast cancer in the U.S. in 2023.3 It is estimated that 90% of all breast cancers are detected at an early stage.4 Approximately 70% of all breast cancer cases are the HR+, HER2- subtype.5 Although the prognosis for HR+, HER2- EBC is generally favorable, high risk patients are three times more likely than those with low risk characteristics to experience recurrence – with the majority being incurable metastatic disease.6 These patients have an increased risk of recurrence during the first two years of endocrine therapy.

"This expanded approval will allow us to bring Verzenio to many more women and men with HR+, HER2-, high risk early breast cancer in the curative setting – before patients experience recurrence, potentially to incurable metastatic disease," said Jacob Van Naarden, chief executive officer of Loxo@Lilly. "The initial adjuvant approval for Verzenio changed the treatment paradigm, and the strength of the monarchE results supporting this approval underscores the role this differentiated CDK4/6 inhibitor can play in reducing the risk of recurrence in early breast cancer."

"This expanded approval for Verzenio is welcome news for our community," said Jean Sachs, chief executive officer of Living Beyond Breast Cancer. "A significant number of women and men have HR+, HER2- early breast cancer at high risk of returning. Making effective treatment options available is crucial to allowing people to make the best care decisions for themselves, together with their healthcare providers. We’re pleased Verzenio will now be available to more people with this type of early breast cancer."

Concurrent with this expanded indication approval in EBC, the FDA has also broadened the indicated use of Verzenio in metastatic breast cancer (MBC) when used in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of people with HR+, HER2- advanced or MBC. This updated MBC indication now includes all adult patients, with the expanded indication including pre-/perimenopausal women when used in combination with ovarian suppression. See below "Indications for Verzenio" for full details on indicated uses in HR+, HER2- advanced or metastatic breast cancer. Verzenio is available in tablet strengths of 50 mg, 100 mg, 150 mg, and 200 mg.

The labeling for Verzenio contains warnings and precautions for diarrhea, neutropenia, interstitial lung disease (ILD/pneumonitis), hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. Perform complete blood counts and liver function tests prior to the start of Verzenio treatment, every two weeks for the first two months, monthly for the next two months and as clinically indicated. Based on results, Verzenio may require dose modification. Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. Advise patients of potential risk to a fetus and to use effective contraception.

See Important Safety Information below and full Prescribing Information for additional information.

Click here to view the early breast cancer infographic.

About the monarchE Study
monarchE was a global, randomized, open-label, two cohort, multicenter Phase 3 clinical trial that enrolled 5,637 adults with HR+, HER2-, node-positive EBC at high risk of recurrence. To be enrolled in Cohort 1 (n=5,120), which is the FDA-approved population, patients had to have 4+ positive nodes or 1-3 positive nodes and at least one of the following: tumors that were ≥5 cm or Grade 3. Patients enrolled in Cohort 2 could not have met the eligibility criteria for Cohort 1. To be enrolled in Cohort 2 (n=517), patients had to have 1-3 positive nodes and Ki-67 score ≥20%. Patients in each cohort were randomized 1:1 to receive either Verzenio 150 mg twice daily plus standard-of-care adjuvant ET (Cohort 1, n=2,555; Cohort 2, n=253) or standard-of-care adjuvant ET alone (Cohort 1, n=2,565; Cohort 2, n=264) for 2 years. ET continued for at least 5 years if deemed medically appropriate. The primary endpoint was IDFS. Consistent with expert guidelines, IDFS was defined as the length of time before breast cancer comes back, any new cancer develops, or death.

About Early Breast Cancer and Risk of Recurrence
It is estimated that 90% of all breast cancers are detected at an early stage.4 Approximately 70% of all breast cancer cases are the HR+, HER2- subtype.5 Although the prognosis for HR+, HER2- EBC is generally favorable, high risk patients are three times more likely than those with low risk characteristics to experience recurrence – with the majority being incurable metastatic disease.6 These patients have an increased risk of recurrence during the first two years of endocrine therapy.

