On January 27, 2021 Eisai reported that it will present four abstracts at the virtual Genitourinary Cancers Symposium 2021 (#GU21) from February 11-13, 2021 (Press release, Eisai, JAN 27, 2021, View Source [SID1234574360]). These investigational data include a late-breaking oral presentation from the pivotal Phase 3 CLEAR study (KEYNOTE-581/Study 307) (NCT02811861) (Abstract # 269) evaluating KEYTRUDA plus LENVIMA and LENVIMA plus everolimus versus sunitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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Additional data to be presented include two abstracts from Study 218 (NCT03173560), which is a Phase 2 trial evaluating the safety and efficacy of two starting doses of LENVIMA (18 mg versus 14 mg once daily) plus everolimus (5 mg once daily) in patients with advanced RCC. These include a health-related quality of life outcomes analysis (Abstract # 314) as well as efficacy analyses by independent imaging review, and by subgroup of patients who received prior anti-PD-1/L1 therapy per investigator assessment (Abstract # 307). A Trial in Progress abstract will also be presented on a Phase 3 study (NCT04586231) exploring the efficacy and safety of LENVIMA plus the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan (MK-6482) versus cabozantinib in patients with advanced RCC who received prior anti-PD-1/L1 therapy (Abstract #TPS372).

"We’re excited to present new investigational data on LENVIMA that we hope will provide the oncology community with optimism at this year’s Genitourinary Cancers Symposium," said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. "We remain relentless in our pursuit to spark change in the oncology space by continuing to evaluate the LENVIMA plus everolimus combination as well as research new potential combination treatment options for renal cell carcinoma patients. We’re dedicated to fighting for patients suffering from this insidious disease and we believe these results mark a big step in the direction of greater therapeutic knowledge and options for this community."

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 and Merck’s HIF-2α inhibitor, belzutifan. To date, 20 trials have been initiated under the LEAP (LEnvatinib And Pembrolizumab) clinical program, which is evaluating the KEYTRUDA plus LENVIMA combination across 13 different tumor types. For more information on the LEAP program, please visit clinicaltrials.gov.

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

The full list of Eisai presentations is included below. All abstracts will be available for viewing on demand via the Genitourinary Cancers Symposium website from February 11 at 8:00 AM EST through February 13, 2021.

Study/Trial

Abstract Name

Virtual Presentation Details

CLEAR study (KEYNOTE-581/Study 307)

A phase 3 trial of lenvatinib in combination with pembrolizumab or everolimus versus sunitinib monotherapy as a first-line treatment for patients with advanced renal cell carcinoma (the CLEAR study)

Oral Presentation (Late-Breaker)

Abstract #: 269

February 13, 2021 at 1:00 PM-2:15 PM EST

Robert Motzer, MD

Study 218

Health-related quality of life outcomes from a Phase 2 open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment

Poster Session

Abstract #: 314

Cristiane Bergerot, PhD

Phase 2 trial of lenvatinib (LEN) at 2 starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma (RCC): results by independent imaging review (IIR) and prior immune checkpoint inhibition (ICI)

Poster Session

Abstract #: 307

Sumanta Pal, MD

Trial in Progress

Phase 3 study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy

Poster Session

Abstract #: TPS372
Robert Motzer, MD

About Renal Cell Carcinoma (RCC)
Worldwide, it is estimated there were more than 430,000 new cases of kidney cancer diagnosed and nearly 180,000 deaths from the disease in 2020. In the U.S. alone, it is estimated there will be more than 76,000 new cases of kidney cancer diagnosed and nearly 14,000 deaths from the disease in 2021. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC. Survival is highly dependent on the stage at diagnosis, and with a five-year survival rate of 12% for metastatic disease, the prognosis for these patients is poor.

About LENVIMA (lenvatinib) Capsules
LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, 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. The combination of LENVIMA and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone. 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.

Important 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.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

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 DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

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.

LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.

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 have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in 13 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, and triple-negative breast cancer) across 20 clinical trials.

