On February 26, 2021 Ipsen (Euronext: IPN; ADR: IPSEY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval for Cabometyx (cabozantinib) in combination with Bristol Myers Squibb’s Opdivo (nivolumab) for the first-line treatment of advanced renal cell carcinoma (aRCC) (Press release, Ipsen, FEB 26, 2021, View Source [SID1234575733]). The European Commission, which has the authority to approve medicines for the European Union (E.U.), will now review the CHMP recommendation and a final decision on the application in the E.U. is expected in the coming months.

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"Advanced renal cell carcinoma is a disease that significantly impacts the lives of people around the world. We’re proud to be able to share that the CHMP has confirmed a positive recommendation for Cabometyx in combination with Opdivo, bringing this impactful new treatment option one step closer for patients," said Howard Mayer, Executive Vice President and Head of Research and Development, Ipsen. "At Ipsen, we are committed to progressing treatment for cancers which have an urgent need for additional therapeutic options and this recommendation marks an important milestone in achieving this."

The CHMP adopted the positive opinion based on results from the pivotal Phase III CheckMate -9ER trial, which demonstrated significant and clinically meaningful improvements in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to sunitinib, with consistent efficacy benefits observed across key subgroups of patients.1 Cabometyx combined with Opdivo was well tolerated and reflected the known safety profiles of the immunotherapy and tyrosine kinase inhibitor (TKI) components in first-line advanced RCC.1 The full data from the CheckMate -9ER trial were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020. At the recent American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Genitourinary Cancers Symposium (ASCO GU), additional data from the CheckMate -9ER trial were also presented, highlighting sustained superior efficacy with a longer duration of follow-up as well as significantly improved health-related quality of life outcomes for the combination versus sunitinib.2,3

Ipsen and its partners have shared the CheckMate -9ER data with regulatory authorities around the world. The combination of Cabometyx and Opdivo was approved by the U.S. Food and Drug Administration (FDA) as first-line treatment for patients living with advanced renal cell carcinoma in January 2021.

"Today’s news is welcomed by physicians treating people living with advanced renal cell carcinoma," 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 positive CHMP opinion brings us one step closer to the promise of a new approach that combines improved treatment outcomes, a favorable tolerability profile and superior health-related quality of life for patients."

About renal cell carcinoma

There are over 400,000 new cases of kidney cancer diagnosed worldwide each year.4 Of these, renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of cases.5,6 It is twice as common in men, and male patients account for over two thirds of deaths.4 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.7,8

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 57 countries, including in the European Union, the U.K., Norway, Iceland, Australia, New Zealand, 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, Peru, Panama, Guatemala, Dominican Republic, Ecuador and Thailand 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, Lebanon, Jordan, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Israel, Mexico, Chile, Peru, Panama, Guatemala, Dominican Republic, Ecuador and Thailand for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.K., Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Ukraine, Turkey, Lebanon, United Arab Emirates, Peru, Panama, Guatemala, Chile, Dominican Republic, Ecuador and Thailand 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 26, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported that its partner Ipsen received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), for CABOMETYX (cabozantinib) in combination with OPDIVO (nivolumab) for the first-line treatment of advanced renal cell carcinoma (RCC) (Press release, Exelixis, FEB 26, 2021, View Source [SID1234575732]). The European Commission, which has the authority to approve medicines for the European Union, will now review the CHMP recommendation, and a final decision on the application is expected in the coming months.

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"On the heels of the FDA approval of CABOMETYX in combination with OPDIVO in the U.S., we are excited that this CHMP recommendation brings our partner Ipsen one step closer to making this combination regimen available as a first-line treatment option for patients with advanced kidney cancer in Europe," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We look forward to hearing the European Commission’s decision in the coming months and to continuing our collaboration with Ipsen as part of our efforts to bring CABOMETYX to more patients with difficult-to-treat cancers."

