On February 8, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported results from a retrospective analysis evaluating CABOMETYX (cabozantinib) activity in brain metastases in patients with renal cell carcinoma (RCC) (Press release, Exelixis, FEB 8, 2021, View Source [SID1234574752]). The findings will be presented as part of the Poster Session: Renal Cell Cancer at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary Cancers Symposium (ASCO GU), which is being held virtually, February 11-13, 2021. All posters will be available on demand beginning at 5:00 a.m. PT on Thursday, February 11.

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In this retrospective analysis of medical records from patients with metastatic RCC with brain metastases, an intracranial response rate of 61% (95% CI: 39%-80%), including a complete response rate of 13%, was seen for patients with progressing intracranial metastases at baseline (Cohort 1; n=25) who were treated with CABOMETYX. Patients without progressing intracranial metastases (Cohort 2; n=44) had an intracranial response rate of 57% (95% CI: 41%-72%). The rate of brain disease progression at six months was 16% for patients with progressive brain disease at baseline and 9% for those without. Median overall survival was 14.7 months for Cohort 1 and 14.1. months for Cohort 2. The reported safety data are consistent with the known safety profile for CABOMETYX.

"With these exciting results, oral systemic cabozantinib is showing intriguing activity on brain metastases in renal cell carcinoma," said Dr. Toni Choueiri, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "The high intracranial response rates seen in this retrospective analysis suggest cabozantinib has the potential for helping patients with difficult-to-treat brain lesions from kidney cancer. We look forward to building on these encouraging findings through the ongoing phase 2 CABRAMET trial (NCT03967522) led by our French colleagues, which is prospectively evaluating cabozantinib in patients with brain metastases from renal cell carcinoma."

"Brain metastases resulting from renal cell carcinoma are especially difficult to treat, as the blood-brain barrier poses a challenge for therapies to reach their targets," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "These encouraging results including a high intracranial response rate, suggest CABOMETYX may reduce the size of brain metastases, without neurological toxicity, and thereby may be of interest to physicians treating kidney cancer patients with brain metastases."

About the Study

For this retrospective study, sponsored by the Dana-Farber Cancer Institute, consecutive medical records from patients with metastatic RCC with brain metastases who had been treated with cabozantinib monotherapy across 15 institutions in the United States (ten centers), Belgium (three centers), Spain (one center) and France (one center) were reviewed.

Patients were divided into two cohorts based on the presence (n=25) or absence (n=44) of progressing intracranial metastases at start of CABOMETYX therapy. Most patients (87%) were International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk, and 75% had been previously treated. Prior brain-directed therapy was received by 65% of patients with progressing brain metatstases and by 93% of those without. All patients were treated with CABOMETYX. Four patients were not included in the intracranial analysis due to brain lesion size under 5 mm.

About RCC

The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

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; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. 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 United States 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 United States.

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 and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. 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 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% 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.

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 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 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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.

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 is observed. 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.

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, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

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.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

On February 8, 2021 Orion Corporation and Bayer reported are expanding the global clinical development program for the oral androgen receptor inhibitor (ARi) darolutamide in the area of prostate cancer (Press release, Orion , FEB 8, 2021, View Source [SID1234574737]). A new Phase III study ARANOTE will evaluate the compound in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC). The study adds to the robust development program for the compound, including the Phase III study ARASENS, which investigates darolutamide in a triple combination with ADT and docetaxel compared to doxetacel and ADT alone in men with mHSPC.

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"Darolutamide is currently approved for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. Now, it is naturally important that we also evaluate the potential of darolutamide in other stages of the disease to offer men with metastatic hormone-sensitive prostate cancer (mHSPC) a new treatment option", said Professor, M.D., Ph.D. Outi Vaarala, Senior Vice President of Research and Development at Orion.

Darolutamide is approved in several markets around the world, including the U.S., the European Union (EU), Brazil, Canada and Japan, for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. Filings in other regions are underway or planned by Bayer. The product is developed jointly by Orion and Bayer.