Factors associated with high risk of recurrence in HR+, HER2- early breast cancer include: positive nodal status, the number of positive nodes, large tumor size (≥5 cm), and high tumor grade (Grade 3). Node-positive means that cancer cells from the tumor in the breast have been found in the lymph nodes near the breast. Although breast cancer is removed through surgery, the presence of cancer cells in the lymph nodes signifies that there is a higher chance of developing recurrence and distant metastatic disease.

About Breast Cancer
Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer worldwide, according to GLOBOCAN. The estimated 2.3 million new cases indicate that 1 in every 8 cancers diagnosed in 2020 is breast cancer. With approximately 685,000 deaths in 2020, breast cancer is the fifth-leading cause of cancer death worldwide.7 In the U.S., it is estimated that there will be more than 300,000 new cases of breast cancer diagnosed in 2023. Breast cancer is the second leading cause of cancer death in women in the U.S.3

About Verzenio (abemaciclib)
Verzenio (abemaciclib) is a targeted treatment known as a CDK4/6 inhibitor. Verzenio is a nonchemotherapy oral tablet.

Verzenio works inside the cell to block CDK4/6 activity and help stop the growth of cancer cells so that they may eventually die (based on preclinical studies). Cyclin-dependent kinases (CDK)4/6 are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4/6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly’s first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

INDICATIONS FOR VERZENIO
VERZENIO is a kinase inhibitor indicated:

in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence.
in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib)
Severe diarrhea associated with dehydration and infection occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, diarrhea occurred in 81 to 90% of patients who received Verzenio. Grade 3 diarrhea occurred in 8 to 20% of patients receiving Verzenio. Most patients experienced diarrhea during the first month of Verzenio treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19 to 26% of patients with diarrhea required a Verzenio dose interruption and 13 to 23% required a dose reduction.

Instruct patients to start antidiarrheal therapy, such as loperamide, at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, neutropenia occurred in 37 to 46% of patients receiving Verzenio. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19 to 32% of patients receiving Verzenio. Across trials, the median time to first episode of Grade ≥3 neutropenia ranged from 29 to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 to 16 days. Febrile neutropenia has been reported in <1% of patients exposed to Verzenio across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. In Verzenio-treated patients in EBC (monarchE), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In Verzenio-treated patients in MBC (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue Verzenio in all patients with Grade 3 or 4 ILD or pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (2 to 6%) and aspartate aminotransferase (AST) (2 to 3%) were reported in patients receiving Verzenio. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days.

Monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or 4 hepatic transaminase elevation.

Venous thromboembolic events (VTE) were reported in 2 to 5% of patients across three clinical trials in 3559 patients treated with Verzenio (monarchE, MONARCH 2, MONARCH 3). VTE included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to VTE have been reported in patients treated with Verzenio.

Verzenio has not been studied in patients with early breast cancer who had a history of VTE. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for EBC patients with any grade VTE and for MBC patients with a Grade 3 or 4 VTE.

Verzenio can cause fetal harm when administered to a pregnant woman, based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for 3 weeks after the last dose. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥10%) observed in monarchE for Verzenio plus tamoxifen or an aromatase inhibitor vs tamoxifen or an aromatase inhibitor, with a difference between arms of ≥2%, were diarrhea (84% vs 9%), infections (51% vs 39%), neutropenia (46% vs 6%), fatigue (41% vs 18%), leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs 4%), headache (20% vs 15%), vomiting (18% vs 4.6%), stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia (13% vs 2%), decreased appetite (12% vs 2.4%), ALT increased (12% vs 6%), AST increased (12% vs 5%), dizziness (11% vs 7%), rash (11% vs 4.5%), and alopecia (11% vs 2.7 %).

