On August 16, 2018 Eisai Inc. and Merck (NYSE: MRK), known as MSD outside of the United States and Canada , reported that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor LENVIMA (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) (Press release, Eisai, AUG 16, 2018, View Source [SID1234528952]). This approval was based on results from REFLECT (Study 304), where LENVIMA demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

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"Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade," said Dr. Ghassan Abou-Alfa , medical oncologist, Memorial Sloan Kettering Cancer Center . "REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it."

Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, LENVIMA should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see "Important Safety Information" below.

REFLECT showed that LENVIMA achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with LENVIMA experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the LENVIMA arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, LENVIMA showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

Median PFS was doubled with LENVIMA compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with LENVIMA versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
LENVIMA showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with LENVIMA versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
Per mRECIST: Treatment with LENVIMA resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with LENVIMA resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
Per RECIST 1.1: Treatment with LENVIMA resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with LENVIMA resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib
In addition, median time to progression (TTP) was doubled with LENVIMA compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with LENVIMA versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with LENVIMA were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with LENVIMA were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for LENVIMA for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

" Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care ( hhc ) mission to improve the lives of patients and their loved ones," said Shaji Procida , President and Chief Operating Officer, Eisai Inc. , and Commercial Head of the Oncology Business Group , Americas at Eisai . "That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck ."

"We are pleased by the FDA approval of LENVIMA as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma," said Dr. Roy Baynes , Senior Vice President and Head of Global Clinical Development , Chief Medical Officer, Merck Research Laboratories . "With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians."

LENVIMA, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016 , LENVIMA was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for LENVIMA in the U.S. in June 2018 . Since the initial launch, more than 10,000 patients were treated with LENVIMA, which is approved in more than 50 countries worldwide.

About the REFLECT Trial (Study 304)
REFLECT was a large (N=954) phase 3, randomized, multicenter, open-label trial conducted by Eisai to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable hepatocellular carcinoma (HCC). Patients at 154 trial sites in 20 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was overall survival, tested first for non-inferiority to sorafenib, then for superiority. Patients randomized to the LENVIMA arm did not have a statistically significant improvement in OS compared to those in the sorafenib arm. The key secondary efficacy endpoints of this study included progression-free survival, time to progression and objective response rate, tested for superiority to sorafenib. The results of the REFLECT trial were published online in The Lancet (Vol 391(10126):1163-1173) on February 9, 2018 .

About Unresectable Hepatocellular Carcinoma (HCC)
The prevalence and mortality rate of hepatocellular carcinoma have been rising steadily over the past decade. Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer. The stage of disease at diagnosis largely determines treatment approach, with potentially curative options, like resection or transplantation, only available for early stage HCC. Unresectable HCC, a type of liver cancer that cannot be removed by surgery, has a worse prognosis, with a median survival of less than one year. Unfortunately, approximately 70% of patients are diagnosed too late to be eligible for resection or transplantation, and there have been limited treatment options available for patients with unresectable disease.

About LENVIMA (lenvatinib) capsules 10 mg and 4 mg
LENVIMA (lenvatinib) is a kinase inhibitor that is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (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)
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. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

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%. Fistulas and gastrointestinal perforations have also been reported in other lenvatinib clinical trials and in post-marketing experience. Pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula, and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present.

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.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

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%).

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 or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC 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 or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

For more information about LENVIMA please see available full Prescribing Information .

About the Eisai and Merck Strategic Collaboration
In March 2018 , Eisai and Merck , through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA (lenvatinib). Under the agreement, the companies will jointly develop and commercialize LENVIMA, both as monotherapy and in combination with Merck ‘s anti-PD-1 therapy KEYTRUDA (pembrolizumab). In addition to ongoing clinical studies of the combination, the companies will jointly initiate new clinical studies evaluating the LENVIMA/KEYTRUDA combination to support 11 potential indications in six types of cancer, as well as a basket trial targeting six additional cancer types. The LENVIMA/KEYTRUDA combination is not approved in any cancer types today.