About the ARANOTE trial
The ARANOTE trial is a randomised, double-blind, placebo-controlled Phase III study of darolutamide in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC). The primary endpoint of this study is radiological progression-free survival (rPFS), as measured as the time from the date of randomisation to the date of first documentation of radiological progressive disease or death due to any cause, whichever occurs first. The trial is expected to enroll about 555 men. Orion and Bayer anticipate that first patients will be enrolled to the study by end of Q1 2021.

About Metastatic Hormone-Sensitive Prostate Cancer
Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2018, an estimated 1.2 million men were diagnosed with prostate cancer, and about 358,000 died from the disease worldwide.1

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately five percent of men will already suffer from prostate cancer with distant metastases when first diagnosed. Men with metastatic hormone-sensitive prostate cancer (mHSPC) will start their treatment with hormone therapy, such as ADT, ARi plus ADT or a combination of the chemotherapy docetaxel and ADT. Despite this first line treatment, most men with metastatic HSPC will eventually progress to castration-resistant prostate cancer (CRPC), which can impact survival and quality of life.

About darolutamide
Darolutamide is approved under the brand name Nubeqa for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease.

Darolutamide is an oral androgen receptor inhibitor (ARi) with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. The compound is also being investigated in a Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS). Information about these trials can be found at www.clinicaltrials.gov.

On February 8, 2021 Ipsen (Euronext: IPN; ADR: IPSEY) reported the first presentation of new analyses from the pivotal Phase III CheckMate -9ER trial demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of Cabometyx (cabozantinib) and Opdivo (nivolumab) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC) (Press release, Ipsen, FEB 8, 2021, View Source;9ER-trial-of-Cabometyx%C2%AE-in-Combination-with-Opdivo%C2%AE-Showed-Significantly-Improved-QoL-Benefits-and-Sustained-Superior-Efficacy-Versus-sunitinib-in-Patients-Living-with-aRCC [SID1234574753]).1 These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Genitourinary Cancers Symposium (ASCO GU) from 11 – 13 February 2021 and featured in the Poster Highlights Session on 13 February 2021 from 9:00 a.m. – 9:45 a.m. EDT.4

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In a new analysis from the CheckMate -9ER trial (Abstract #308) with a median follow-up of two years (23.5 months), Cabometyx in combination with Opdivo continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation.1 No new safety signals were identified with extended follow-up. Across the full study population, the combination doubled median PFS (17.0 months vs. 8.3 months, respectively; HR 0.52; 95% CI: 0.43 to 0.64), the trial’s primary endpoint, compared to sunitinib. The ORR indicated that nearly twice as many patients responded to Cabometyx in combination with Opdivo vs. sunitinib (54.8% vs. 28.4) and the combination maintained improvements in OS, demonstrating a 34% reduction in the risk of death compared to sunitinib (HR: 0.66; 95% CI: 0.50 to 0.87). In an exploratory analysis, the combination was associated with a disease control rate (including complete response, partial response and stable disease) of 88.2% vs. 69.9% with sunitinib and a complete response rate of 9.3% compared to 4.3% with sunitinib. Among patients treated with Cabometyx in combination with Opdivo, 6.6% discontinued both agents due to TRAEs, 9.7% discontinued Opdivo only and 7.2% discontinued Cabometyx only.1

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of Cabometyx with Opdivo showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).1

"There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma," said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. "In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also, of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease"

In a second analysis from the CheckMate -9ER trial (Abstract #285) conducted with 18.1 months of median follow-up, patients treated with the combination of Cabometyx and Opdivo reported statistically significant health-related quality of life (HRQoL) benefits.2 Treatment with Cabometyx in combination with Opdivo was associated with a lower treatment burden, decreased the risk of confirmed deterioration in HRQoL and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.2

"As the advances in treatments for kidney cancer transform outcomes for patients, the goals of therapy have expanded from increasing survival to improving quality of life," said Dr. Cristina Suárez, Medical Oncologist at the Vall d´Hebron University Hospital, Barcelona, Spain and a lead investigator on the Phase III CheckMate -9ER trial. "The additional analyses presented at ASCO (Free ASCO Whitepaper) GU mean that physicians treating people living with advanced renal cell carcinoma can consider this combination at diagnosis as a first-line option to improve patient outcomes and significantly reduce the risk of deterioration in health-related quality of life scores for their patients. This, in addition to the extended follow-up outcomes data including patients with sarcomatoid features, point to this combination becoming an important treatment approach."