The most frequently reported ≥5% Grade 3 or 4 adverse reaction that occurred in the Verzenio arm vs the tamoxifen or an aromatase inhibitor arm of monarchE were neutropenia (19.6% vs 1%), leukopenia (11% vs <1%), diarrhea (8% vs 0.2%), and lymphopenia (5% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for monarchE in ≥10% for Verzenio plus tamoxifen or an aromatase inhibitor with a difference between arms of ≥2% were increased serum creatinine (99% vs 91%; .5% vs <.1%), decreased white blood cells (89% vs 28%; 19.1% vs 1.1%), decreased neutrophil count (84% vs 23%; 18.7% vs 1.9%), anemia (68% vs 17%; 1% vs .1%), decreased lymphocyte count (59% vs 24%; 13.2 % vs 2.5%), decreased platelet count (37% vs 10%; .9% vs .2%), increased ALT (37% vs 24%; 2.6% vs 1.2%), increased AST (31% vs 18%; 1.6% vs .9%), and hypokalemia (11% vs 3.8%; 1.3% vs 0.2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole vs anastrozole or letrozole, with a difference between arms of ≥2%, were diarrhea (81% vs 30%), fatigue (40% vs 32%), neutropenia (41% vs 2%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3.1%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 1%), diarrhea (9% vs 1.2%), leukopenia (7% vs <1%)), increased ALT (6% vs 2%), and anemia (6% vs 1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole with a difference between arms of ≥2% were increased serum creatinine (98% vs 84%; 2.2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs 0.6%), anemia (82% vs 28%; 1.6% vs 0%), decreased neutrophil count (80% vs 21%; 21.9% vs 2.6%), decreased lymphocyte count (53% vs 26%; 7.6% vs 1.9%), decreased platelet count (36% vs 12%; 1.9% vs 0.6%), increased ALT (48% vs 25%; 6.6% vs 1.9%), and increased AST (37% vs 23%; 3.8% vs 0.6%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant vs fulvestrant, with a difference between arms of ≥2%, were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 2.7%), thrombocytopenia (16% vs 3%), alopecia (16% vs 1.8%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4.5%), pyrexia (11% vs 6%), and weight decreased (10% vs 2.2%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (25% vs 1%), diarrhea (13% vs 0.4%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (5.7% vs 3.5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant with a difference between arms of ≥2% were increased serum creatinine (98% vs 74%; 1.2% vs 0%), decreased white blood cells (90% vs 33%; 23.7% vs .9%), decreased neutrophil count (87% vs 30%; 32.5% vs 4.2%), anemia (84% vs 34%; 2.6% vs .5%), decreased lymphocyte count (63% vs 32%; 12.2% vs 1.8%), decreased platelet count (53% vs 15%; 2.1% vs 0%), increased ALT (41% vs 32%; 4.6% vs 1.4%), and increased AST (37% vs 25%; 3.9% vs 4.2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), constipation (17%), leukopenia (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were diarrhea (20%), neutropenia (24%), fatigue (13%), and leukopenia (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (99%; .8%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 26.6%), anemia (69%; 0%), decreased lymphocyte count (42%; 13.8%), decreased platelet count (41%; 2.3%), increased ALT (31%; 3.1%), and increased AST (30%; 3.8%).

Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

Please see full Prescribing Information for Verzenio.

AL HCP ISI 12OCT2021

On March 3, 2023 Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) ("Teva") reported that it successfully upsized its offering and priced approximately $2,490,000,000 (equivalent) of its sustainability-linked senior notes (the "Notes") (Press release, Teva, MAR 3, 2023, View Source [SID1234628140]). The principal amount of the offering was increased from the previously announced offering size of $2,060,000,000 (equivalent) and the maximum tender amount of Teva’s previously announced debt tender offer was increased from $2,250,000,000 to $2,500,000,000. Teva expects to use the net proceeds from the offerings (i) to fund the announced tender offers to purchase, for cash, its 7.125% Senior Notes due 2025, 6.000% Senior Notes due 2025, 4.500% Senior Notes due 2025, 2.800% Senior Notes due 2023, 6.000% Senior Notes due 2024 and 3.150% Senior Notes due 2026 for a maximum combined aggregate purchase price (exclusive of accrued and unpaid interest) of up to $2,500,000,000 (as it may be amended prior to expiration thereof), (ii) to pay fees and expenses in connection therewith and (iii) to the extent of any remaining proceeds, the repayment of outstanding debt upon maturity, tender offer or earlier redemption. Net proceeds may be temporarily invested pending application for their stated purpose.