On August 15, 2018 Neuralstem, Inc. (Nasdaq:CUR), a biopharmaceutical company focused on the development of nervous system therapies based on its neural stem cell and small molecule compound technologies, reported its financial results for the second quarter ended June 30, 2018 (Press release, Neuralstem, AUG 15, 2018, View Source [SID1234528876]).

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"We are pleased to report a productive second quarter of 2018 as we continue to advance our pipeline of innovative neural stem cell and small molecule therapies," said Jim Scully, interim Chief Executive Officer of Neuralstem. "We are especially excited about the advancement of our lead stem cell therapy candidate, NSI-566, into a Phase 2 trial in ischemic stroke, as well as its potential application to other areas of unmet medical need. Additionally, based on encouraging preclinical data, we look forward to exploring our small molecule NSI-189’s potential treatment applications, including Angelman Syndrome and Alzheimer’s Disease."

Clinical Highlights

NSI-566, is a spinal cord-derived neural stem cell line that is being evaluated to treat paralysis associated with stroke, Amyotrophic Lateral Sclerosis (ALS) and chronic spinal cord injury (cSCI). NSI-566 is Neuralstem’s lead stem cell therapy candidate.

In July, Neuralstem announced initiation of a Phase 2 clinical trial evaluating NSI-566 as a potential treatment for ischemic stroke. This trial, which will be a randomized, double-blind, controlled study, is based on the positive results from the open-label Phase 1 safety study and is intended to further test the safety and efficacy of NSI-566 to reverse paralysis in stroke patients where half of their body has been partially paralyzed. James Li, Ph.D., Executive Vice President of Asia Operations of Suzhou Neuralstem Ltd, will be managing this trial which will be taking place at Bayi Brain Hospital in Beijing, China, and commenced on August 1, 2018. In Phase 1, NSI-566 treatment of 9 chronically hemiparetic stroke patients resulted in statistically significant improvement from baseline of motor functioning and clinical status.

In June, the Company announced the results from a study published in Cell Stem Cell that support the potential therapeutic application of transplanted NSI-566 in patients with chronic spinal cord injury (cSCI). The manuscript, entitled "A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury," presented a detailed analysis of motor and sensory function and electrophysiology results which showed improvement in three of the four patients after NSI-566 transplantation. The study’s primary objective was to evaluate the safety of NSI-566 transplantation in subjects with stable thoracic spinal cord injury, and additional endpoints measured included changes in neurologic deficits, neurophysiology, and neuropathic pain.

In May, the Company announced the results from a study published in the Annals of Clinical and Translational Neurology in a manuscript entitled "Long-term Phase 1/2 Intraspinal Stem Cell Transplantation Outcomes in Amyotrophic Lateral Sclerosis" that support the potential of transplanted human spinal cord-derived neural stem cells (HSSC) to stabilize functioning of ALS patients. The study evaluated the impact of HSSC transplantation on functional outcomes, as measured using the ALSFRS-R scale, and on a composite statistic that combined functional and survival outcomes. Results were evaluated against matched controls derived from two historical datasets and showed significantly better ALSFRS-R scores at 24 months, as well as the composite functional/survival score in subjects receiving HSSC. The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated questionnaire that measures physical function in performing activities of daily living (ADLs).
NSI-189, is a small molecule benzylpiperazine-aminopyridine, in clinical development for MDD and in preclinical development for Angelman syndrome, irradiation-induced cognitive impairment, Type 1 and Type 2 diabetes, and stroke.

In August, the Company announced it had been granted orphan drug designation by the FDA for the treatment of Angelman Syndrome. In pre-clinical models, NSI-189 has demonstrated the ability to restore long term potentiation (LTP), a measure of synaptic plasticity and an in vitro biomarker of memory. Angelman Syndrome (AS) is a rare congenital genetic disorder caused by a lack of function in the UBE3A gene on the maternal 15th chromosome. It affects approximately one in 15,000 people – about 500,000 individuals globally. Symptoms of AS include developmental delay, lack of speech, seizures, and walking and balance disorders. Patients with AS may never walk or speak and require life-long care. Life expectancy is normal which places a significant burden on patients and caregivers. There are currently no FDA-approved therapies for the treatment of Angelman syndrome. The FDA’s orphan-drug designation program provides special status and incentives to encourage the development of drugs for diseases affecting fewer than 200,000 people in the U.S. Orphan drug designation confers seven years of market exclusivity upon FDA approval, as well as other development incentives, such as tax credits related to clinical trial expenses, an exemption from the FDA-user fee and FDA assistance in clinical trial design.

