Positive Results from Registrational Study of LENVIMA® (lenvatinib) and KEYTRUDA® (pembrolizumab) in Advanced Endometrial Carcinoma Published in the Journal of Clinical Oncology

On March 19, 2020 Eisai reported that positive results from a Phase 2 study (Study 111/KEYNOTE-146) of lenvatinib (marketed as LENVIMA), an orally available kinase inhibitor discovered by Eisai, in combination with pembrolizumab (marketed as KEYTRUDA), Merck’s anti-PD-1 therapy, in patients with advanced endometrial carcinoma have been recently published in the online version of the Journal of Clinical Oncology (Lead author: Vicky Makker, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center and lead investigator; Title of paper: "Lenvatinib and pembrolizumab in patients with advanced endometrial cancer"; DOI: 10.1200/JCO.19.02627) (Press release, Eisai, MAR 19, 2020, View Source [SID1234555718]).

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The Study 111/ KEYNOTE 146 data reported in the publication were results from the Phase 2 open-label, single-arm trial in patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting, with a median follow-up of 18.7 months. The primary analyses focused on 108 patients; 94 patients had tumors that were not MSI-H (microsatellite instability-high) or mismatch repair deficient (dMMR), 11 patients had tumors that were MSI-H or dMMR, and three patients had tumors of unknown status. Patients were treated with lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every three weeks.

The primary endpoint was objective response rate (ORR) at week 24. Key secondary endpoints include overall ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), safety and tolerability at the time of data cutoff (January 10, 2019). Tumor responses for primary and secondary endpoints were assessed by investigators per irRECIST. Pre-specified exploratory endpoints include independent imaging review (IIR) per irRECIST and RECIST version 1.1 and antitumor activity by PD-L1 status.

As a result of this study, lenvatinib plus pembrolizumab was granted accelerated approval for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. This was reviewed under the FDA’s Real-Time Oncology Review (RTOR) and Project Orbis pilot programs. Under Project Orbis, the FDA, the Australian Therapeutic Goods Administration (TGA) and Health Canada collaboratively reviewed applications for the two oncology drugs combined, allowing for simultaneous decisions in all three countries. Currently, two multicenter, randomized, Phase 3 studies in advanced endometrial carcinoma are underway (Study 309/KEYNOTE-775 [NCT03517449] and LEAP-001/ENGOT-en9 [NCT03884101]); for more information, visit clinicaltrials.gov.

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

This release discusses investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such FDA-approved products will gain FDA approval.

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. In 2018, it was estimated there were more than 382,000 new cases and nearly 90,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 80% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). Stages of endometrial cancer range from stage I through IVB.

About LENVIMA (lenvatinib) Capsules

LENVIMA (lenvatinib) is a kinase inhibitor that is indicated:

In combination with KEYTRUDA, for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial
LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

Selected Safety Information

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus– treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions

In EC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab – treated patients were fatigue (65%), hypertension (65%), musculoskeletal pain (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain (33%), headache (33%), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%), dyspnea (24%), cough (21%) and rash (21%).

Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%) and proteinuria (5%).

Fatal adverse reactions occurred in 3% of patients receiving LENVIMA + pembrolizumab, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.

Serious adverse reactions occurred in 52% of patients receiving LENVIMA + pembrolizumab. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

Permanent discontinuation due to adverse reaction (Grade 1-4) occurred in 21% of patients who received LENVIMA + pembrolizumab. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%).

Use in Specific Populations

Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease. No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

Please see Prescribing Information for LENVIMA (lenvatinib) at View Source

About the Eisai and Merck Strategic Collaboration

In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies will jointly initiate new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program, which will evaluate the combination to support 11 potential indications in six types of cancer (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial cancer). The LEAP clinical program also includes a new basket trial targeting six additional cancer types (biliary tract cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer).

Moleculin Biotech, Inc. Reports Financial Results for the Year Ended December 31, 2019

On March 19, 2020 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors, reported its financial results for the year ended December 31, 2019 and provided a business update (Press release, Moleculin, MAR 19, 2020, View Source [SID1234555717]).