On January 27, 2021 Shasqi, a clinical-stage biotechnology company developing precision oncology therapeutics with its proprietary Click Activated Protodrugs Against Cancer (CAPACTM) platform, reported the publication of two preclinical studies highlighting the potential of the company’s click chemistry-based approach to the development of treatments for a range of solid cancers (Press release, Shasqi, JAN 27, 2021, View Source [SID1234574359]). The paper, "Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation" was published in the journal Chemical Science on January 5, 2021 and the paper, "SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected and Non–Injected Lesions” was published in the journal Advanced Therapeutics on January 20, 2021. Shasqi is currently advancing its lead clinical candidate, SQ3370, a click-activated protodrug therapy, in a phase 1 clinical trial.

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"A goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. The limitations of targeted therapies, which benefit only a small subset of patients, make this goal difficult to achieve in practice," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "We believe our platform has the potential to overcome these limitations and benefit patients regardless of biomarker status or genetics. The published evidence reinforces the ability of our lead candidate, SQ3370, to do that in preclinical models. We are now in the process of evaluating this approach in our first clinical trial and look forward to sharing data later this year."

Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation. Wu, K., et. al., Chemical Science. January 5, 2021

Protodrugs of various chemotherapy agents were tested in vitro to evaluate cytotoxicity, solubility, stability and activation. These studies rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was 19.1-times the maximum-tolerated dose of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the maximum-tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. Combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice.

SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected and Non–Injected Lesions. Srinivasan, S., et. al.. Advanced Therapeutics. January 20, 2021

This study found that the Shasqi’s Click Activated Protodrugs Against Cancer (CAPAC) platform is capable of developing medicines to treat a range of tumor types and that SQ3370 is tolerated well above the maximum dose of conventional doxorubicin. In preclinical models, SQ3370 increased survival by 63 percent over conventional doxorubicin and induced a potent systemic anti–tumor response against injected as well as non–injected lesions. The sustained anti–tumor response correlated with activation of the immune system which was measured at both lesions.

SQ3370 is the first click chemistry-based treatment to be tested in humans. This study, SQ3370-001, is currently enrolling patients with advanced sarcomas and other solid tumors in the United States and Australia (ClinicalTrials.gov NCT04106492). The company presented preclinical and trial-in-progress data from the SQ3370 program in late 2020.

CAPAC and SQ3370
SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform, a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. The platform utilizes the biocompatible chemical reaction between an attenuated trans-cyclooctene-modified protodrug and a tetrazine-modified biopolymer. The biopolymer is injected into the target tumor lesion, where it precisely captures and activates an infused protodrug. Unlike traditional targeted therapies, the CAPAC platform is agnostic to tumor characteristics that can vary from patient to patient, such as biomarker expression and enzymatic activity. CAPAC is highly modular and can be applied to a wide variety of cancer therapeutics.

On January 27, 2021 Scopus BioPharma Inc. (Nasdaq: "SCPS") reported that it intends to effectuate an exchange offer (the "Exchange") pursuant to which Scopus BioPharma common stock would become exchangeable for units (the "X Units") of the company (Press release, Scopus BioPharma, JAN 27, 2021, View Source [SID1234574358]).

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The Exchange is being designed to reward existing holders of common stock and to provide incentives for long-term ownership of our securities by existing and prospective new investors.

Each X Unit issuable pursuant to the Exchange would be comprised of one share of common stock, identical to the company’s currently outstanding common stock, and one newly-issuable warrant (the "X Warrant"). Holders of common stock would be entitled to receive one X Unit for each share of common stock tendered.

Holders of common stock would be able to tender all, some or none of their common stock. Shares of common stock not tendered would remain outstanding and unmodified.

There would be no cash or other consideration payable to participate in the Exchange.

It is the company’s intention to apply to Nasdaq for listing of both the X Units and the X Warrants.

The securities contained within each X Unit would become separable and separately tradable and transferable on January 3, 2022. The company would be permitted to allow for such separate trading at an earlier date in its sole discretion.

Each newly-issuable X Warrant would be exercisable for one share of the company’s common stock at an exercise price of $9.00 per share. The X Warrants would become exercisable, subject to any applicable regulatory and/or Nasdaq approval, on January 2, 2023 through and including January 3, 2028. On or after January 2, 2024, the company would, at its sole option, be able to redeem the X Warrants if the common stock trades at or above $27.00 per share, subject to an applicable number of qualifying trading days and other conditions.