Cabometyx in combination with Opdivo is under review with health authorities globally following the combination’s approval for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021.

"We’re pleased to share these positive results at ASCO (Free ASCO Whitepaper) GU, building on the growing body of data for the use of Cabometyx in first- and second-line settings. These data further support the importance of research investigating outcomes which really matter to patients," said Prof. Dr. Steven Hildemann, Executive Vice President, Chief Medical Officer, Head of Global Medical Affairs and Patient Safety, Ipsen. "The validations of the type II variation applications to the European Medicines Agency (EMA) for Cabometyx in combination with Opdivo last year brought this new combination regimen one step closer to the previously untreated kidney cancer patient population. Despite recent advances, these patients remain in need of more therapeutic options that extend survival and improve quality of life."

A further notable presentation at ASCO (Free ASCO Whitepaper) GU evaluated the use of Cabometyx versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC) (Abstract #293).3

A retrospective observational cohort study evaluating outcomes associated with Cabometyx or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment3

Cabometyx (n = 187)

Other TKI (n=60)

p value

6-month response rate (RR6months, primary)

50.8%

33.3%

<0.001

Overall response rate (ORR)

53.5%

38.3%

0.041

Overall survival (OS) (95% CI)

6 months

81.9 (75.5, 86.8)

75.1 (61.5, 84)

0.765

12 months

61.5 (53.5, 68.4)

59.6 (44.7, 71.8)

18 months

51.7 (43.1, 59.6)

45.9 (29.6, 60.7)

Time to treatment discontinuation (TTD, median months)

6.2

3.1

0.015

Dose reductions

47.1%

41.7%

0.466

Discontinuation due to adverse events (AEs)

31.3%

40.4%

Findings from the study suggest that Cabometyx is an effective and well tolerated option, associated with a significantly higher response rate and a lower discontinuation rate versus other TKIs included in the study, after treatment with CPIs.3

Follow Ipsen on Twitter via @IpsenGroup and keep up to date with ASCO (Free ASCO Whitepaper) GU Symposium news and updates by using the hashtag #GU21.

About renal cell carcinoma
There are over 400,000 new cases of kidney cancer diagnosed worldwide each year.5 Of these, renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of cases.6,7 It is twice as common in men, and male patients account for over two thirds of deaths.5 If detected in the early stages, the five-year survival rate is high, but for patients with advanced or late-stage metastatic RCC the survival rate is much lower, around 12%, with no identified cure for this disease.8,9

About the CheckMate -9ER trial
CheckMate -9ER is an open-label, randomized, multi-national Phase III trial evaluating patients with previously untreated advanced or metastatic RCC. A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to Cabometyx plus Opdivo (n = 323) versus sunitinib (n = 328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Cabometyx (cabozantinib)
Cabometyx is currently approved in 54 countries, including in the European Union, the U.S., the U.K., Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong-Kong, Singapore, Macau, Jordan, Lebanon, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile, Panama and New Zealand for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, the U.K., Norway, Iceland, Canada, Australia, Brazil, Taiwan, Hong Kong, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Saudi Arabia, Israel, Mexico, Chile, Panama and New Zealand for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.S., the U.K., Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Ukraine, Lebanon and Panama for HCC in adults who have previously been treated with sorafenib.

The detailed recommendations for the use of Cabometyx are described in the Summary of Product Characteristics (SmPC) and in the U.S. Prescribing Information (PI).

Cabometyx is marketed by Exelixis, Inc. in the United States and by Takeda Pharmaceutical Company Limited in Japan. Ipsen has exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Cabometyx is a registered trademark of Exelixis, Inc.

