On January 29, 2021 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported an update from its Phase II study of bemcentinib in combination with anti-PD-1 therapy pembrolizumab (BGBC008) in refractory non-small cell lung cancer (NSCLC) patients at an oral presentation at the 2020 World Conference on Lung Cancer Singapore (WCLC) (Press release, BerGenBio, JAN 29, 2021, View Source [SID1234574403]).

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The presentation will provide updated data from Cohort B of the study, assessing the safety and efficacy of bemcentinib in combination with anti-PD-1 therapy pembrolizumab, in 16 refractory NSCLC patients previously treated with a PD-L1 or PD-1 checkpoint inhibitor (CPI) as a monotherapy. Recruitment is ongoing in these patient populations.

The primary endpoint of the study is Overall Response Rate with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints include Disease Control Rate, Progression Free Survival, Overall Survival and safety.

Interim data from Cohort B showed that the overall response rate among the seven evaluable cAXL positive patients was 14% with a disease control rate of 86% and a 2.5-fold improvement in progression free survival rate in the cAXL positive patients. In the seven cAXL negative patients, all showed clinical progression with 29% of patients demonstrating clinical benefit following treatment. The interim data shows that bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in refractory lung cancer. Furthermore, whole tumour gene
expression analysis identified an AXL positive gene signature characteristic of an immune suppression mechanism, in patients
with acquired (Cohort B) resistance to CPIs.

Dr. Matthew Krebs, who will deliver the presentation at WCLC
commented: "These promising interim data suggest that bemcentinib is well tolerated in these vulnerable patient groups and may reverse acquired resistance to checkpoint inhibition by targeting AXL positive macrophages and regulatory dendritic cells. These findings support further development of AXL inhibition with bemcentinib to extend efficacy of immunotherapy in biomarker-selected refractory NSCLC."

The full abstract can be found on the WCLC website.

Title: A phase II study of the oral selective AXL inhibitor bemcentinib with
pembrolizumab in refractory patients with advanced NSCLC

Presenting Author: Dr. Matthew G. Krebs PhD.

Session/Abstract ID: Immunotherapy (Phase II/III Trials) / # 3647

Date/Time: Friday 29th January 2021 at 09.50 Singapore Time / 02.50 CET

The presentation will be available on BerGenBio’s website from 29 January
2021.

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL expression defines a very poor prognosis subgroup in most cancers. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

On January 29, 2021 AstraZeneca and Daiichi Sankyo Company reported that its datopotamab deruxtecan (Dato-DXd; DS-1062) and Enhertu (trastuzumab deruxtecan) showed encouraging results from both antibody drug conjugates (ADCs) in patients with advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, JAN 29, 2021, View Source [SID1234574402]). The data were presented today in two oral presentations during the World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC).

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Updated results from the TROPION-PanTumor01 Phase I trial showed promising clinical activity for datopotamab deruxtecan, a TROP2-directed ADC, in patients with advanced or metastatic NSCLC.

Additionally, an interim analysis of the HER2-overexpressing cohort of the DESTINY-Lung01 Phase II trial showed preliminary evidence of antitumour activity for Enhertu, a HER2-directed ADC, in patients with metastatic NSCLC.

Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

Cristian Massacesi, Senior Vice President, Head of Late-Stage Development, Oncology R&D, said: "Antibody drug conjugates have transformative potential for the targeted treatment of advanced lung cancer, and the early data for datopotamab deruxtecan and Enhertu suggest a promising durable benefit in patients who have limited treatment options. Both are potent ADCs, and we look forward to further clinical data from these development programmes in patients with lung cancer."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "Developing innovative therapies for patients with lung cancer, including those that target TROP2 and HER2, are important as few treatment options remain once progression occurs in the metastatic setting following treatment with platinum-based chemotherapy and immune checkpoint inhibitors. We are encouraged by these preliminary results, which may indicate a durability of effect of datopotamab deruxtecan. We remain committed with AstraZeneca to our bold development plan, particularly the ongoing pivotal Phase III trial of datopotamab deruxtecan monotherapy in patients with metastatic non-small cell lung cancer."

