On October 22, 2015 Merrimack (Nasdaq: MACK) reported that ONIVYDE (irinotecan liposome injection) has been approved by the U.S. Food and Drug Administration (FDA) in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy (Press release, Merrimack, OCT 22, 2015, View Source [SID:1234507770]).

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ONIVYDE is not indicated for use as a single agent. With this approval, ONIVYDE in combination with 5-FU and leucovorin becomes the first and only FDA-approved treatment option for patients in this setting.

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"This is an important day for patients facing pancreatic cancer," said Andrea Wang-Gillam, M.D., Ph.D., Associate Professor of Medicine, Clinical Director of GI Oncology Program, Division of Oncology, at Washington University School of Medicine, St. Louis, and a key investigator on the ONIVYDE Phase 3 NAPOLI-1 study. "With a long history of failed clinical studies in the post-gemcitabine setting, this approval is a significant achievement in the oncology community. It brings a new therapy to the many patients who are facing this aggressive disease and are in need of treatment options."

"We are thrilled to be able to deliver this groundbreaking therapy to patients battling metastatic pancreatic cancer," said Robert Mulroy, President and CEO of Merrimack. "Pancreatic cancer is an aggressive and devastating disease, with very few patients surviving beyond one year. ONIVYDE provides a clinically significant treatment option to a patient population where there is currently no standard of care. We are grateful to the many patients, clinicians, researchers and partners that worked with us to make ONIVYDE available. Today’s approval by the FDA is a pivotal milestone in our company’s history, representing years of hard work and commitment to our mission of engineering new treatment options for cancer patients in need."

The FDA approval is based on the results of an international Phase 3 randomized, controlled study (NAPOLI-1). In this study, ONIVYDE in combination with 5-FU and leucovorin achieved its primary endpoint of a significant improvement in overall survival (p=0.014, unstratified HR=0.68, 95% CI: [0.50-0.93]) with a 45% improvement in median overall survival of 6.1 months for patients receiving the ONIVYDE combination regimen compared to 4.2 months for patients who received 5-FU and leucovorin alone. The ONIVYDE combination also demonstrated improvement in progression free survival (3.1 months vs. 1.5 months, HR=0.55, 95% CI: [0.41-0.75]). The monotherapy regimen in this study did not achieve its primary endpoint and, therefore, ONIVYDE is not indicated as a single agent. The most common adverse reactions ( > 20 %) of ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis and pyrexia, and the most common severe laboratory abnormalities ( > 10% Grade 3 or 4) were lymphopenia and neutropenia. For additional safety information, please see Important Safety Information including Boxed Warning below.

"This is a pivotal achievement for the pancreatic cancer community because it provides a new treatment option for some patients facing this difficult disease," said Julie Fleshman, President and CEO of the Pancreatic Cancer Action Network. "We applaud the dedication of those involved in this advancement, knowing it will impact our goal to double pancreatic cancer survival by 2020."

There are approximately 49,000 patients diagnosed with pancreatic cancer each year in the United States1, the overwhelming majority of whom have adenocarcinoma2. Most patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment for locally advanced disease or during first- or second-line therapy for metastatic disease, but are left with no standard of care therapy upon progression3. ONIVYDE in combination with 5-FU and leucovorin is now approved for these patients whose disease has progressed following gemcitabine-based therapy.

Merrimack expects ONIVYDE to be available in the United States next week and is committed to supporting rapid physician and patient access to this therapy. PROVYDE (ONIVYDE Access Center) offers a variety of reimbursement support services for healthcare providers and financial assistance services for patients. For more information, please call 1-844-ONIVYDE or visit www.ONIVYDE.com.

Baxalta Incorporated (NYSE: BXLT) is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under the exclusive licensing agreement that Merrimack and Baxalta entered into in September 2014. In May 2015, the European Medicines Agency (EMA) accepted for review Baxalta’s marketing authorization application (MAA) for ONIVYDE based on the same clinical results.

"We are excited that ONIVYDE (nal-IRI) will now be available to people living with metastatic pancreatic cancer in the U.S. after they progress from gemcitabine-based therapy," said David Meek, Executive Vice President and President of Oncology at Baxalta. "Looking ahead, Baxalta continues to work toward marketing authorization in Europe with the goal of providing nal-IRI to patients in more countries around the world in need of new options."

PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize ONIVYDE in Taiwan. PharmaEngine filed a New Drug Application (NDA) with the Taiwan FDA in May 2015.

About the NAPOLI-1 Study

The NAPOLI-1 study was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. The study evaluated ONIVYDE in combination with 5-FU and leucovorin administered every two weeks and as a monotherapy administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomized across the three arms. The primary endpoint of the study was overall survival. The ONIVYDE combination regimen demonstrated a significant increase in median overall survival versus 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.014, unstratified HR=0.68, 95% CI: [0.50-0.93]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm (HR=1.00, p=0.97 [unstratified log-rank test]). Patients were enrolled at 76 sites in North America, South America, Europe, Asia and Oceania.