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Management Discussion

Walter Klemp, Chairman and CEO of Moleculin, stated, "2019 marked a pivotal year for Moleculin, as we achieved several key milestones in our three core technologies and six oncology drug candidates, strengthened our financial position, and bolstered our leadership team. Notably, we are extremely excited by the progress we made advancing our lead candidate, Annamycin, a ‘next generation anthracycline’ demonstrating little to no cardiotoxicity. In the recently completed Phase 1 portion of our US Phase 1/2 clinical trial in AML, Annamycin met its primary endpoint and demonstrated a clean safety profile with no evidence of cardio-toxicity when delivered to patients at or below the lifetime maximum anthracycline dose established by the FDA. These findings were consistent with an independent review of Annaymcin, in which the independent expert concluded that he ‘does not see evidence of cardio-toxicity.’ We are looking forward to further advancing this trial in 2020, as the FDA has already granted Annamycin Fast Track status and Orphan Drug Designation for AML. We plan to discuss with the FDA a plan to accelerate our approval pathway for a pivotal Phase 2 trial by relying on our European trial to establish a recommended Phase 2 dose, which we believe will be the fastest and most efficient way for us to enter Phase 2. We also look forward to filing an Investigational New Drug (IND) application for the treatment of tumor metastases to the lung in 2020."

Mr. Klemp continued, "We are also pleased by the progress made in both our WP1066 and WP1122 programs. In our WP1066 portfolio, Emory University received FDA approval for their IND status request for our STAT3 Inhibitor in a pediatric brain tumor clinical trial. This approval enables us to explore a new approach for treating pediatric brain cancer. Pre-clinical research at Emory demonstrated WP1066’s significant anti-tumor effect on medulloblastoma cell lines, and we are very encouraged to continue to explore this potential solution for treating this rare condition. Additionally, we reported positive data from the Phase 1 ‘proof-of-concept’ clinical trial with WP1220 for the treatment of cutaneous T-cell lymphoma (CTCL), which demonstrated a median reduction of 56% in skin cancer lesions. We also made great strides within our WP1122 portfolio where we began preclinical testing of a new approach to Pancreatic cancer, by attacking cancer through inhibiting tumor metabolism. "

Mr. Klemp concluded, "We are excited to build off the tremendous progress made in 2019 across our entire drug portfolio. We believe we are well positioned to continue the momentum in 2020 and look forward to the upcoming WP1066 trial at Emory University, advancing WP1220 into a Phase 2 clinical trial, and the potential accelerated FDA approval pathway and Phase 2 trial of Annamycin. And, this momentum has taken on a new dimension with our recent announcement of our agreement with UTMB to test WP1122 for antiviral properties on many viruses, including Coronavirus. We continue to work diligently towards our near-term goals of delivering on Phase 2 clinicals trial for WP1220 and our ‘next generation anthracycline,’ Annamycin. We look forward to sharing our progress throughout the year."

Recent Milestones and Accomplishments:

Next Generation Anthracycline – Annamycin

Received positive independent report confirming absence of cardiotoxicity (unlike currently approved anthracyclines)
Announced positive results and successful completion of the Phase 1 portion of the AML Phase 1/2 trial in the US and plans to seek accelerated FDA approval for pivotal Phase 2 trial in AML
Found to be active against tumor metastases to the lung in pre-clinical testing
Confirmed anti-tumor efficacy of Annamycin in AML through new animal data
Expanded production to support positive clinical activity
Received FDA Fast Track designation and filed for new patents covering the production and reconstitution of Annamycin
Immune/Transcription Modulators – WP1066 Portfolio

Emory University received FDA Approval of IND for STAT3 inhibitor in Investigator Initiated Clinical Trial
Filed for patent protection on behalf of MD Anderson covering combination of immune-stimulating/transcriptional modulator, including combination with radiation therapy
Received Emory University Clinical Trial Review Committee approval in pediatric brain tumor trial
Presented preclinical pancreatic cancer data at American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting
Received Orphan Drug Designation from FDA
Metabolism/Glycosylation Inhibitors – WP1122 Portfolio

Final data from Phase 1 proof-of-concept clinical trial for the treatment of cutaneous T-cell lymphoma
Began preclinical testing of new approach to Pancreatic cancer, opportunity to attack cancer by inhibiting tumor metabolism
Entered into an agreement with University of Texas Medical Branch at Galveston (UTMB) to conduct research on WP1122, and other molecules of the Company, for antiviral properties against a range of viruses, including Coronavirus
Corporate Strategy