TROPION-PanTumor01 trial results
In the TROPION-PanTumor01 Phase I trial, an objective response rate (ORR) ranging from 21 to 25%, as assessed by independent central review, was observed in 159 patients with advanced or metastatic NSCLC receiving different doses of datopotamab deruxtecan (4mg/kg, 6mg/kg or 8mg/kg), as of data cut-off on 4 September 2020. Thirty two confirmed complete or partial responses were seen, and an additional five complete or partial responses are still too early to confirm. Efficacy data were preliminary due to immaturity of follow-up across dose groups, but preliminary efficacy results may support durability of clinical activity. A disease control rate (DCR) ranging from 67 to 80% was observed with a median progression-free survival (PFS) ranging from 4.3 to 8.2 months across the three doses of datopotamab deruxtecan.

Alexander Spira, MD, PhD, FACP, Oncologist, Virginia Cancer Specialists, US Oncology Research and Johns Hopkins Oncology, said: "These updated preliminary results from TROPION-PanTumor01 are encouraging, as responses were seen across all three doses of datopotamab deruxtecan, underscoring the potential of targeting TROP2 with an antibody drug conjugate in advanced or metastatic non-small cell lung cancer. We look forward to seeing the results from the Phase III trial, which will further evaluate datopotamab deruxtecan versus chemotherapy, the current standard of care for patients with advanced disease that has progressed following treatment with platinum chemotherapy and immunotherapy."

Summary-of-TROPION-PanTumor01-results
The majority of patients across all three doses were previously treated with three or more prior lines of therapy including platinum-based chemotherapy (94%) or immunotherapy (84%). Median duration of follow-up was 7.4 months. As of data cut-off, 39% of patients remained on treatment with datopotamab deruxtecan.

Datopotamab deruxtecan demonstrated a manageable safety profile in the TROPION-PanTumor01 Phase I trial, which was consistent with what has been previously reported. Overall, the 4mg/kg and 6mg/kg doses were better tolerated than the 8mg/kg dose. The most common Grade 3 or greater treatment-emergent adverse events (TEAEs) included mucosal inflammation, anaemia, stomatitis and fatigue, with patients treated at the 8mg/kg dose experiencing higher rates overall. Fourteen cases (8%) of interstitial lung disease (ILD) occurred as determined by an independent adjudication committee. The majority of ILD cases (12/14) were observed with the 8mg/kg cohort, including three deaths (Grade 5). One Grade 3 ILD event was seen with the 4mg/kg dose and one Grade 2 ILD event was seen with the 6mg/kg dose.

Based on the efficacy and safety findings, the 6mg/kg dose has been identified as the recommended dose for the registrational TROPION-Lung01 Phase III trial.

DESTINY-Lung01 trial results
In the interim results of cohort 1 from the DESTINY-Lung01 Phase II trial the primary endpoint of confirmed ORR, assessed by independent central review, was 24.5% for extensively treated patients with HER2-overexpressing (defined as IHC3+ or IHC2+) metastatic NSCLC treated with Enhertu (6.4mg/kg) (n=49). Patients achieved a DCR of 69.4% with a median PFS of 5.4 months. After a median follow-up of 6.1 months, the estimated median duration of response (DoR) was 6.0 months, and the median overall survival (OS) was 11.3 months.

Patients were treated with a median of three prior lines of therapy with most receiving platinum-based chemotherapy (91.8%) or immunotherapy (73.5%). Median treatment duration was 18 weeks. As of data cut-off on 30 May 2020, 22% of patients remained on treatment with Enhertu.

Interim data (n=42) from the HER2-mutant (HER2m) metastatic NSCLC cohort of DESTINY-Lung01 were previously presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) virtual meeting, and also featured as an encore presentation at WCLC. The results showed Enhertu achieved a clinically meaningful tumour response in patients with HER2m metastatic NSCLC.