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This is Teva’s second offering of Sustainability-Linked Senior Notes. The transaction demonstrates Teva’s continued strong commitment to sustainable finance and is tied to targets that include improving access to Teva’s portfolio of medicines in low- and middle-income countries (LMICs) and reducing Teva’s absolute greenhouse gas (GHG) emissions.

The Notes consist of (i) Teva Pharmaceutical Finance Netherlands II B.V.’s ("Teva Finance II") €800,000,000 aggregate principal amount of 7.375% EUR-denominated Sustainability-Linked Senior Notes maturing in 2029, (ii) Teva Finance II’s €500,000,000 aggregate principal amount of 7.875% EUR-denominated Sustainability-Linked Senior Notes maturing in 2031, (iii) Teva Pharmaceutical Finance Netherlands III B.V.’s ("Teva Finance III" and, together with Teva Finance II, the "Issuers") $600,000,000 aggregate principal amount of 7.875% USD-denominated Sustainability-Linked Senior Notes maturing in 2029 and (iv) Teva Finance III’s $500,000,000 aggregate principal amount of 8.125% USD-denominated Sustainability-Linked Senior Notes maturing in 2031.

The settlement of the Notes is expected to occur on or about March 9, 2023, subject to customary closing conditions.

The Notes will be unsecured senior obligations of the Issuers and will be unconditionally guaranteed on a senior unsecured basis by Teva. The offering and sale of the Notes were made pursuant to our effective automatic shelf registration statement on Form S-3, including our base prospectus, filed with the Securities and Exchange Commission (the "SEC") on October 27, 2021. The offering of these Notes was made only by means of a prospectus supplement and accompanying base prospectus, which have been filed with the SEC. Before you invest, you should

read the prospectus supplement and accompanying prospectus along with other documents that Teva has filed with the SEC for more complete information about Teva and this offering. These documents are available at no charge by visiting EDGAR on the SEC website at View Source Alternatively, a copy of the prospectus supplement and accompanying base prospectus related to this offering may be obtained, when available, by contacting Citigroup Global Markets Europe AG, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, United States (Tel: +1 (800) 831-9146, e-mail: [email protected]); Citigroup Global Markets Inc., c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, United States (Tel: +1 (800) 831-9146, e-mail: [email protected]); Goldman Sachs Bank Europe SE, Marienturm, Taunusanlage 9-10, 60329 Frankfurt am Main, Germany, Attention: High Yield Syndicate Desk (Tel: +49 69 7532 1000, Fax: +44 (0)207 774 2330); Mizuho Securities Europe GMBH, Taunustor 1, 60310 Frankfurt am Main, Germany, Attention: Primary Debt (Tel: +49 69 42729 3140, email: [email protected]); Mizuho Securities USA LLC, 1271 Avenue of the Americas, New York, NY 10020, United States, Attention: Debt Capital Markets (Fax: +1 (212) 205-7812); MUFG Securities (Europe) N.V., World Trade Center, Tower H, 11th Floor, Zuidplein 98, 1077 XV Amsterdam, The Netherlands, Attention: Legal-Primary Markets (email: [email protected]); MUFG Securities Americas Inc., 1221 Avenue of the Americas, New York, NY 10020-1001, United States, Attention: Capital Markets Group (Phone: +1 877 649 6848); or PNC Capital Markets LLC, 10th Floor, 300 Fifth Avenue, Pittsburgh, PA 15222, Unites States, Attention: Securities Settlement, toll-free 855-881-0697 or by email: [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction.