Entered into sublicense agreement with WPD Pharmaceuticals requiring WPD to provide a minimum of $4 million in development expenditures over a four-year period
Appointed Dr. Martin Tallman, Chief of Leukemia of Memorial Sloan Kettering Cancer Center, and Dr. James L. Abbruzzese, Chief of Medical Oncology Division at Duke University, to Science Advisory Board
Appointed Dr. Hongbo Zhai, former Senior Faculty and Supervisor of Postdoctoral Fellow at University of California San Francisco, to Science Advisory Board
Anticipated 2020 Milestones

First patient treated in the Phase 1 clinical trial with WP1066 for the treatment of pediatric brain tumors at Emory University
IND submission for Annamycin for the treatment of tumor metastases to the lung
Pre-IND Meeting with FDA/EMA concerning a Phase 2 clinical trial with WP1220 for the treatment of CTCL
File IND/CTA for a Phase 2 clinical trial with WP1220 for the treatment of CTCL
FDA End of Phase 1 meeting for Annamycin in AML
Achieving an MTD or a dose level at or above 300 mg/m2 in EU AML Phase 1/2 trial for Annamycin
Benefit from non-dilutive financial funding for additional clinical trials
Financial Results for the Year Ended December 31, 2019

Research and development ("R&D") expense was $11.0 million and $9.7 million for the years ended December 31, 2019 and 2018, respectively. The increase in R&D of approximately $1.3 million mainly relates to: increased clinical trial activity (2 drugs in 3 clinical trials in 2018, versus 3 drugs in 4 clinical trials in 2019) including the manufacturing of additional drug product and the issuance of common stock for $0.5 million, related to the exercise of the option to reacquire certain license rights in Germany under the Dermin License Agreements. These increases were offset by a reduction of $0.7 million in various other R&D expenses.

General and administrative ("G&A") expense was $6.3 million and $5.2 million for the years ended December 31, 2019 and 2018, respectively. The increase in G&A of approximately $1.1 million was mainly attributable to an increase in payroll costs for additional finance and office staff, stock-based compensation expense for vested warrants issued to a consultant, and annual employee stock options.

The net loss for the year ended December 31, 2019 was $13.2 million, which included non-cash expenses of approximately $1.5 million of stock-based compensation in 2019 as compared to $1.1 million in 2018.

Liquidity and Capital Resources

As of December 31, 2019, we had cash and cash equivalents of $10.7 million and prepaid expenses and other of $2.7 million. We also had $2.2 million of accounts payable and $1.4 million of accrued expenses. A significant portion of the accounts payable and accrued expenses are due to work performed in relation to our clinical trials. For the years ended December 31, 2019 and 2018, we used approximately $17.2 million and $12.2 million of cash in operating activities, respectively, which represents cash outlays for research and development and general and administrative expenses in such periods. The increase in 2019 reflects the increase in clinical and preclinical activity over 2018. For the year ended December 31, 2019, net proceeds from financing activities were $20.9 million, predominately from the sale of our common stock and warrants. In 2018, approximately $12.0 million was raised predominately through the sale of shares of common stock and the exercise of warrants. Cash used in investing activities for the year ended December 31, 2019 was approximately $0.05 million primarily for the purchases of employee computer equipment and office furniture.

We believe that our cash resources as of December 31, 2019, along with the additional funding received subsequent to year-end, will be sufficient to meet our projected operating requirements towards the end of the third quarter of 2020. This expectation does not consider unplanned preclinical and clinical activity, additional funding, including but not limited to, equity issuances including the use of the Lincoln Park or ATM facilities.

Novocure Announces Optune Lua™ as the Brand Name for the NovoTTF-100L™ System

On March 19, 2020 Novocure (NASDAQ: NVCR) reported that Optune Lua is the brand name for the NovoTTF-100L System in malignant pleural mesothelioma (MPM). The U.S. Food and Drug Administration (FDA) previously approved Novocure’s Tumor Treating Fields delivery system concurrent with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced or metastatic MPM (Press release, NovoCure, MAR 19, 2020, View Source [SID1234555713]).