The overall safety and tolerability profile of Enhertu was consistent with previous trials. In the HER2-overexpressing cohort of DESTINY-Lung01, the most common Grade 3 or greater TEAEs were decreased neutrophil count and fatigue. There were eight cases of treatment-related ILD or pneumonitis, as determined by an independent adjudication committee including two Grade 1, three Grade 2 and three deaths (Grade 5). In the HER2m cohort of DESTINY-Lung01, there were five cases of ILD or pneumonitis, as determined by an independent adjudication committee. All cases were Grade 2.

About NSCLC
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths.1 NSCLC accounts for approximately 80-85% of all lung cancers. 2,3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.5 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers.6 TROP2 expression has been associated with poor overall and disease-free survival in several types of solid tumours. TROP2 expression has been observed in up to 64% of adenocarcinoma and up to 75% of squamous cell carcinoma NSCLC.7-9

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis. It has been reported in up to one third of patients with NSCLC.10-12

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately 2-4% of patients with NSCLC.11,13-15 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.13,14

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial designed to evaluate the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours, including NSCLC and triple-negative breast cancer (TNBC), that are refractory to or relapsed from standard treatment — or for whom no standard treatment is available.

The first part of the trial (dose escalation) assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion in patients with unresectable advanced NSCLC. The second part of the trial (dose expansion) is further assessing the safety and tolerability of datopotamab deruxtecan at selected dose levels (4mg/kg, 6mg/kg and 8mg/kg) in patients with NSCLC, and in patients with unresectable/advanced or metastatic TNBC.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, DCR, time to response, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.16

About DESTINY-Lung01
DESTINY-Lung01 is a global, Phase II, open-label, multicentre, two-cohort trial evaluating the safety and efficacy of Enhertu in 170 patients with HER2m (6.4mg/kg) or HER2- overexpressing (defined as IHC3+ or IHC2+; 6.4mg/kg and 5.4mg/kg) unresectable and metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS and OS.17

Daiichi Sankyo Collaboration
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US only) and datopotamab deruxtecan (Dato-DXd; DS-1062) are two lead DXd ADCs in the oncology pipeline of Daiichi Sankyo, and the most advanced programmes in AstraZeneca’s ADC scientific platform.

Each ADC is engineered using Daiichi Sankyo’s proprietary and portable DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen. Both Enhertu (a HER2-directed ADC) and datopotamab deruxtecan (a TROP2-directed ADC) consist of a monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019, and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

AstraZeneca aims to address the unmet needs of patients with EGFRm tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing LAURA, NeoADAURA and FLAURA2 Phase III trials. AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing SAVANNAH and ORCHARD Phase II trials, which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines.

The Company is also evaluating the potential of ADCs to improve patient outcomes in NSCLC. Enhertu is in development for metastatic non-squamous HER2-overexpressing or HER2m NSCLC including trials in combination with other anticancer treatments. In addition, datopotamab deruxtecan is in early development for advanced NSCLC where TROP2 is overexpressed in the majority of tumours.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation, which represent up to three quarters of all patients with lung cancer. Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (POSEIDON and PEARL Phase III trials) and for patients in earlier stages of disease, including potentially curative settings (MERMAID-1, MERMAID-2, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC Phase III trials) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the NeoCOAST, COAST and HUDSON Phase II trials in combination with potential new medicines from the early-stage pipeline, including Enhertu.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On January 29, 2021 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, "the Company") reported the financial results for the first nine months (April 1, 2020 – December 31, 2020) of the fiscal year 2020 (FY2020) ending March 31, 2021 (Press release, Astellas, JAN 29, 2021, View Source [SID1234574380]).

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1. Qualitative information on consolidated financial results for the first nine months of FY2020 (1) Business performance
Consolidated financial results (core basis) in the first nine months of FY2020 are shown in the table below.

