On May 31, 2017 Eli Lilly and Company (NYSE: LLY) reported that its Phase 3 RANGE study of CYRAMZA (ramucirumab) met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement (Press release, Eli Lilly, MAY 31, 2017, View Source [SID1234519328]). The Phase 3 global, randomized, double-blinded, placebo-controlled trial is evaluating ramucirumab in combination with docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. Bladder cancer accounts for the majority of all urothelial carcinoma.

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With these results, RANGE is the first Phase 3 study of any therapy to show superior PFS over chemotherapy in a post-platinum setting in urothelial cancer. Also, ramucirumab is the first antiangiogenic agent to extend PFS in a Phase 3 trial in urothelial cancer. Patients previously treated with a checkpoint inhibitor were allowed to enroll in the RANGE study.

The safety profile observed in the RANGE study at this analysis was consistent with what has been previously observed for ramucirumab. Grade ≥3 adverse events occurring at a rate of five percent or greater and that were higher on the ramucirumab-plus-docetaxel arm compared to the placebo-plus-docetaxel arm were neutropenia, febrile neutropenia and hypertension. Detailed efficacy and safety results will be submitted for presentation at a future medical meeting.

"People with advanced urothelial cancer – an aggressive disease – who have progressed on prior therapy need more treatment options that can help to control their disease," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology.

While there have been several recent advancements to treat this type of cancer, most patients progress despite treatment with existing therapies, including immune checkpoint inhibitors. Dr. Garraway added, "Until now, no Phase 3 study has demonstrated superior PFS over chemotherapy in this setting. These results are encouraging and we look forward to seeing the overall survival results when they are mature. Lilly would like to thank the patients, investigators and clinical trial sites that are participating in this study."

Although the primary endpoint has been met, Lilly anticipates that overall survival (OS) results are likely to be required for global regulatory submissions. Final OS results are currently expected in mid-2018. Investigators, patients and Lilly study personnel involved in patient-level decision making will remain blinded to patient-treatment assignments until that time.

RANGE is the first Phase 3 trial investigating ramucirumab in urothelial cancer patients. In a Phase 2 study in the same treatment setting, patients treated with ramucirumab and docetaxel showed a statistically significant improvement in PFS and disease control rate, and a numerically higher objective response rate, compared to the docetaxel-only arm.1 Overall, RANGE is the sixth positive Phase 3 trial of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer – three of the world’s leading causes of cancer-related death.

Notes to Editor

About the RANGE Study
The RANGE trial, which enrolled 531 patients globally, is a randomized, double-blinded study designed to evaluate the safety and efficacy of ramucirumab and docetaxel versus placebo and docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The trial includes: 1) patients who progressed following adjuvant and/or neoadjuvant therapy; 2) patients who progressed following first-line metastatic therapy; and 3) patients who had received prior platinum-based and immune checkpoint inhibitor regimens. The trial’s primary endpoint is progression-free survival and other secondary endpoints include overall survival, objective response rate, disease control rate and duration of response.

About Urothelial Cancer
Urothelial cancer includes carcinomas that arise in the urothelial or transitional cells that line the urinary collecting system including the bladder, which is the most common site for this type of tumor. Other potential primary sites of this cancer include the renal pelvis, ureter and urethra. Bladder cancer accounts for the majority of all urothelial carcinoma.

Worldwide, bladder cancer ranks ninth in the top most common cancers overall,2 and the ninth leading cause of cancer-related deaths, afflicting approximately 430,000 people per year and resulting in more than 165,000 deaths.3 The global incidence of bladder cancer increased 11 percent from 2008 to 2012. In the U.S., bladder cancer is the sixth most common and deadly cancer,4 with an estimated 79,000 new cases and nearly 17,000 deaths expected in 2017.5

Generally, this is an aggressive disease and unfortunately, despite recently approved therapies, most patients who have disease progression will eventually succumb to their cancer.

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Ramucirumab is being investigated in a broad global development program that has enrolled more than 10,000 patients across more than 70 trials worldwide. There are several studies underway or planned to investigate ramucirumab as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types.

Ramucirumab is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. Ramucirumab inhibited angiogenesis in an in vivo animal model.

About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.

INDICATIONS

Gastric Cancer
CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA




WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND
IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.