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"The Optune brand emphasizes the unique product offerings of Novocure’s Tumor Treating Fields delivery systems and suggests the prospect of hope and optimized care," said Pritesh Shah, Novocure’s Chief Commercial Officer. "Optune Lua is easy to pronounce and remember, and should help patients, caregivers and providers ask for the treatment by name."

With the FDA’s approval of the Optune Lua brand name, all of Novocure’s Tumor Treating Fields delivery systems are aligned under a single brand family, Optune. The addition of a suffix to the Optune brand name helps differentiate between Tumor Treating Fields delivery systems for the treatment of MPM, glioblastoma and future potential indications.

About Optune Lua

Optune Lua is a noninvasive, antimitotic cancer treatment for MPM. Optune Lua delivers Tumor Treating Fields to the region of the tumor.

Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing affected cancer cells to die. Tumor Treating Fields does not stimulate or heat tissue and targets dividing cancer cells of a specific size. Tumor Treating Fields causes minimal damage to healthy cells. Mild to moderate skin irritation is the most common side effect reported. Tumor Treating Fields is approved in certain countries for the treatment of adults with glioblastoma and in the U.S. for mesothelioma, two of the most difficult cancer types to treat. The therapy shows promise in multiple solid tumor types – including some of the most aggressive forms of cancer.

Caution: Federal law restricts this device to sale by or on the order of a physician. Humanitarian Device. Authorized by Federal Law for use in the treatment of adult patients with unresectable, locally advanced or metastatic, malignant pleural mesothelioma concurrently with pemetrexed and platinum-based chemotherapy. The effectiveness of this device for this use has not been demonstrated

Approved Indications

Optune Lua is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM) to be used concurrently with pemetrexed and platinum-based chemotherapy.

Important Safety Information

Contraindications

Do not use Optune Lua in patients with implantable electronic medical devices such as pacemakers or implantable automatic defibrillators, etc. Use of Optune Lua together with implanted electronic devices has not been tested and may lead to malfunctioning of the implanted device.

Do not use Optune Lua in patients known to be sensitive to conductive hydrogels. Skin contact with the gel used with Optune Lua may commonly cause increased redness and itching, and may rarely lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions

Optune Lua can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure.

The most common (≥10%) adverse events involving Optune Lua in combination with chemotherapy were anemia, constipation, nausea, asthenia, chest pain, fatigue, medical device site reaction, pruritus, and cough.

Other potential adverse effects associated with the use of Optune Lua include: treatment related skin toxicity, allergic reaction to the plaster or to the gel, electrode overheating leading to pain and/or local skin burns, infections at sites of electrode contact with the skin, local warmth and tingling sensation beneath the electrodes, muscle twitching, medical device site reaction and skin breakdown/skin ulcer.

If the patient has an underlying serious skin condition on the treated area, evaluate whether this may prevent or temporarily interfere with Optune Lua treatment.

Do not prescribe Optune Lua for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune Lua in these populations have not been established.

Please visit www.optunelua.com to see Optune Lua Instructions For Use (IFU) for complete information regarding the device’s indications, contraindications, warnings, and precautions.

Hansoh Pharma’s AMEILE (almonertinib) Receives Marketing Authorization in China for Second-line Treatment for Patients With EGFR T790m-mutation Non-small Cell Lung Cancer

On March 19, 2020 Hansoh Pharmaceutical Group Company Limited ("Hansoh Pharma"), a leading biopharmaceutical company in China, reported that the National Medical Products Administration (NMPA) has granted marketing authorization for AMEILE (almonertinib, previously also known as HS-10296) once daily tablets for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), who have progressed on or after other EGFR tyrosine kinase inhibitor (TKI) therapy (Press release, Jiangsu Hansoh Pharmaceutical, MAR 19, 2020, View Source [SID1234555712]).

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AMEILE is the second 3rd generation EGFR TKI to be approved for metastatic NSCLC patients with EGFR T790M. The approval of AMEILE provides a highly efficacious treatment option with favorable safety profile for advanced NSCLC patients.