Revenue, core operating profit and core profit decreased across the board. Revenue-Sales of main products XTANDI for the treatment of prostate cancer and XOSPATA for the treatment of acute myeloid leukemia continued to grow.

In addition, growth of the co-promotion revenue of PADCEV for the treatment of urothelial cancer, which was launched in the United States in December 2019, contributed to revenue.

-Moreover, sales of Betanis / Myrbetriq / BETMIGA for the treatment of overactive bladder ("OAB") showed steady progress, and new product group in Japan achieved sales growth, including those of EVENITY for the treatment of osteoporosis, Suglat and SUJANU Combination Tablets for the treatment of diabetes mellitus.
-However, revenue decreased mainly due to the loss of market exclusivity of Vesicare for the treatment of OAB in Europe and Celecox for the treatment of inflammation and pain in Japan, and the termination of sales agreements for Symbicort for the treatment of asthma, human vaccines of KM Biologics Co., Ltd. and Micardis family for the treatment of hypertension. Sales were also negatively impacted due to the spread of COVID-19.

As a result of the above, revenue in the first nine months of FY2020 decreased by 4.8% compared to those in the corresponding period of the previous fiscal year ("year-on-year") to ¥940.9 billion. Core operating profit / Core profit-Gross profit decreased by 1.8% year-on-year to ¥753.2 billion.

The cost-to-revenue ratio fell by 2.5 percentage points year-on-year to 20.0%, mainly due to changes in product mix.-Selling, general and administrative expenses increased by 2.7% year-on-year to ¥363.0 billion.

There was a decrease in expenses due to refraining from promotional activities, etc. due to the spread of COVID-19, but total selling, general and administrative expenses increased due to the increase of co-promotion fees associated with the growth of sales of XTANDI in the United States, and there was a one-off reducing factor on expenses from a reversal of loss allowances in the corresponding period of the previous fiscal year.-Research and development (R&D) expenses increased by 5.7% year-on-year to ¥168.8 billion.

There was a decrease in development expenses due to the impact of the spread of COVID-19 on the execution of a portion of clinical trials, but total R&D expenses increased due to an increase in development expenses for key post-POC pipeline projects, and the addition of R&D expenses from Audentes Therapeutics, Inc., which was acquired in January 2020. The R&D cost-to-revenue ratio was up 1.8 percentage points year-on-year to 17.9%.-Amortisation of intangible assets increased by 12.0% year-on-year to ¥17.3 billion.

As a result of the above, core operating profit decreased by 13.6% year-on-year to ¥203.7 billion, and core profit decreased by 13.1% year-on-year to ¥166.6 billion. 3 Impact of exchange rate on financial results The exchange rates for the yen in the first nine months of FY2020 are shown in the table below. The resulting impacts were a ¥7.3 billion decrease in revenue and a ¥3.6 billion decrease in core operating profit compared with if the exchange rates of the first nine months of FY2019 were applied.

Average rate First nine months
Consolidated financial results on a full basis in the first nine months of FY2020 are shown in the table below. Revenue, operating profit, profit before tax and profit decreased across the board. The full basis financial results include "Other income," "Other expenses," which are excluded from the core basis financial results. In the first nine months of FY2020, "Other income" was ¥7.0 billion (¥15.1 billion in the same period of the previous fiscal year) and "Other expenses" was ¥51.3 billion (¥13.4 billion in the same period of the previous fiscal year).

As "Other expenses," the Company recorded impairment losses of ¥30.2 billion in relation to the termination of development for the anti-TIGIT antibody ASP8374/PTZ-201 in the first six months of FY2020, and as a result, the decrease in profit was larger compared to the financial results on a core basis. * Prograf: Includes Advagraf, Graceptor, and ASTAGRAF XL.-Sales of XTANDI increased by 15.0% year-on-year to ¥342.7 billion. Sales increased in all regions of Japan, United States, Established Markets, Greater China, and International.-Sales of XOSPATA increased by 80.7% year-on-year to ¥17.6 billion. This was due to its sales growing in Japan and United States in addition to the contribution of its sales in Established Markets, where it was launched in November 2019.-Co-promotion revenue of PADCEV amounted to ¥9.4 billion in United States.-Sales of Betanis / Myrbetriq / BETMIGA increased by 1.0% year-on-year to ¥122.3 billion.