CABOMETYX is currently approved in the European Union as a monotherapy for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy, for previously untreated intermediate- or poor-risk advanced RCC, and for hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib. The CHMP recommendation to approve CABOMETYX in combination with OPDIVO for the first-line treatment of advanced RCC follows the submission of type II variations to the marketing authorizations to the EMA by Ipsen and Bristol Myers Squibb, respectively, and validation of the submissions in September 2020. The submissions are based on results from the phase 3 CheckMate -9ER trial in which the combination regimen doubled progression-free survival (PFS) and objective response rate (ORR) while significantly improving overall survival (OS) compared with sunitinib. The trial was the basis for the U.S. Food and Drug Administration (FDA) approval of CABOMETYX in combination with OPDIVO in January 2021.

About CheckMate -9ER
CheckMate -9ER is an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to CABOMETYX at a dose of 40 mg once-daily and OPDIVO (n = 323) versus sunitinib (n = 328). The primary efficacy analysis compares the doublet combination regimen of CABOMETYX and OPDIVO versus sunitinib in all randomized patients. Secondary endpoints include OS and ORR. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by Exelixis, Ipsen and Takeda.

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 hepatocellular carcinoma who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. 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.

On February 26, 2021 XNK Therapeutics AB ("XNK") reported that it is entering into a joint Phase II clinical study to treat patients with multiple myeloma using XNK’s leading drug candidate in combination with Sanofi’s anti-CD38 antibody Sarclisa (isatuximab) (Press release, CellProtect Nordic Pharmaceuticals, FEB 26, 2021, View Source [SID1234575731]). XNK and Sanofi are both collaborative partners within NextGenNK Competence Center coordinated by Karolinska Institutet.

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The investigator-initiated Phase II study is made possible by the three parties’ contributions to the trial. XNK will provide its novel autologous NK cell-based product to the study set to take place at the Karolinska University Hospital in Stockholm, Sweden.

"Performing this Phase II study together with Karolinska Institutet is an important step for XNK in its ambition to combat multiple myeloma," said Johan Liwing, CEO of XNK Therapeutics. "Combining our efforts together with the present partners highlights just how far XNK has progressed with its patented technology platform."

"We really look forward towards conducting this exciting clinical trial including partnering with XNK Therapeutics," said Hareth Nahi, Associate Professor at KI.

The study ISA-HC-NK (EudraCT: 2020-000994-26) compares XNK’s leading drug candidate combined with isatuximab vs isatuximab as a consolidation treatment following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma.

XNK is a collaborative partner within NextGenNK, a recently established Competence Center for the development of next-generation NK cell-based cancer immunotherapies coordinated by Karolinska Institutet and supported by Sweden’s Innovation Agency (Vinnova).

On February 26, 2021 BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a clinical-stage biopharmaceutical company founded to discover, create, test and deliver meaningful medicines for patients with genetic diseases and cancers with clear genetic drivers, reported its financial results for the fourth quarter and full year ended December 31, 2020 and provided an update on the Company’s operations (Press release, BridgeBio, FEB 26, 2021, View Source [SID1234575730]).

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Since its last quarterly update, BridgeBio completed its acquisition of Eidos Therapeutics, Inc. (formerly Nasdaq: EIDX) (Eidos) in January 2021, acquiring all of the outstanding shares of Eidos common stock that BridgeBio did not already own. The merger returns BridgeBio and Eidos to a single unified company and is intended to allow BridgeBio to unlock the full potential of acoramidis, a potential best-in-class therapy for patients with transthyretin (TTR) amyloidosis (ATTR).

Acoramidis for ATTR is one of BridgeBio’s four core value driver programs along with encaleret (CaSR inhibitor) for autosomal dominant hypocalcemia type 1 (ADH1), low-dose infigratinib (FGFR inhibitor) for achondroplasia, and BBP-631, an AAV5 gene therapy for congenital adrenal hyperplasia (CAH). Pivotal or potential proof-of-concept data is anticipated for each of the programs by the end of 2021 or early 2022.