About Pancreatic Cancer

Pancreatic cancer is rare and deadly. It accounts for only 3% of all cancer cases2, but is the fourth leading cause of cancer-related death4, leading to a five year survival rate of only 7%1. Each year an estimated 49,000 new cases are diagnosed in the United States1, two-thirds of which are among people aged 65 or older5. There are an estimated 338,000 new cases diagnosed each year worldwide6.

The pancreas is composed of two main cell types: exocrine and endocrine. Exocrine tumors are the most common type of pancreatic cancer, accounting for 96% of all cases1. Adenocarcinoma, a sub-type of exocrine tumors, comprises 95% of all exocrine tumors2.

Because the signs and symptoms of pancreatic cancer are non-specific and may not appear until the disease has spread to other sites, approximately 80% of patients are not candidates for surgery4, instead receiving chemotherapy as the mainstay of their therapy. The majority of these patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment or during first- or second-line therapy for metastatic disease 3. There is no consensus on the standard of care for patients with metastatic pancreatic cancer previously treated with a gemcitabine-based therapy.

About ONIVYDE [pronounced \ ‘on – ih – vide \]

ONIVYDE, also known as MM-398 or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. For more information please visit www.ONIVYDE.com.

IMPORTANT SAFETY INFORMATION

INDICATION
ONIVYDE (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA
Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

CONTRAINDICATION
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia
ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients.

Severe Diarrhea
ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset > 24 hours after chemotherapy) and early-onset diarrhea (onset < 24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea.

In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea.

Interstitial Lung Disease (ILD)
Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reactions
Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment.

ADVERSE REACTIONS

The most common ( > 20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a > 5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%]), late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4% ), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).

Of less common ( < 20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a > 2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%).

The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a > 5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).
ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients.

Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV.

The most common serious adverse reactions ( > 2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

DRUG INTERACTIONS
Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme-inducing therapies > 2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors > 1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS
Pregnancy and Reproductive Potential
Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment.

Lactation
Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment.

Pediatric
Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

DOSAGE AND ADMINISTRATION
The recommended dose of ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to < Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD.

On October 22, 2015 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), an Israeli biopharmaceutical company primarily focused on late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported that the U.S. National Cancer Institute ("NCI") has awarded Apogee Biotechnology Corporation ("Apogee") a $225,000 Small Business Innovation Research Program ("SBIR") grant to support a pre-clinical study with YELIVA (ABC294640) for the treatment of prostate cancer (Press release, RedHill Biopharma, OCT 22, 2015, View Source [SID:1234507765]). In March 2015, RedHill acquired from Apogee the exclusive worldwide rights to YELIVA (ABC294640), a proprietary, first-in-class, orally-administered sphingosine kinase-2 ("SK2") selective inhibitor.

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Following prior pre-clinical studies in early-stage and advanced prostate cancer models, the NCI grant is intended to support additional studies with YELIVA (ABC294640) to determine its therapeutic efficacy in in vitro and in vivo models of prostate cancer in combination with radiotherapy. These pre-clinical studies could potentially support future clinical studies with YELIVA (ABC294640) for this important indication with over 200,000 estimated new cases of prostate cancer in the U.S. in 20151.

The previous prostate cancer pre-clinical study, supported by a grant from the Pennsylvania Department of Health, a Prostate Cancer Foundation Young Investigator award, and a Prostate Cancer Foundation Mazzone Challenge award, is described in an article authored by scientists from Apogee and from the Kimmel Cancer Center at Thomas Jefferson University, and was initially published online in Molecular Cancer Research. The article, entitled "Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression" 2, describes the findings of the pre-clinical study, suggesting that oral administration of YELIVA (ABC294640) disrupts multiple oncogenic signaling pathways that are deregulated in prostate cancer, including significant inhibition of tumor growth, proliferation and cell cycle progression. In particular, the article noted that YELIVA (ABC294640) inhibited, in vitro, several very resistant types of prostate cancer. The authors of the article conclude that their pre-clinical findings support the hypotheses that SK2 activity is required for prostate cancer growth and that YELIVA (ABC294640) could represent a new pharmacological agent for the treatment of aggressive prostate cancer.

A Phase I/II clinical study was recently initiated in the U.S. evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), primarily in patients with HIV-related DLBCL. The study is being conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans and is supported by a grant awarded to Apogee from the NCI Small Business Technology Transfer (STTR) program.

A Phase II study of YELIVA (ABC294640) for the treatment of refractory or relapsed multiple myeloma is planned to be initiated by early 2016. The study will be conducted at Duke University Medical Center and has received Institutional Review Board (IRB) approval from Duke University (DUHS IRB). The study is supported by a $2 million grant awarded to Apogee, in conjunction with Duke University, from the NCI SBIR Program.