While sales grew in United States, Established Markets and Greater China, sales decreased in Japan and International due to decreased demand, etc. associated with the reduction of patient visits to hospitals/clinics as a result of the impact of the spread of COVID-19.-Sales of Vesicare decreased by 31.8% year-on-year to ¥24.7 billion mainly due to the impact of the effect of generic drugs resulting from the loss of market exclusivity for the drug in Europe.

-Sales of Prograf decreased by 5.4% year-on-year to ¥138.3 billion. While sales grew in Greater China, sales decreased in other regions.
-In Japan, new product group sales continued to increase, including those of EVENITY, Suglat and SUJANU Combination Tablets. On the other hand, the main factors for the decrease in sales were the loss of market exclusivity for Celecox and the termination of sales agreements for Symbicort, human vaccines of KM Biologics Co., Ltd. and Micardis family.

-In United States, sales of pharmacologic stress agent Lexiscan decreased due to decreased demand associated with the reduction of patient visits to hospitals/clinics as a result of the impact of the spread of COVID-19, mainly in the first three months of FY2020. 6 Revenue by region is shown in the table below. Revenue in United States increased, and revenue in Established Markets achieved similar levels year on year. On the other hand, revenue in Japan, Greater China and International decreased.

(2) Financial position i. Assets, equity and liabilities In the first three months of FY2020, the consolidated statement of financial position as of March 31, 2020 was retrospectively revised due to adjustments of fair value of assets acquired and liabilities assumed for Audentes Therapeutics, Inc., which was acquired in January 2020.

As a result, goodwill increased, and intangible assets and deferred tax liabilities decreased in comparison to the figures prior to the retrospective adjustment. The Company is still in the process of finalizing the fair value measurement as of December 31, 2020. An overview of the consolidated statement of financial position as of December 31, 2020 and the main changes from the end of the previous fiscal year after the retrospective adjustment are shown below. Assets Total assets as of December 31, 2020 saw a decrease of ¥18.3 billion compared to the end of the previous fiscal year to ¥2,296.8 billion.

As of December 31, 2020: ¥1,433.5 billion (a decrease of ¥14.1 billion)-Property, plant and equipment decreased by ¥13.4 billion compared to the end of the previous fiscal year to ¥255.2 billion.-Goodwill decreased by ¥10.5 billion compared to the end of the previous fiscal year to ¥267.8 billion, and intangible assets decreased by ¥27.6 billion compared to the end of the previous fiscal year to ¥697.2 billion. Intangible assets decreased mainly due to the recording of impairment losses in relation to the termination of development for the anti-TIGIT antibody ASP8374/PTZ-201 in the first six months of FY2020.

As of December 31, 2020: ¥863.3 billion (a decrease of ¥4.2 billion)-Cash and cash equivalents decreased by ¥11.9 billion compared to the end of the previous fiscal year to ¥306.5 billion.

Equity Total equity as of December 31, 2020 saw an increase of ¥79.4 billion compared to the end of the previous fiscal year to ¥1,368.6 billion, making the ratio of equity attributable to owners of the parent to gross assets 59.6%.-While profit stood at ¥132.9 billion, the Company paid ¥76.2 billion of dividends of surplus. 8 Liabilities Total liabilities decreased by ¥97.8 billion compared to the end of the previous fiscal year to ¥928.2 billion.

As of December 31, 2020: ¥292.4 billion (an increase of ¥65.1 billion)-Other financial liabilities increased by ¥69.7 billion compared to the end of the previous fiscal year to ¥199.0 billion mainly due to converting ¥80.0 billion from short-term borrowings to long-term borrowings in the first three months of FY2020.