Warnings and Precautions

Hemorrhage

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.
Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.
Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRRs)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.
Gastrointestinal Perforations

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported at a rate of < 0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to < 2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels > 3 g over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.
Most Common Adverse Reactions—Combination With Paclitaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).
Most Common Adverse Reactions—Combination With Docetaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; < 1% vs < 1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs < 1%), thrombocytopenia (13% vs 5%; 3% vs < 1%), lacrimation increased (13% vs 5%; < 1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
In patients ≥65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).
For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).
Most Common Adverse Reactions—Combination With FOLFIRI

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs < 1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; < 1% vs 0%), proteinuria (17% vs 5%; 3% vs < 1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs < 1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.
The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).
Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.
Drug Interactions

No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.
Use in Specific Populations

Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.
Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing.
RB-P-HCP ISI 16FEB2017

On May 31, 2017 Array BioPharma Inc. (Nasdaq: ARRY) and Ono Pharmaceutical Co., Ltd. ("Ono") reported a license, development and commercialization partnership for Array’s late-stage novel oncology compounds, binimetinib and encorafenib (Press release, Array BioPharma, MAY 31, 2017, View Source [SID1234519327]). As a result of this agreement, Ono will receive rights to develop and commercialize binimetinib and encorafenib in Japan and South Korea. Binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, are currently in two global Phase 3 trials, for the treatment of patients with BRAF-mutant melanoma (COLUMBUS) and BRAF-mutant colorectal cancer (BEACON CRC).

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Under the terms of the agreement, Array will receive an upfront payment of $31.6 million (¥3.5 billion) and retains exclusive commercialization rights for binimetinib and encorafenib in the United States, Canada and Israel. Array is entitled to receive up to an additional $156 million (¥17.3 billion) if certain development and commercial milestones are achieved. A portion of these milestones is related to the Phase 3 BEACON CRC trial. In addition, Array will be eligible for robust, tiered, double-digit royalties based on product sales in Japan and South Korea. Ono will obtain the right to conduct clinical trials of binimetinib and encorafenib in Japan and South Korea, as well as participate in all future global development of binimetinib and encorafenib by contributing 12% of those future costs.

"In Ono, we selected a market leader in immuno-oncology with a rapidly growing product portfolio and recent track record of successful development and commercialization in Japan," said Ron Squarer, Chief Executive Officer, Array BioPharma. "This partnership allows us to remain focused on commercializing binimetinib and encorafenib in the US, while benefiting from Ono’s clear expertise in these key markets."

"We are very delighted to collaborate on binimetinib and encorafenib with Array, a leading company with proven and successful experience in research and development of molecularly targeted therapy," said Gyo Sagara, President, Representative Director and Chief Executive Officer, Ono. "These two compounds have shown promising efficacy and safety in the previous clinical trials and we believe that both compounds can be a new therapeutic option as a combination therapy for patients with BRAF-mutant melanoma, BRAF-mutant colorectal cancer and beyond."

Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.

– See more at: View Source#sthash.DZ4N6w4S.dpuf

On Inspyr Therapeutics (OTCQB:NSPXD), a clinical-stage biotechnology company, and Lewis and Clark Pharmaceuticals, a privately-held biotechnology company, reported that they have entered into an agreement to create an integrated company with a proprietary platform driving a pipeline of novel therapeutics (Press release, Inspyr Therapeutics, MAY 30, 2017, View Source [SID1234520533]).

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Under this agreement, Inspyr will purchase Lewis and Clark in an all-stock transaction and will execute plans to leverage a team with significant experience to advance a broader pipeline of novel therapeutics. The boards of directors of both Inspyr and Lewis and Clark have unanimously approved the proposed agreement, which is subject to customary closing conditions as well as reaching a definitive agreement on all of the terms.

“By combining the strengths of each organization, we are creating an integrated biopharmaceutical company with a unique ability to potentially improve outcomes for patients in a variety of therapeutic areas. Our capabilities will span from the discovery of new molecules through clinical development and regulatory filings,” said Peter Grebow Ph.D., Chairman of Inspyr. “Over the last 12 months, we embarked on a path to unlock the potential of our lead therapy Mipsagargin, strengthen the management team and broaden the pipeline. We will now have proprietary platform technology, additional expertise and laboratory facilities, while also broadening the pipeline. We believe this transaction immediately creates a stronger company and longer term allows us to explore new options to generate additional value from this proprietary platform and pipeline of novel therapies.”

“Our proprietary platform has been validated with multiple therapies and we are eager to advance into IND-enabling studies,” said Robert Thompson, Ph.D., Founder and Chief Executive Officer of Lewis and Clark Pharmaceuticals. “We are excited to leverage the Inspyr team’s expertise in translational medicine and clinical development, in particular for oncology therapeutics, to accelerate our pipeline toward the clinic and unlock additional value from this technology.”