On February 8, 2021 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported that it has commenced an underwritten public offering of up to $100 million of its American Depositary Shares ("ADSs"), each ADS representing one ordinary share (Press release, Autolus, FEB 8, 2021, View Source [SID1234574929]). All ADSs to be sold in the proposed offering will be offered by Autolus. Autolus also intends to grant the underwriters a 30-day option to purchase up to an additional $15 million of ADSs at the public offering price, on the same terms and conditions. The offering is subject to market conditions, and there can be no assurance as to whether or when the offering may be completed or the actual size or terms of the offering.

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J.P. Morgan and Wells Fargo Securities are acting as joint bookrunners for the offering. Kempen & Co, Mizuho Securities and Needham & Company are acting as co-managers.

The securities are being offered pursuant to an effective shelf registration statement that was previously filed with the Securities and Exchange Commission ("SEC"). A preliminary prospectus supplement relating to the securities will be filed with the SEC and will be available on the SEC’s website at www.sec.gov.

When available, copies of the preliminary prospectus supplement and the accompanying prospectus relating to these securities may be obtained for free from either of the joint book-running managers for the offering, J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at +1 866 803 9204 or by email at [email protected]; or Wells Fargo Securities, LLC, Attention: Equity Syndicate Department, 500 West 33rd Street, New York, New York, 10001, at (800) 326-5897 or email a request to [email protected]. For the avoidance of doubt, such prospectus will not constitute a "prospectus" for the purposes of Regulation (EU) 2017/1129 and will not have been reviewed by any competent authority in any member state in the European Economic Area.

This press release does not constitute an offer to sell or the solicitation of an offer to buy securities, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of that jurisdiction.

On February 7, 2021 The Board of Directors in Medivir AB (publ) ("Medivir" or the "Company") reported that has decided to summon an extraordinary general meeting on 11 March 2021 to propose a directed issue (the "Directed Issue") to the Company’s existing specialist investor LINC AB ("LINC"), controlled by the Company’s board member Bengt Julander (Press release, Medivir, FEB 7, 2021, View Source [SID1234574711]).

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In the rights issue, from which the preliminary results was announced on 5 February 2021 (the "Rights Issue"), Bengt Julander (through LINC) among others entered into subscription and guarantee commitments. The Rights Issue was substantially oversubscribed and no guarantee commitments needed to be utilized. Through an over-allotment option related to the Rights Issue (the "Over-allotment Option") the specialist investor Healthinvest Partners AB was added to the Company’s shareholder base. As a result of the strong interest in the Rights Issue and in order to further strengthen the Company’s institutional shareholder base, the Board of Directors has decided to summon an extraordinary general meeting on 11 March 2021 to propose a directed issue of approximately SEK 28 million to Bengt Julander (through LINC).

Since the Directed Issue is directed to a company controlled by board member Bengt Julander, part of the Company’s category of related parties referenced in the Swedish Companies Act (sw. ABL) chapter 16 (2005:551), the Directed Issue requires approval by the Company’s shareholders representing at least nine tenths of the votes casted as well as the shares represented at the extraordinary general meeting on 11 March 2021, for which a notice will be published separately. Bengt Julander did not participate in the decision regarding the Directed Issue by the Board of Directors.

The extraordinary general meeting will decide on the proposal to issue a total of 3,600,000 new series B shares, directed to Bengt Julander (through LINC), at a subscription price of SEK 7.73 per share, corresponding to the closing price as of 5 February 2021. The reason for deviating from the shareholders’ preferential rights in the Directed Issue is to strengthen the Company’ institutional shareholder base and the proceeds will be used to accelerate the Company’s existing business plan, mainly focusing on the development of MIV-818.

Through the Directed Issue, the number of shares in Medivir will increase from 52,135,651 series B shares, including the shares issued in connection with the Rights Issue and the Over-allotment Option, to 55,735,651 series B shares, corresponding to a dilutive effect of approximately 6.5 per cent of the total number of outstanding shares and votes in the Company. Following the completion of the Directed Issue, LINC will hold shares in the Company corresponding to approximately 10 per cent of the total number of outstanding shares in the Company.

Advisors
ABG Sundal Collier is the financial advisor and Vinge is the legal advisor to Medivir in connection with the transaction.