As of December 31, 2020: ¥635.8 billion (a decrease of ¥162.9 billion)-As of December 31, 2020, the balance of bonds amounted to ¥165.0 billion. Other financial liabilities decreased by ¥156.2 billion compared to the end of the previous fiscal year to ¥189.5 billion due to the conversion from short-term borrowings to long-term borrowings stated above, repayments, etc.ii. Cash flow Cash flows from operating activities Net cash flows from operating activities in the first nine months of FY2020 increased by ¥54.9 billion year-on-year to ¥225.1 billion

.-Income tax paid decreased by ¥20.0 billion year-on-year to ¥10.5 billion. Cash flows from investing activities Net cash flows used in investing activities in the first nine months of FY2020 was ¥67.7 billion, a decrease in outflow of ¥6.7 billion year-on-year. Cash flows from financing activities Net cash flows used in financing activities in the first nine months of FY2020 was ¥171.3 billion, an increase in outflow of ¥46.1 billion year-on-year.

-While proceeds from long-term borrowings amounted to ¥80.0 billion, the balance of bonds and short-term borrowings decreased by ¥161.0 billion. Dividends paid increased by ¥2.6 billion year-on-year to ¥76.2 billion.

As a result, cash and cash equivalents totaled ¥306.5 billion as of December 31, 2020, a decrease of ¥11.9 billion compared to the end of the previous fiscal year.(3) Consolidated business forecasts for FY2020 and other forward-looking statements The Company’s business forecasts are presented on a core basis and full basis. The consolidated full-year business forecasts for FY2020 are shown below.

The Company has left its business forecasts unchanged from the consolidated full-year business forecasts announced in October 2020.Business Combinations For the nine months ended 31 December 2020 Audentes Therapeutics, Inc. On 15 January 2020, Audentes Therapeutics, Inc. became a consolidated subsidiary of the Company through a cash tender offer followed by a merger. During the three months ended 30 June 2020, further facts came to light and additional analysis was performed on the fair value measurement of the assets acquired and liabilities assumed at the acquisition date. As a result, the provisional fair values were adjusted as follows.

The initial accounting for the business combination is incomplete as of 31 December 2020 as Astellas Pharma Inc. and its subsidiaries are still in the process of finalizing the fair value measurement.Goodwill mainly comprises the value of expected synergies arising from the acquisition and future economic benefits, which is not separately recognised. Financial assets at FVTOCI (debt instruments) are included in "Other financial assets" in the condensed interim consolidated statement of financial position.

Along with this adjustment, the Company retrospectively revised the corresponding balances in the condensed interim consolidated statement of financial position as of 31 March 2020. As a result, intangible assets and deferred tax liabilities decreased by 13,734 million yen and 2,992 million yen respectively, and goodwill increased by 10,743 million yen.

On January 29, 2021 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the conditional approval for NEXPOVIO (selinexor) in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy (Press release, Karyopharm, JAN 29, 2021, View Source [SID1234574431]).

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The positive CHMP opinion is a scientific recommendation for marketing authorization and one of the final steps before the European Commission (EC) makes a decision on Karyopharm’s marketing authorization application (MAA). An EC marketing authorization through the centralized procedure is valid in all 27 European Union member countries as well as the European Economic Area countries Iceland, Liechtenstein and Norway.

"We are delighted that the CHMP has adopted a positive opinion for NEXPOVIO, which could lead to Karyopharm’s first regulatory approval in Europe," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "This positive opinion highlights the CHMP’s recognition of the positive clinical benefit-risk profile for oral NEXPOVIO and takes Karyopharm one step closer to bringing this important medicine to European patients in need of novel multiple myeloma treatment options. We look forward to the European Commission’s final decision on the NEXPOVIO MAA, which is expected by April of 2021."

The MAA is supported by data from the Phase 2b STORM study which evaluated selinexor in patients with heavily pretreated, triple class refractory multiple myeloma and published in the New England Journal of Medicine (Chari, et al.) in August 2019.