Scopus is a biopharmaceutical company developing transformational therapeutics based on groundbreaking scientific and medical discoveries. The company’s lead drug candidate is a novel, targeted immuno-oncology gene therapy for the treatment of multiple cancers. This drug candidate is highly distinctive, encompassing both gene therapy and immunotherapy by synthetically linking siRNA to an oligonucleotide TLR9 agonist, creating the potential for targeted gene silencing with simultaneous TLR stimulation and immune activation in the tumor microenvironment.

On January 27, 2021 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing and commercializing global first-in-class and/or best-in class therapeutics in hematology and oncology, reported that the National Medical Products Administration (NMPA) accepted its New Drug Application (NDA) for ATG-010 (Selinexor, XPOVIO), a first-in-class oral selective inhibitor of nuclear export (SINE) compound, for the treatment of patients with relapsed/refractory multiple myeloma (rrMM) (Press release, Antengene, JAN 27, 2021, View Source [SID1234574357]). This is the fifth NDA for ATG-010 submitted by Antengene, after the four NDAs recently submitted in Australia, South Korea, Singapore and Hong Kong in the Asia Pacific region, and also the first NDA of SINE compounds in mainland China, a step closer to providing a novel option to Chinese patients diagnosed with hematological malignancies.

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Antengene has recently submitted NDAs in multiple markets for ATG-010 across three indications for multiple myeloma and diffuse large B-cell lymphoma. Recently, the National Comprehensive Cancer Network (NCCN) has also added five ATG-010 regimens to its guidelines for multiple myeloma or diffuse large B-cell lymphoma. ATG-010 is the first approved SINE compound in the world. It induces the apoptosis of cancer cells in vitro and in vivo by causing the nuclear storage and activation of tumor suppressor proteins and other growth-regulating proteins, and by down-regulating the intracytoplasmic levels of various oncogenic proteins while normal cells are not affected. Clinical studies have demonstrated that ATG-010 has clinical effects in multiple types of hematological and solid tumors with manageable safety profile.

"We are delighted to see the acceptance of the NDA submission in China for ATG-010 in rrMM, which marks another important milestone and one step closer to bringing ATG-010 to patients in China." said Dr. Jay Mei, M.D., Ph.D., Founder, Chairman and CEO of Antengene. "In addition to its effectiveness in hematological malignancies, there are several clinical trials in multiple solid tumor indications with ATG-010 including a global Phase 3 trial in endometrial cancer (SIENDO) and a Phase 3 trial in liposarcoma (SEAL) which have shown encouraging results. We continue to prepare to commercialize ATG-010 in China and across the APAC region so that cancer patients can benefit from this novel cancer medicine."

About ATG-010 (selinexor, XPOVIO)

ATG-010 (selinexor, XPOVIO), a first-in-class and only-in-class oral selective inhibitor of nuclear export (SINE) compound discovered and developed by Karyopharm Therapeutics Inc. (NASDAQ: KPTI), is currently being developed by Antengene, which has the exclusive development and commercial rights in certain Asia-Pacific markets, including Greater China, South Korea, Australia, New Zealand and the ASEAN countries.

In July 2019, the US Food and Drug Administration (FDA) approved selinexor (XPOVIO) in combination with low-dose dexamethasone for the treatment of relapsed/refractory multiple myeloma (rrMM) and in June 2020 approved selinexor (XPOVIO) as a single-agent for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL). In December 2020, selinexor (XPOVIO) also received FDA approval as a combination treatment for multiple myeloma after at least one prior therapy. A Marketing Authorization Application (MAA) has also been submitted to the European Medicines Agency (EMA) with a request for conditional approval of selinexor in this same rrMM indication. Selinexor (XPOVIO) is so far the first and only oral SINE compound approved by the FDA and is the first drug approved for the treatment of both MM and DLBCL. Selinexor (XPOVIO) is also being evaluated in several other mid-and later-phase clinical trials across multiple solid tumor indications, including liposarcoma and endometrial cancer. In November 2020, at the Connective Tissue Oncology Society 2020 Annual Meeting (CTOS 2020), Antengene’s partner, Karyopharm, presented positive results from the Phase 3 randomized, double blind, placebo controlled, cross-over SEAL trial evaluating single agent, oral selinexor (XPOVIO) versus matching placebo in patients with liposarcoma. Karyopharm also announced that the ongoing Phase 3 SIENDO trial of selinexor (XPOVIO) in patients with endometrial cancer passed the planned interim futility analysis and the Data and Safety Monitoring Board (DSMB) recommended the trial should proceed as planned without any modifications. Top-line SIENDO trial results are expected in the second half of 2021.