On March 3, 2023 Sarepta Therapeutics, Inc. (the "Company") reported that its has entered into separate, privately negotiated exchange agreements (the "Exchange Agreements") with certain holders of its 1.50% Convertible Senior Notes due 2024 (the "Notes") (Filing, 8-K, Sarepta Therapeutics, MAR 3, 2023, View Source [SID1234628139]). Under the terms of the Exchange Agreements, the holders have agreed to exchange with the Company approximately $313.5 million in aggregate principal amount of Notes held by them for (i) approximately 3,843,459 shares of the Company’s common stock, which is equal to 12.2589 shares per $1,000 principal amount of Notes exchanged plus (ii) an additional number of shares of the Company’s common stock per $1,000 principal amount of Notes exchanged equal to the quotient of (a) $301.90 divided by (b) the average of the daily volume-weighted average prices of the Company’s common stock over the one trading day period on March 3, 2023 (collectively, the "Shares"). These exchange transactions are expected to close on March 7, 2023, subject to the satisfaction of customary closing conditions.

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The foregoing description of the Exchange Agreements is qualified in its entirety by reference to the form of Exchange Agreement, a copy of which is attached as Exhibit 10.1 hereto.

Item 3.02
Unregistered Sales of Equity Securities.

The disclosure under Item 1.01 above is incorporated by reference herein.

The issuance of the Shares under the Exchange Agreements is being made in reliance on the exemption from the registration requirements of the Securities Act of 1933, as amended (the "Securities Act"), provided by Section 4(a)(2) of the Securities Act. The Shares will be issued only to investors that qualified as institutional "accredited investors" (as such term is defined in Rule 501 of the Securities Act) and "qualified institutional buyers" (as such term is defined in Rule 144A of the Securities Act).

The Shares have not been registered under the Securities Act or the securities laws of any state or other jurisdiction, and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the Securities Act and such other jurisdictions.

Forward-Looking Statements

This Current Report on Form 8-K contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including, but not limited to, statements about the completion of the proposed transactions. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include, without limitation, satisfaction of customary closing conditions related to the proposed transactions. In addition, applicable risks also include those that are listed under the heading "Risk Factors" and elsewhere in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, and in the Company’s subsequent filings with the Securities and Exchange Commission. Except as otherwise noted, these forward-looking statements speak only as of the date of this Form 8-K. All forward-looking statements are qualified in their entirety by this cautionary statement.

On March 3, 2023 INmune Bio, Inc. (NASDAQ: INMB) (the "Company"), a clinical-stage immunology company focused on developing treatments that harness the patient’s innate immune system to fight disease, its financial results for the year ended December 31, 2022 and provides a business update (Press release, INmune Bio, MAR 3, 2023, View Source [SID1234628138]).

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Q4 2022 and 2022 Corporate Highlights:

DN-TNF Platform Highlights (XPro and INB03):

· Consolidating the Mild Cognitive Impairment (MCI) Phase 2 trial into the Mild Alzheimer’s Disease Phase 2 study which will become a single Phase 2 AD trial. The combined trials should improve our ability to demonstrate a clinical benefit in patients receiving XPro, accelerate enrollment, and reduce costs. Including patients with MCI in the Phase 2 AD trial does not significantly increase the trial size and should shorten the time to last patient enrolled. Patients that complete the six-month Phase 2 AD study are eligible to enroll into a 12-month Open Label Extension trial (OLE). The OLE study is a 12-month study where long-term safety and efficacy of XPro treatment in patients with early AD are evaluated. Topline readout of Phase 2 AD trial is expected in 2H 2024.

· Phase 2 AD Trial open in Canada following receipt of No Objection Letter from Health Canada in November.

· Received research and development rebates from Australia and the United Kingdom in early 2023 that totaled approximately $6.4 million USD. The Company will reinvest the cash rebate in increasing recruitment and enrollment in Australia where we expect to continue to receive future rebates associated with research and development spend, in Canada to expand the Phase 2 AD program and in other foreign jurisdictions to allow the enrollment of early AD patients into the ongoing Phase 2 AD trial.