Karyopharm intends to submit a second regulatory filing to the EMA (Type II variation) by April 2021 based on the data from the confirmatory Phase 3 BOSTON study, which evaluated once-weekly NEXPOVIO in combination with once-weekly Velcade and low-dose dexamethasone in patients with multiple myeloma after at least one prior therapy with the goal of further expanding the global reach of NEXPOVIO to additional patients in need of new treatment options.

About the Phase 2b STORM Pivotal Trial

The Phase 2b STORM trial (Selinexor Treatment of Refractory Myeloma) was an international, multi-center, single-arm, open-label study which enrolled 122 patients (Part 2 of the trial) with heavily pretreated, triple class refractory multiple myeloma. Patients in the trial had a median of seven previous therapeutic regimens, including a median of 10 unique antimyeloma agents.

For the study’s primary endpoint, oral selinexor achieved an overall response rate of 26% (95% confidence interval [CI], 19, 35) and the trial therefore met its primary endpoint. Minimal response per IMWG criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease. All responses were adjudicated by an Independent Review Committee. The median overall survival was 8.6 months in the total population studied and 15.6 months in patients who had a minimal response or better.

Karyopharm’s request for conditional approval in Europe is based upon the same patient population that served as the basis for XPOVIO’s accelerated FDA approval in the U.S. Specifically, it includes the efficacy and safety data from a pre-specified sub-group analysis of 83 patients in the STORM study whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pre-treated population than in the overall trial population. The overall response rate in this patient population was 25.3%.

The most common adverse reactions (≥20%) were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.

About Multiple Myeloma in Europe

Multiple myeloma (MM) is an incurable cancer with significant morbidity and the second most common hematologic malignancy. In 2020, there were approximately 51,000 new cases and 32,000 deaths from MM in Europe1. While the treatment of MM has improved over the last 20 years, and overall survival has increased considerably, the disease remains incurable, and nearly all patients will eventually relapse and develop disease that is refractory to all approved anti-MM therapies. Therefore, there continues to be a high unmet medical need for new therapies, particularly those with novel mechanisms of action.

About NEXPOVIO (selinexor)

NEXPOVIO, which is marketed as XPOVIO in the U.S., is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. NEXPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). NEXPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. XPOVIO is approved in the U.S. in multiple hematologic malignancy indications, including in combination with Velcade (bortezomib) and dexamethasone for the treatment of patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. A Marketing Authorization Application for NEXPOVIO for patients with penta-refractory multiple myeloma is also currently under review by the European Medicines Agency and received a positive CHMP opinion in January 2021. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

On January 29, 2021 Gan & Lee Pharmaceuticals Co., Ltd. (hereinafter referred to as Gan & Lee) (Shanghai: 603087.SH), a global biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for GLR2007, for the treatment of patients with glioblastoma (Press release, Gan and Lee Pharmaceuticals, JAN 29, 2021, View Source;lee-has-been-granted-fast-track-designation-by-the-us-fda-301218146.html [SID1234574430]). GLR2007 is a cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor that Gan & Lee is developing for the treatment of advanced solid tumors including glioblastoma, an aggressive form of brain cancer with a low survival rate. Although considered a rare disease, glioblastoma is the most common brain and central nervous system (CNS) malignancy, accounting for 45.2% of malignant primary brain and CNS tumors[1].

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The one-year survival rate for glioblastoma is 39.3%. By year two and year five post-diagnosis, the survival rate drops to 16.9% and 5.5%, respectively. The average survival time for untreated patients is only three months[2]. Current available treatments improve prognosis only by a matter of months. According to Julius Huang, Director of Global Clinical Sciences, Gan & Lee, "The poor prognosis and low survival rates for glioblastomas, demonstrate an unmet need for new treatment options." The FDA’s Fast Track Designation is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Receiving Fast Track Designation potentiates frequent meetings and written communication with the FDA. The GLR2007 application is also eligible for Rolling Review and may be eligible for Accelerated Approval, and Priority Review[3].