In July, the Company presented preclinical data at the Alzheimer’s Association International Conference in Chicago, Illinois, demonstrating that oral administration of NSI-189 in a mouse model of Alzheimer’s Disease leads to a significant amelioration and/or improvement in cognition measures and anxiety. Results were presented in a poster titled ‘Effect of Neurogenic Compound NSI-189 on Indices of Cognition and Anxiety in a Mouse Model (5XFAD) of Alzheimer’s Disease.’ The study was carried out by Dr. Corinne Jolivalt’s laboratory at the University of California, San Diego, and found that treatment with NSI-189 significantly improved learning ability as well as retention, short-term memory and anxiety levels of mice.
Corporate Highlights

Effective August 1, Jim Scully was appointed as interim chief executive officer by the Board of Directors. Mr. Scully succeeds Mr. Rich Daly, former Neuralstem president and chief executive officer. Mr. Scully brings to Neuralstem a wealth of experience from a range of senior executive roles in the pharmaceutical and broader healthcare industry, including leadership roles in financial and strategic planning, global business development and general management at Takeda Pharmaceuticals, Astellas Pharmaceuticals, Abbott Laboratories and Walgreens.

Also, effective August 1, the Board of Directors appointed William Oldaker as Chairman of the Board. Mr. Oldaker has served as a director of Neuralstem since April 2007. Additionally, he is a founder and partner in the Washington, D.C. law firm, Oldaker & Willison PLLP, and is a member of the Colorado, D.C. and Iowa Bar Associations, the Bar Association for the Court of Appeals, D.C., and the Bar of the United States Supreme Court.
Financial Results for the Quarter Ended June 30, 2018

Cash Position and Liquidity: At June 30, 2018, cash and investments was $7.1 million as compared to $9.7 million at March 31, 2018. The $2.6 million decrease reflects a $0.6 million loss for the period adjusted for certain non-cash items including a $1.4 million gain related to the change in fair value of our liability classified warrants, $760,000 net cash outflows related to changes in operating assets and liabilities, and $200,000 of share-based compensation. The Company expects its existing cash, cash equivalents and short-term investments to fund its operations based on its current operating plans, into the first quarter of 2019.

Operating Loss: Operating loss for the second quarter ended June 30, 2018 was $2.0 million compared to a loss of $4.2 million for the comparable period of 2017. Operating loss for the six months ended June 30, 2018 was $4.4 million compared to a loss of $8.5 million for comparable period of 2017.

The decrease in operating loss for both the three- and six-month periods was primarily related to decreases in clinical trial and related costs due to the completion of the NSI-189 Phase 2 clinical trial, decreases in personnel, facility and related expenses due to ongoing corporate restructuring and cost reduction efforts offset by revenues from a milestone-based royalty and reimbursements under a National Institute of Health (NIH) grant.

Net Loss: Net loss for the second quarter ended June 30, 2018 was $0.6 million, or $0.04 per share (basic), compared to a loss of $4.6 million, or $0.39 per share (basic), for the comparable period of 2017. The decrease in net loss was primarily due to a decrease in operating loss and the non-cash charges related to the change in the fair value of liability classified warrants.

Net loss for the six months ended June 30, 2018 was $2.8 million, or $0.18 per share (basic), compared to a loss of $12.2 million, or $1.06 per share (basic), for the comparable period of 2017. The decrease in net loss was primarily due to a decrease in operating loss and the non-cash charges related to the change in the fair value of liability classified warrants and warrant inducement expenses in the 2017 period and a decrease in interest expense related to our long-term debt which matured in April 2017.