On January 27, 2021 Orexo reported that Q4 2020, incl. Full Year Report (Press release, Orexo, JAN 27, 2021, View Source [SID1234574355])

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Q4 2020 highlights

Total net revenues of SEK 159.2 m (238.1 last year, 196.2 m excl. Abstral EU and US)
Net earnings of SEK -49.6 m (38.9)
EBITDA of SEK 1.0 m (85.8)
US Pharma segment (ZUBSOLV US) net revenues of SEK 143.1 m (190.5), EBIT of SEK 94.4 m (95.5)
Cash flow from operating activities of SEK -11.2 m (60.2), cash balance of SEK 505.3 m (816.8)
Secured a preferred position for ZUBSOLV as the only branded product on national commercial and Medicare Part D formularies of the largest PBM in the commercial segment in the US, Express Script, from January 1, 2021
Finalized the technical development of modia, a digital therapy for opioid use disorder, for which Orexo owns the exclusive global rights
Entered an exclusive license and supply agreement with Accord Healthcare for ZUBSOLV covering 29 European countries
A new patent for ZUBSOLV, with protection until 2032, was issued by the US Patent and Trademark Office (USPTO)
Financial outlook provided for 2021, see page 14
Important events after the period

A new patent for OX124, overdose rescue medication, was issued by the USPTO protecting the technology until 2039
SEK m, unless otherwise stated

Progress while adjusting to new market dynamics

From a management perspective, the most important factor for success is to be an agile company, ready to accelerate development and to capture opportunities when they arise, but also be prepared to shift priorities when the market requires it. The quarter has seen progress on many fronts, with US Pharma showing net revenue growth in local currency comparing to last quarter and improved EBIT margin, Digital Therapeutics (DTx) testing new reimbursement routes and launching new commercialization concepts. Our lead pipeline project, a rescue medication for opioid overdose, OX124, received positive feedback from the FDA on the IND application enabling a request for Fast Track Designation of the product and we also reported an exclusive license and supply agreement for ZUBSOLV in Europe.

Strong financial base to enable investments in DTx and launch of OX124

Our full year OPEX was SEK 617 million, which is significantly less than the guidance of SEK 750-800 million communicated in our Q2 report. The guidance in Q2 was based on the significant interest in DTx in the beginning of the Covid-19 pandemic and our expectation that payers and healthcare providers would follow the FDA’s decision to include digital therapies under the Public Health Emergency Policy and find pragmatic routes for reimbursement. While the interest in Orexo’s digital therapies remains high, building a new market requires patience. We start to see concrete and promising development with regards to DTx reimbursement, which is a cornerstone to accelerate growth.

Looking ahead, we expect to increase the investment in DTx as we see a progression in sales and a clearer picture emerges regarding the multiple routes to reimbursement. 2021 will also require significant investments in OX124, as we enter the pivotal trial starting in the summer this year. To ensure we have financial headroom to invest in opportunities when they arise, both internally in our products and our pipeline and through business development, we intend to refinance our existing corporate bond during Q1 2021 with a new corporate bond issue.

Expanding the commercialization model in DTx

The expectations of our DTx portfolio in 2020 were boosted by the FDA’s decision to implement a Public Health Emergency Policy allowing commercialization of digital therapies within the CNS space without the ordinary approval process. We anticipated that the payers would adopt similar pragmatism to the reimbursement processes as a response to the Public Health Emergency Policy, but the reimbursement process is following the pattern we anticipated before Covid-19, i.e. a new disruptive treatment will take time to review and implement. As a result, we are testing several new concepts for reimbursement of our digital therapies in parallel, while making the DTx available through direct purchase for patients. The lead concept is a treatment program where we, in collaboration with selected healthcare providers, offer patients treatment under the supervision of a physician. Provided the physicians and the patients follow certain guidelines, this treatment program is currently available for reimbursement for a large portion of the US population. The program is being tested in Pennsylvania to a limited number of patients to ensure the reimbursement will follow the expected path before we launch nationwide. The same program will also be available for individual physicians to treat patients under a direct contract with Orexo. In addition to this program, we are finalizing a program for employers, working with patient to patient communication, and continue our work with payers to drive reimbursement.