· Announced pre-clinical data that support a pioneering approach to treating Duchenne Muscular Dystrophy (DMD) targeting soluble TNF (sTNF) using a Dominant-Negative TNF (DN-TNF) biologic significantly decreased muscle damage and inflammation and promote muscle growth in the mouse mdx model of DMD. The company formed a wholly owned subsidiary, DN02, Inc., which will hold all the intellectual property to facilitate partnering and business development activities for DMD without impacting the Company’s CNS programs. There are currently no approved drugs that promote muscle regeneration in DMD patients.

· FDA review of Chemistry Manufacturing and Controls (CMC) associated with a clinical hold on XPro AD trial in the U.S. is ongoing. The Company continues to have dialog with the FDA to address the FDA’s clinical hold questions. We plan to open US Phase 2 trials sites for XPro in AD when the current hold is lifted. The Company continues to enroll patients in AUS and CAN and is working to open additional international regulatory venues. We will inform investors when each new country opens. We expect the US will open in plenty of time to include Phase 2 patients, however there are no negative consequences to the development program if all or most of the Phase 2 patients are enrolled outside of the US.

· The polysarcosine (pSar) DN-TNF program converts XPro from a single drug into a DN-TNF drug platform. Polysarcosine is a novel half-life extender that effectively replaces the PEG half-life extender used in XPro. The pSar program is an essential part of INmune Bio’s business development efforts. XPro has been designated for the CNS programs, including AD, TRD, ALS and other neurological diseases. The pSar program provides at least 3 new DN-TNF biologics that are eligible for composition-of-matter IP and have unique biologic characteristics that allow partnering DN-TNF opportunities beyond CNS, such as oncology, DMD and other diseases. Each drug is a novel DN-TNF compound that will require a unique development program. DMD and oncology are the first two pSar programs that are targeted for partnering.

· MUC4 expressing cancers include breast cancer, HER2+ breast cancer, triple negative breast cancer, gastric and pancreatic cancer which are candidates for DN-TNF therapy. In pre-clinical models, INB03 DN-TNF reduces MUC4 expression to decrease resistance to immunotherapy. A pSar DN-TNF compound with new composition-of-matter IP is in animal testing and if positive, this unique DN-TNF drug will be moved into a strategic partnering program in oncology. Data on combination of DN-TNF with trastuzumab-deruxtecan (Enhertu) was presented at SABCS in November 2022. Additional data will be presented at AACR (Free AACR Whitepaper) in April 2023

INKmune Platform:

· IND to be filed this month for the use of INKmune to treat patients with metastatic castration-resistant prostate cancer (mCRPC) in the US. Excluding skin cancer, prostate cancer is the most common cancer in men. "Despite advances in the treatment of men with metastatic castration-resistant prostate cancer, the lethal form of the disease, median survival remains short and novel treatment approaches are urgently needed," said Matt Rettig MD, Professor of Medicine and Urology, Medical Director of the Prostate Cancer Program at the David Geffen School of Medicine at UCLA and member of the Jonsson Comprehensive Cancer who will be Principal Investigator (PI) of the INKmune trial. "Current treatment paradigms, including chemotherapy, second generation androgen receptor signaling inhibitors, and others have largely been maximized for therapeutic benefit. Although immunotherapy has shown activity and promise in other solid tumors, immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been unsuccessful to date. Given the promise of immunotherapy, establishing the efficacy of an ‘off-the-shelf" immuno-therapeutic approach for mCRPC would be practice changing and could profoundly impact the care and quality of life for mCRPC patients. Harnessing the innate anti-tumor activity of NK cells represents a golden opportunity to advance immunotherapy to effectively and safely treat mCRPC. Now is the time to pursue such an approach." The Phase I/II design will enroll patients at several medical centers in the US.

· Additional sites have opened to support the ongoing phase I trial in high risk MDS/AML. A second site in the UK, The Royal Hallamshire Hospital at Sheffield University Medical School enrolled a patient this week with treatment scheduled for March 9th. A third site in Europe, Attikon University Hospital in Athens, Greece, will open shortly.