BridgeBio had its second NDA accepted by the FDA and is preparing for its first two commercial launches this year, pending FDA approval, for infigratinib for the treatment of cholangiocarcinoma (CCA), or bile duct cancer, as a second-line or later therapy in patients with advanced and/or metastatic CCA with FGFR2 fusions or translocations, and for fosdenopterin for the treatment of MoCD Type A, an ultra-rare, life-threatening genetic disorder that results in severe and largely irreversible neurological injury for infants and children. Additionally, the Company initiated two new clinical trials and progressed 17 additional ongoing trials. BridgeBio established a joint venture with Maze Therapeutics to advance precision medicine to treat cardiovascular disease and entered into a partnership agreement with the University of California, San Francisco to drive the advancement of academic innovations in genetically driven diseases into potential therapeutics for patients.

"We are hopeful that the scientific innovation we are pursuing at scale begins to translate into meaningful gains for patients this year. We are on track to deliver near-term pivotal or potential proof-of-concept data in our four core value driver programs. The successful completion of our acquisition of Eidos allows us to further focus BridgeBio’s clinical and commercialization engine on acoramidis for patients suffering from ATTR," said BridgeBio CEO and founder, Neil Kumar, Ph.D. "We are also starting the year in a strong financial position following our recent debt financing, which enables us to progress the 19 ongoing clinical trials and over 30 programs in our pipeline, as well as to prepare for the anticipated launch of our first two drugs, if approved."

Major milestones anticipated in 2021 or early 2022 for BridgeBio’s four core value drivers:

Acoramidis (AG10) – TTR stabilizer for ATTR-CM: Topline results from Part A of the ATTRibute-CM trial are expected in late 2021 or early 2022 and from Part B in 2023. If Part A is successful, BridgeBio expects to submit an application for regulatory approval of acoramidis in 2022. ATTR is a form of amyloidosis caused by the accumulation of misfolded TTR protein. It is estimated to affect more than 400,000 people in the United States and the European Union and is largely undiagnosed today.

Encaleret – calcium-sensing receptor (CaSR) inhibitor for ADH1: Early results from an ongoing Phase 2 proof-of-concept study will be shared at the Endocrine Society’s 2021 Annual Meeting (ENDO) on March 20th. If the development program is successful, encaleret could be the first approved therapy for ADH1, a condition caused by gain of function variants in the CaSR gene estimated to be carried by 12,000 individuals in the United States alone.

Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia: Initial data from the ongoing Phase 2 dose ranging study are expected in the second half of 2021. Achondroplasia is the most common form of genetic short stature and one of the most common genetic diseases, with 55,000 cases in the United States and European Union. Low-dose infigratinib is the only known product candidate in development for achondroplasia that targets the disease at its genetic source and the only orally administered product candidate in clinical-stage development.

BBP-631 – AAV5 gene therapy candidate for CAH: Initiation of a first-in-human Phase 1/2 study is expected in the second half of 2021, with initial data anticipated in late 2021 or early 2022. CAH is one of the most prevalent genetic diseases potentially addressable with AAV gene therapy, with more than 75,000 cases in the United States and European Union. The disease is caused by deleterious mutations in the gene encoding an enzyme called 21-hydroxylase, leading to lack of endogenous cortisol production. BridgeBio’s AAV5 gene therapy candidate is designed to provide a functional copy of the 21-hydroxylase-encoding gene (CYP21A2) and potentially address many aspects of the disease course.
Recent pipeline progress and corporate updates:

Completed acquisition of Eidos Therapeutics in January 2021, acquiring of all of the outstanding shares of Eidos common stock that BridgeBio did not already own. The merger returns Eidos to BridgeBio’s vibrant ecosystem of innovation and is intended to allow BridgeBio to deploy its full clinical and commercial infrastructure to support the development and global commercialization plans underway for Eidos’ product candidate, acoramidis, a potential best-in-class therapy for patients with ATTR-CM.

Raised nearly $750 million in gross proceeds in February 2021 through issuance of 2.25% Convertible Senior Notes due in 2029. The Company expects current cash, cash equivalents and marketable securities to support its planned operations into 2023.