ZUBSOLV decline diminishing while impact of Covid-19 continues

With bipartisan support for the ongoing opioid crisis in the US, I am pleased to see politicians returning their attention to the opioid crisis. The former US administration recently paved the way for all US physicians to prescribe medical-assisted treatment (MAT) for opioid dependence, and we are confident that in the event of changes under the new administration, addressing the opioid crisis will remain a key priority. With the ongoing Covid-19 pandemic having significantly worsened this crisis, there is a pressing need increase access to treatment. Such a change will likely drive a sustained strong market growth, which will benefit Orexo and ZUBSOLV.

This quarter we had a small net sales increase compared to Q3 and a strong EBIT margin of 66 percent. Apart from some one-time adjustments, this result is explained by minimal decline from former exclusive contracts and stable development in the open segment. When Covid-19 is behind us, we expect a stabilization of the business and growth. ZUBSOLV is the only promoted daily treatment in opioid dependence in the US, and Covid-19 restrictions have had a severe impact on our ability to promote the product. In combination with our core market segment, the commercial segment, being stagnant due to the unemployment caused by Covid-19, it is a challenging market place during the pandemic. However, the Covid-19 challenges also provides learning of how to be more efficient in the sales process, which will benefit us long term. We expect ZUBSOLV will continue to be an important EBIT contributor in the years to come and with the broad launch of modia, our digital therapy for opioid use disorder, in the second half of 2021 we will see increased commercial synergies between our digital therapies and ZUBSOLV, both from a cost and revenue perspective.

OX124 development progressing to plan

As the US death tolls associated with overdose of fentanyl continue, we are confident OX124 is urgently needed, with the promise of being the most powerful nasal delivery of naloxone in the market. I am very pleased with the progress we have made during the quarter. With continued progress according to plan, in Q1 2021 we will receive a decision on the Fast Track application, continue to establish a commercial supply chain, improve the IP protection and register the brand name for OX124. In Q2 2021 we will manufacture the batches required for regulatory stability data and we will start the pivotal clinical trial. If the Fast Track application is approved we will be ready to submit an application for approval in Q1 2022. Without Fast Track the process will be delayed as we expect the FDA will require additional stability data to support proposed shelf life of the commercial product.

Summary and Outlook

In the last quarterly report I highlighted the pressing need for Orexo’s products as a result of the Covid-19 pandemic. The Covid-19 pandemic has unfortunately escalated, and the need for our products is even greater than before. The delays to get the DTx products reimbursement is certainly frustrating, especially given the clear demand for such products in the current climate. However, I also have to respect that Covid-19 has had a severe impact on many organizations and their ability to operate as normal. This aside, we are encouraged by the positive feedback we receive from customers and the steady progression we see in the number of patients testing and buying our DTx products in January. I remain confident that 2021 will show the commercial potential of these products, while we continue to enjoy strong and stable EBIT contribution from ZUBSOLV and prepare the new drug application for OX124.Uppsala, Sweden,

Presentation

At 2.00 pm CET, the same day as the announcement of the report, Orexo invites analysts, investors and media to attend an audiocast with a web presentation where Nikolaj Sørensen, CEO, and Joseph DeFeo, CFO, will present the report. After the presentation a Q&A will be held. Questions can also be sent in advance to [email protected], no later than 11.00 am CET. Please view the instructions below on how to participate.Internet: View Source SE +46 8 50 558 358 UK +44 333 300 9267 US +1 833 249 8403 The presentation material will be available on Orexo’s website prior to the audiocast, view Investors/Reports, presentations and audicastsThis information is information that Orexo AB (publ.) is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out above, at 8.00 am CET on January 28, 2021.