· The first four patients treated with INKmune were presented at the American Society for Hematology in December. INKmune treatment was associated with the rapid and sustained generation of cancer killing memory-like NK cells in the blood of 3 of 4 patients treated. The INKmune primed NK cells developed the ability to kill NK-resistant tumor cells in-vitro which was absent before treatment. INKmune also initiated increases in important systemic cytokines TNF-a, IL-15, MIP1-a, MIP1-b and IL2Ra which are associated with increased NK cell function and survival.

· The ASH (Free ASH Whitepaper) 2023 presentation included bioinformatics data showing that INKmune primed NK cells, in contrast to IL-15 primed NK cells, upregulates 30 mitochondrial survival proteins and more than 40 nutrient receptors on the NK cell; increasing survival potential in the TME. These data, when combined with the therapeutic persistence data presented in the INKmume treated patients and data on the function of INKmune primed NK cells presented at the Innate Killer Symposia 2022 supports the use of INKmune therapy to treat patients with solid tumors.

· The Company announced positive pre-clinical data in prostate cancer, renal cell carcinoma, ovarian cancer and nasopharyngeal cancer tumor cell lines resistant to natural killer killing. These pre-clinical studies are essential steps in bridging INKmune from the bench to the bedside and guide the INKmune solid tumor development program.

Upcoming Events and Milestones:

· Top-line results for the Phase 2 XPro trial for treatment of neuroinflammation as a cause of Alzheimer’s Disease is expected in 2H 2024.

· We will initiate a Phase 2 trial of XPro in patients with Treatment Resistant Depression that is partially funded by a $2.9 million NIH grant upon resolution of the FDA manufacturing review.

· Additional open-label Phase 1 trial data of INKmune in high-risk MDS/AML in 2023.

· Initiation of a Phase I/II program in a prostate cancer upon the acceptance of the IND by the FDA.

Financial Results for the Year Ended December 31, 2022:

Net loss attributable to common stockholders for the year ended December 31, 2022 was approximately $27.3 million, compared to approximately $ 30.3 million for the year ended December 31, 2021.

Research and development expense totaled approximately $17.1 million for the year ended December 31, 2022 to approximately $20.5 million during the year ended December 31, 2021.

General and administrative expense was approximately $9.3 million for the year ended December 31, 2022 compared to approximately $8.8 million during the year ended December 31, 2021.

Other expense was approximately $1.3 million for the year ended December 31, 2022 compared to approximately $1.2 million during the year ended December 31, 2021.

As of December 31, 2022, the Company had cash and cash equivalents of approximately $52.2 million.

As of March 2, 2023, the Company had approximately 17.9 million common shares outstanding.

Earnings Call Information

To participate in this event, dial approximately 5 to 10 minutes before the beginning of the call. Please ask for the INmune Bio Fourth Quarter Conference Call when reaching an operator.

Date: March 2, 2023
Time: 4:30 PM Eastern Time
Participant Dial-in: 1-877-407-0784
Participant Dial-in (international): 1-201-689-8560
Conference ID: 13735978

A live audio webcast of the call can be accessed using this link or clicking here:
View Source;tp_key=9a74893972

A transcript will follow approximately 24 hours from the scheduled call. A replay will also be available through March 9 by dialing 1-844-512-2921 or 1-412-317-6671 (international) and entering PIN no. 13735978

About Metastatic Castration-Resistant Prostate Cancer (mCPRC

Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of 1.4 million and 375,000 deaths in 2020. In the United States, it is estimated that there were 268,490 new cases and 34,500 deaths in 2022. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, the prostate cancer grows and spreads to other parts of the body, despite the use of androgen deprivation therapy (ADT) to block the action of male sex hormones. Approximately 10-20% of patients with prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years

About XPro

XPro is a next-generation inhibitor of tumor necrosis factor (TNF) that is currently in clinical trial and acts differently than currently available TNF inhibitors in that it neutralizes soluble TNF (sTNF), without affecting trans-membrane TNF (tmTNF) or TNF receptors. XPro could have potential substantial beneficial effects in patients with neurologic disease by decreasing neuroinflammation. For more information about the importance of targeting neuroinflammation in the brain to improve cognitive function and restore neuronal communication visit this section of the INmune Bio’s website.