NDA accepted by the FDA for infigratinib, an oral FGFR1-3 selective inhibitor, for individuals with CCA as a second-line or later therapy in patients with advanced and/or metastatic CCA with FGFR2 fusions or translocations. The NDA has been granted Priority Review designation and is being reviewed under the Real-Time Oncology Review (RTOR) pilot program. BridgeBio has also submitted for regulatory review in Australia and Canada under Project Orbis, an initiative of the FDA’s Oncology Center of Excellence that allows for concurrent submission and review of oncology drugs among participating international regulatory agencies.

BBP-681 – Topical PI3Ka inhibitor for venous malformations (VMs), lymphatic malformations (LMs), and venolymphatic malformations (VLMs) associated with PIK3CA or TEK mutations: Dosed first patient in Phase 1/2 clinical trial.

BBP-398 – SHP2 inhibitor for tumors driven by RAS and receptor tyrosine kinase mutations: Dosed first patient in Phase 1 clinical trial.

Established Contour Therapeutics, a joint venture between BridgeBio and Maze Therapeutics, focused on transforming and advancing breakthrough precision medicine approaches designed to treat cardiovascular disease, the leading cause of death worldwide.

Established collaboration agreement with the University of California, San Francisco to advance the discovery of therapies for genetically driven diseases.
Fourth Quarter and Full-Year 2020 Financial Results:

Cash, Cash Equivalents and Marketable Securities

Cash, cash equivalents and marketable securities, excluding restricted cash, totaled $607.1 million as of December 31, 2020, compared to $577.1 million as of December 31, 2019. The net increase in cash balance of $30.0 million reflects $537.0 million in net proceeds received from the issuance of our 2.50% Convertible Senior Notes due 2027 (2027 Notes), $24.1 million in net proceeds received from Eidos’ at-the-market issuance of shares, offset by payment of $75.0 million to repurchase BridgeBio shares in capped call transactions in connection with the issuance of our 2027 Notes, $49.3 million payment related to capped call option, $15.3 million payments of interest on our debts, and $391.5 million primarily related to operating expenses.

Cash, cash equivalents and marketable securities, excluding restricted cash, totaled $710.7 million as of September 30, 2020, resulting in a decrease of $103.6 million as compared to December 31, 2020. The decrease in cash reflects $2.0 million payments of interests on our debts and $109.6 million primarily relating to operating expenses, partially offset by a receipt of $8.0 million in upfront payment under the license agreement with LianBio.

Operating Expenses

Operating expenses for the three months and year ended December 31, 2020 were $127.6 million and $482.7 million, respectively, as compared to $92.5 million and $306.8 million, respectively, for the same periods in the prior year. The increases in operating expenses of $35.1 million and $175.9 million during the respective periods were attributable to the increase in external-related costs, including manufacturing validation activities for our late-stage programs, and increase in personnel costs resulting from an increase in the number of employees to support the progression in our research and development programs, including our increasing research pipelines, and overall growth of our operations.

Operating expenses for the three months ended December 31, 2020 decreased by $0.5 million when compared to the operating expenses for the three months ended September 30, 2020 of $128.1 million.

Our research and development expenses have not been significantly impacted by the global outbreak of COVID-19 for the periods presented. While we experienced some delays in certain of our clinical enrollment and trial commencement activities, we continue to adapt in this unprecedented time to enable alternative site, telehealth and home visits, at-home drug delivery, as well as mitigation strategies with our contract manufacturing organizations. The longer-term impact of COVID-19 on our operating expenses is currently unknown.

(1)The condensed consolidated financial statements as of and for the year ended December 31, 2019 are derived from the audited consolidated financial statements as of that date. Certain reclassifications have been made to the condensed consolidated balance sheet as of December 31, 2019.
(2)December 31, 2019 amounts include long-term marketable securities of $31.1 million.

On February 26, 2021 BioInvent International AB (publ) (Nasdaq Stockholm: BINV) reported that the company’s total number of shares as per February 26, 2021 amounts to 42,210,495 shares, corresponding to an equal number of votes (Press release, BioInvent, FEB 26, 2021, View Source,c3296287 [SID1234575729]). The increase in the number of shares and votes results from the directed issue of MSEK 143 to Swedish and international institutional investors by issuance of 2,834,399 shares, announced on February 23, 2021.

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