Research and Development Expenses: The $1.0 million of research and development expenses for the quarter ended June 30, 2018 represents a $1.6 million, or 61% decrease over the comparable period of 2017. This decrease was primarily attributable to a $710,000 decrease in personnel and facility expenses due to ongoing corporate restructuring and cost reduction efforts, a $310,000 decrease in clinical trial and related costs due to the completion of our NSI-189 Phase 2 clinical trial and a $410,000 decrease in non-cash share-based compensation expense along with $90,000 of reimbursements under a NIH grant.

The $2.2 million of research and development expenses for the six months ended June 30, 2018 represents a $3.3 million, or 60% decrease over the comparable period of 2017. This decrease was primarily attributable to a $1.8 million decrease in personnel and facility expenses due to ongoing corporate restructuring and cost reduction efforts, a $540,000 decrease in clinical trial and related costs due to the completion of the NSI-189 Phase 2 clinical trial, a $720, 000 decrease in our non-cash share-based compensation expense along with $180,000 of reimbursements under a NIH grant.

General and Administrative Expenses: The $1.3 million of general and administrative expenses for the second quarter ended June 30, 2018 represents a $380,000, or 23% decrease over the comparable period of 2017. This decrease was primarily attributable to a $400,000 decrease in payroll and related expenses due to corporate restructuring and cost reduction efforts coupled with a $40,000 decrease in non-cash share-based compensation expense partially offset by a $70,000 increase in tax and insurance expenses.

The $2.4 million of general and administrative expenses for the six months ended June 30, 2018 represents a $530,000, or 18% decrease over the comparable period of 2017. This decrease was primarily attributable to a $560,000 decrease in payroll and related expenses coupled with a $40,000 decrease in consulting and professional service expenses due to corporate restructuring and cost reduction efforts partially offset by a $90,000 increase in our tax and insurance expenses.

On August 15, 2018 Genprex, Inc. (NASDAQ:GNPX), a clinical stage gene therapy company developing a new approach to treating cancer based upon a novel proprietary technology platform, reported a clinical and corporate update, and the filing of quarterly results for the second quarter ended June 30, 2018 on Form 10-Q with the Securities and Exchange Commission (Press release, Genprex, AUG 15, 2018, View Source [SID1234528893]).

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Rodney Varner, Chairman and CEO, remarked, "We have made significant progress in recent months to advance the development of Oncoprex for treatment of non-small cell lung cancer (NSCLC), including engaging collaborators with expertise and other resources necessary for important pre-clinical and clinical services. We also obtained an additional $10 million in capital, which provides additional financial resources to position the Company to achieve its critical milestones in its path toward developing and commercializing Oncoprex. "

Julien L. Pham, MD, MPH, President and Chief Operating Officer, stated, "We are moving toward resuming enrollment in the Phase I/II clinical evaluating the combination of Oncoprex and erlotinib (Tarceva) for the treatment of Stage IV non-small cell lung cancer (NSCLC), adding an additional preclinical trial to study Oncoprex in combination with immunotherapies, and progressing with manufacturing scale-up."

Clinical Development Highlights (May 2018 to present)

Selected Accenture to provide clinical data management services to help accelerate the clinical development of Genprex’s lead drug candidate, Oncoprex.
Entered an agreement to use WIRB-Copernicus Group (WCG) to provide site selection and feasibility services, including Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) oversight for new clinical trial sites that Genprex anticipates adding to participate in its Phase I/II clinical trial evaluating the combination of OncoprexTM and erlotinib (Tarceva) in NSCLC.
Selected 4Clinics as a CRO to provide clinical and regulatory support for the clinical development program in the form of biostatistics, statistical programming and analysis, as well as medical and scientific writing for the Phase I/II clinical trial.