On March 3, 2023 Plus Therapeutics, Inc. (the "Company") reported that it has entered into a Subscription and Investment Representation Agreement (the "Subscription Agreement") with Richard J. Hawkins, its Chairman of the board of directors of the Company, who is an accredited investor (the "Purchaser"), pursuant to which the Company agreed to issue and sell one (1) share of the Company’s Series F Preferred Stock, par value $0.001 per share (the "Preferred Stock"), to the Purchaser for $1,000 in cash (Filing, 8-K, Cytori Therapeutics, MAR 3, 2023, View Source [SID1234628136]). The sale closed on March 3, 2023. Additional information regarding the rights, preferences, privileges and restrictions applicable to the Preferred Stock is set forth under Item 5.03 of this Current Report on Form 8-K and is incorporated herein by reference.

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The Subscription Agreement contains customary representations and warranties and certain indemnification rights and obligations of the parties.

The foregoing summary of the Subscription Agreement does not purport to be complete and is subject to, and qualified in its entirety by, such document, which is filed as Exhibit 10.1 to this Current Report on Form 8-K and is incorporated herein by reference.

Item 3.02. Unregistered Sales of Equity Securities.

The disclosure required by this Item is included in Item 1.01 of this Current Report on Form 8-K and is incorporated herein by reference. Based in part upon the representations of the Purchaser in the Subscription Agreement, the offering and sale of the Preferred Stock was exempt from registration under Rule 506 of Regulation D under Section 4(a)(2) of the Securities Act of 1933, as amended.

Item 3.03. Material Modifications to Rights of Security Holders.

The disclosure required by this Item is included in Item 5.03 of this Current Report on Form 8-K and is incorporated herein by reference.

Item 5.03. Amendments to Articles of Incorporation or Bylaws; Change in Fiscal Year.

On March 3, 2023, the Company filed a certificate of designation (the "Certificate of Designation") with the Secretary of State of the State of Delaware, effective as of the time of filing, designating the rights, preferences, privileges and restrictions of the Preferred Stock. The Certificate of Designation provides that the Preferred Stock will have 50,000,000 votes per share of Preferred Stock and will vote together with the Company’s common stock, $0.001 par value (the "Common Stock") as a single class exclusively with respect to any proposal to amend the Company’s Amended and Restated Certificate of Incorporation (as may be amended and/or restated from time to time, the "Amended Certificate") to effect a reverse stock split of the Common Stock ( "Reverse Stock Split"). The Preferred Stock will be voted, without action by the holder, on any such proposal in the same proportion as shares of Common Stock are voted on such proposal. The Preferred Stock otherwise has no voting rights except as otherwise required by the General Corporation Law of the State of Delaware.

The Preferred Stock is not convertible into, or exchangeable for, shares of any other class or series of stock or other securities of the Company. The Preferred Stock has no rights with respect to any distribution of assets of the Company, including upon a liquidation, bankruptcy, reorganization, merger, acquisition, sale, dissolution or winding up of the Company, whether voluntarily or involuntarily. The holder of the Preferred Stock will not be entitled to receive dividends of any kind.

The outstanding share of Preferred Stock shall be redeemed in whole, but not in part, at any time: (i) if such redemption is approved by the board of directors in its sole discretion or (ii) automatically and effective upon the approval by the Company’s stockholders of a Reverse Stock Split. Upon such redemption, the holder of the Preferred Stock will receive consideration of $1,000 in cash.

The foregoing summary of the Certificate of Designation does not purport to be complete and is subject to, and qualified in its entirety by reference to the Certificate of Designation, a copy of which is attached hereto as Exhibit 3.1 and is incorporated herein by reference.

Item 9.01. Financial Statements and Exhibits.