Lung cancer remains the leading cause of cancer-related deaths worldwide and in China. EGFR mutation is the most common mutation and accounts for about 40% of NSCLC patients in China. Approximately 50% of NSCLC patients will develop drug-resistant T790M mutation following treatment with first or second generation EGFR TKI. In its registrational study, APOLLO (n=244), patients taking AMEILE has shown a median progression-free-survival (mPFS) of greater than a year, the longest in its class as a monotherapy in second line therapy. AMEILE provides a new option with favorable safety profile and high efficacy for NSCLC patients in China, and is another illustration of Hansoh Pharma’s steadfast commitment in developing life-changing medicines to help patients and families in need around the world.

The NMPA’s approval of AMEILE was supported by clinical results from APOLLO study, a multicenter, open-label, single-arm Phase 2 study conducted in patients with recurrent NSCLC harboring EGFR T790M mutations. In this study, a total of 244 patients were treated with 110mg of almonertinib. The primary endpoint was objective response rate (ORR) as determined by blinded independent central review (ICR). Key secondary endpoints include PFS assessed by ICR, disease control rate (DCR), duration of response (DoR), and overall survival (OS). In APOLLO trial, ORR was 68.9%, DCR was 93.4%, mPFS was 12.3 months, and ORR in patients with CNS metastasis was 61.5%.[1,2] Further, almonertinib was well tolerated, where most common AEs were grade 1 or 2, with less than three percent patients discontinued treatment with almonertinib due to drug-related AEs. There was no interstitial lung disease reported during this study while neither grade 3 rash nor QT prolongation was observed. The most commonly observed adverse events, regardless of attribution, were blood creatine phosphokinase increased, rash, pruritus, aspartate aminotransferase increased, and alanine aminotransferase increased. [1,2]

"AMEILE has demonstrated a compelling efficacy and tolerability in NSCLC patients with EGFR mutations," said Professor Shun Lu, the Principal Investigator of APOLLO trial and Professor of Shanghai Chest Hospital, Affiliated Hospital of Shanghai Jiao Tong University. "AMEILE provides a new targeted-therapy option for NSCLC patients with EGFR-mutations, especially for patients with brain metastasis."

"Almonertinib serves as a promising option for NSCLC patients, which is supported by the efficacy and safety data from APOLLO as well as other studies," said Professor James Chih-Hsin Yang of Graduate institute of Oncology at National Taiwan University College of Medicine.

About Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths among both men and women globally and in China. In 2018, there were approximately 867,500 new diagnoses of lung cancer in China, of which 737,400, or approximately 85%, were recorded as NSCLC in 2018, with a five-year survival rate of only 19.3%. About 40% of these are EGFR mutation-positive and approximately 50% of patients treated with first- or second-generation EGFR TKI therapy will acquire resistance related to the T790M mutation. [3]

About Almonertinib

Almonertinib 110mg once-daily tablet is a medicine indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an NMPA-approved test, who have progressed on or after prior EGFR TKI therapy. Almonertinib has high, nanomolar inhibitory activity against common EGFR mutations as well as drug-resistant T790M mutations in preclinical studies.

Celsion Corporation to Hold Year-End 2019 Financial Results Conference Call on Thursday, March 26, 2020

On March 19, 2020 Celsion Corporation (NASDAQ: CLSN) reported that the Company will host a conference call to discuss financial results for the year ended December 31, 2019 and provide an update on its development programs for ThermoDox, its proprietary heat-activated liposomal encapsulation of doxorubicin and GEN-1, an IL-12 DNA plasmid vector formulated into a nanoparticle with a non-viral delivery system at 11:00 a.m. EDT on Thursday, March 26, 2020 (Press release, Celsion, MAR 19, 2020, View Source [SID1234555711]).

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To participate in the call, interested parties may dial 1-800-367-2403 (Toll-Free/North America) or 1-334-777-6978 (International/Toll) and ask for the Celsion Corporation Fourth Quarter and Year-End 2019 Earnings Call (Conference Code: 8257530) to register ten minutes before the call is scheduled to begin. The call will also be broadcast live on the internet at www.celsion.com. The call will be archived for replay on Friday, March 27, 2020 and will remain available until April 10, 2020. The replay can be accessed at 1-719-457-0820 or 1-888-203-1112 using Conference ID: 8257530. An audio replay of the call will also be available on the Company’s website, www.celsion.com, for 90 days after 2:00 p.m. EDT Thursday, March 26, 2020.