Entered an agreement with The University of Texas MD Anderson Center under which Genprex is sponsoring a pre-clinical study intended to develop a novel therapeutic approach for the treatment of cancer using a combination of the multifactorial tumor suppressor gene TUSC2 and immunotherapy, including the immune checkpoint inhibitors anti-PD1 and/or anti CTLA-4. This study will include the identification of biomarkers to predict the response to TUSC2-immunotherapy combinations.
Amended its agreement with The University of Texas MD Anderson Cancer Center to resume patient enrollment in its Phase I/II trial evaluating the combination of Oncoprex and erlotinib (Tarceva) for the treatment of Stage IV non-small cell lung cancer (NSCLC).
Corporate Update

Entered an agreement with the University of Texas at Austin Dell Medical School to establish executive offices at the school’s Health Discovery Building, joining the WorkSpaces @ Texas Health CoLab. WorkSpaces @ Texas Health CoLab is designed to identify and support people and companies that share Dell Medical School’s commitment to improving health outcomes to patients and reducing healthcare costs.
Established offices in Cambridge, MA, where Dr. Julien Pham, President and COO will oversee the clinical development of Genprex’s lead drug candidate, Oncoprex.
Completed a $10 million private placement.
Forward Looking Statements

Statements contained in this press release that are not statements of historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because these statements are subject to risks and uncertainties, the actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements about Genprex’s business plans, statements about the timing and success of the Company’s existing and planned clinical trials, statements about the development of the Company’s current and potential future product candidates, statements about the Company’s plans to seek regulatory approval of its product candidates, and statements about the services the Company expects to receive from its development partners and the effect of those services on the development of Oncoprex. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost and timing of the Company’s product candidate development activities and current and planned clinical trials; the Company’s ability to execute on its strategy; regulatory developments in the United States and foreign countries; the Company’s estimates regarding expenses, future revenue and capital requirements; and the ability of the Company’s development partners to provide services to the Company and the Company’s ability to utilize those services, and the ability of those services to influence the development of Oncoprex. These and other risks and uncertainties are described more fully under the caption "Risk Factors" and elsewhere in Genprex’s filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Genprex does not undertake any obligation to update these statements to reflect any events that occur or facts that exist after the date on which the statements were made.

On August 15, 2018 CEL-SCI Corporation (NYSE American: CVM) reported that the Independent Data Monitoring Committee (IDMC) for the Company’s pivotal Phase 3 head and neck cancer study of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) has completed its recent review of the Phase 3 study data (Press release, Cel-Sci, AUG 15, 2018, View Source [SID1234528894]). The data from all 928 enrolled patients were provided to the IDMC by the clinical research organization (CRO) responsible for data management of this Phase 3 study.

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The IDMC made the following recommendation:

The IDMC recommendation is to continue the trial until the appropriate number of events have occurred.
IDMCs are committees commonly used by sponsors of clinical trials to protect the interests of the patients and the integrity of the study data in ongoing trials, especially when the trials involve patients with life threatening diseases, and when, as in cancer clinical trials, they extend over long periods of time.

On August 15, 2018 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology (I-O) company with a pipeline of immune checkpoint antibodies, cancer vaccines and adoptive cell therapies1, reported that Merck, known as MSD outside the United States and Canada, initiated a Phase I clinical trial of an undisclosed antibody candidate discovered by Agenus, under the two companies license and research collaboration (Press release, Agenus, AUG 15, 2018, View Source [SID1234528898]). Based on this milestone and under the terms of the agreement, Agenus received a $4 million milestone payment and is entitled to receive up to an additional $95 million in success milestones from Merck.

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"We continue to deliver on all milestones with our existing partners." said Garo H. Armen, Ph.D., Chairman and CEO of Agenus. "This is yet another validation of our antibody discovery platform and expertise in the field and adds to our successes in delivering first in class discoveries to patients. Notably, besides this, we also have two other partnered programs advancing to the clinic this year, each triggering additional milestone payments to Agenus."

This milestone is the second under the collaboration, originally announced in April 2014. According to the terms of the agreement, Merck is responsible for all product development expenses for the antibody candidate, and Agenus is eligible to receive up to an additional $95 million in milestone payments, as well as royalties on worldwide product sales.