Inspyr will become an integrated biopharmaceutical company focused on advancing a broad pipeline of novel therapies to treat cancer, inflammation, and other serious diseases. Inspyr’s lead product candidate Mipsagargin, a novel prodrug therapeutic for cancer, is being developed initially for hepatocellular carcinoma (HCC), or liver cancer. Lewis and Clark’s pipeline of novel proprietary and potentially first-in-class adenosine receptor modulator based compounds are currently in advanced preclinical development as oncology or anti-inflammatory agents. For more information on the pipeline, please visit View Source

Key strategic benefits from creating an integrated company include:
• Novel proprietary technology platform. Lewis and Clark’s industry-leading proprietary technology platform is based on adenosine chemistry and biology. From this platform, Lewis and Clark has developed multiple adenosine receptor modulator based compounds that are advancing into studies to support planned Investigational New Drug (IND) applications. Inspyr intends to leverage this platform to explore future potential license opportunities.
• Broad pipeline of novel therapies for oncology and inflammation.

Lewis and Clark’s pipeline of novel proprietary therapies includes four lead programs: a dual A2A/A2B antagonist, an A2A antagonist, an A2B antagonist, and an A2A agonist. These therapies are highly potent and selective, with important molecular properties that enable enhanced distribution in tissue and penetration of human skin. These therapies are in advanced preclinical development.
The dual A2A/A2B antagonist has both immune function modulation and anti-angiogenic properties and thus has potential as an immuno-oncology and anti-angiogenic agent to treat multiple types of solid and hematological malignancies.
The A2A agonists offers the potential to treat inflammatory and autoimmune diseases as arthritis, Crohn’s disease, diabetic nephropathy, and psoriasis.
The A2B antagonist offers the potential to treat asthma, type 2 diabetes, atherosclerosis, and nonalcoholic fatty liver disease.
Inspyr’s lead therapy, Mipsagargin, currently is in development for the treatment of solid tumors.
– For liver cancer, Mipsagargin in combination with Nexavar is being evaluated in a preclinical study in liver tumor models that express different levels of PSMA, the target of Mipsagargin. Inspyr is finalizing the design of a clinical study to examine the potential benefits of Mipsagargin in combination with Nexavar in patients with advanced hepatocellular carcinoma (HCC), or liver cancer.
– For gastric cancer, Inspyr has initiated a preclinical study in gastric cancer tumor models that express different levels of PSMA. In this initial study, Mipsagargin will be evaluated first in combination with paclitaxel and in a subsequent study will be evaluated in combination with DC101 (Cyramza surrogate antibody).
– Utilizing Lewis and Clark’s wet laboratory facilities, Inspyr has the potential to internally develop additional pro-drugs targeting PSMA with different toxic payloads.

• Experienced leadership. Inspyr’s team has significant clinical development, translational medicine, and business operations experience in the biopharmaceutical industry. Lewis and Clark, which was founded by Robert Thompson, Ph.D, an industry-recognized leader in adenosine chemistry, has a team with significant expertise in preclinical development, toxicology, regulatory filings, adenosine receptor pharmacology, physiology, and molecular biology.

Pursuant to the terms of the transaction, Lewis and Clark Pharmaceuticals will become a wholly-owned subsidiary of Inspyr. Upon the closing of the transaction, existing Lewis and Clark stockholders are expected to own 50% of Inspyr’s common shares, on an as converted basis.

About Inspyr Therapeutics
Inspyr Therapeutics, Inc. develops therapies for cancer using a novel technology platform that combines a powerful therapeutic (thapsigargin) with a patented prodrug delivery system that targets the release of drugs within solid tumors. Mipsagargin, its lead drug candidate, has been studied in a Phase 2 clinical trial in patients with Nexavar-refractory hepatocellular carcinoma (HCC) and has been granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) in this indication. For additional information on Inspyr Therapeutics, visit www.inspyrtx.com.

About Lewis and Clark Pharmaceuticals
Lewis and Clark Pharmaceuticals is a privately-held biotechnology company developing novel proprietary compounds from an industry-leading technology platform based on adenosine chemistry and biology. In addition, Lewis and Clark maintains fully-equipped, state-of-the-art organic and analytical chemistry laboratories located in Charlottesville, Virginia. The Company’s chemists and toxicologist have expertise in chemical synthesis and analysis, non-clinical dose formulation and plasma concentration analysis, assay development, and toxicology.