A third Phase II clinical study is planned to evaluate YELIVA (ABC294640) as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy. This study is planned to be funded directly by RedHill, which is also funding the data management and providing the drug for the NCI-supported studies.

The ongoing and planned Phase II studies follow numerous successful pre-clinical studies conducted with YELIVA (ABC294640) in GI, inflammation, radioprotection and oncology models, as well as a Phase Ib study in patients with advanced solid tumors, supported by grants awarded to Apogee from the National Cancer Institute (NCI) and the FDA’s Office of Orphan Products Development (OOPD).

The Phase I/II clinical study in patients with refractory/relapsed diffuse large B-cell lymphoma and the Phase Ib clinical study in cancer patients with advanced solid tumors are registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies.

About YELIVA (ABC294640):

YELIVA (ABC294640) is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anti-cancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA (ABC294640) blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anti-cancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA (ABC294640) was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI, and radioprotection models, as well as the ABC-101 Phase Ib clinical study in cancer patients with advanced solid tumors. A Phase I/II clinical study evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. The development of YELIVA (ABC294640) was funded to date primarily by grants and contracts from U.S. federal and state government agencies to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development.

On October 22, 2015 MacroGenics, Inc. (Nasdaq: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, autoimmune disorders and infectious diseases, and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported a collaboration to evaluate the combination of MacroGenics’ anti-HER2 product candidate, margetuximab, with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in a Phase 1b/2 clinical trial in patients with advanced gastric cancer (Press release, MacroGenics, OCT 22, 2015, View Source [SID:1234507764]).

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Margetuximab is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2, which is an antigen critical for the growth of many types of tumors, including breast and gastroesophageal cancers. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

"The combination of our proprietary Fc-optimized anti-HER2 antibody, with expected enhanced immune-mediated killing properties, and the anti-PD-1 antibody KEYTRUDA, is intended to exploit potentially complementary biology," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Treatment options for patients with advanced HER2-positive gastric cancer are extremely limited. The combination of mechanisms engaged by margetuximab and KEYTRUDA could provide an important alternative for patients who do not respond to currently available regimens."

"Today, there is a great opportunity and need to bring forward new scientific breakthroughs for the treatment of gastric cancer," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "Evaluating the potential of combination therapies through strategic collaborations in difficult-to-treat tumor types continues to be an important part of our immuno-oncology clinical development program for KEYTRUDA."

The Phase 1b/2 multicenter, open-label clinical trial will be conducted in two parts. The Phase 1b portion is designed to determine the safety and tolerability of margetuximab in combination with KEYTRUDA in patients with advanced gastric cancer, while the Phase 2 portion will evaluate the anti-tumor activity of margetuximab in combination with KEYTRUDA in patients with advanced HER2-positive gastric cancer. Trial startup activities are underway and MacroGenics expects to begin enrolling patients by the first quarter of 2016. The agreement includes a provision where the parties may extend the collaboration to include a potential Phase 3 clinical trial.

The agreement is between MacroGenics and Merck, through a subsidiary. Additional details were not disclosed.

About Gastric Cancer

Gastric cancer, also called stomach cancer, is a type of cancer that begins in the stomach. Most gastric cancers are adenocarcinomas, which develop from the cells of the innermost lining (mucosa) of the stomach. Among others, risk factors for gastric cancer include gender, age, ethnicity, geography and bacterial infection with Helicobacter pylori. More than 70 percent of gastric cancer cases occur in developing countries, with half of all cases occurring in Eastern Asia (predominately China). Worldwide, gastric cancer is the fifth most common type of cancer and the third leading cause of cancer death.

About Margetuximab

Margetuximab is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2, an antigen critical for the growth of many types of tumors, including breast and gastroesophageal cancers. Using its Fc-optimization platform, MacroGenics has designed the Fc region of margetuximab to enhance the killing of tumor cells through an Fc-dependent mechanism, including antibody dependent cell-mediated cytotoxicity, or ADCC. MacroGenics has initiated dosing of patients in SOPHIA, a Phase 3 pivotal study evaluating margetuximab plus chemotherapy against trastuzumab plus chemotherapy in third-line HER2-positive metastatic breast cancer patients. The purpose of the SOPHIA study is to determine whether patients treated with margetuximab plus chemotherapy have longer progression-free and overall survival than patients treated with trastuzumab plus chemotherapy. For more information about this trial, please visit www.sophiastudy.com or www.clinicaltrials.gov.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA in Melanoma Trial

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Selected Safety Information for KEYTRUDA (pembrolizumab) in NSCLC Trial

Pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis occurred in patients receiving KEYTRUDA (pembrolizumab). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, myasthenia gravis, bullous pemphigoid, and Guillain-Barre syndrome.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA (pembrolizumab) can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

On October 22, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported the company has initiated submission of its rolling New Drug Application (NDA) to the U.S. Food & Drug Administration (FDA) for cabozantinib for the treatment of advanced renal cell carcinoma (RCC) patients who have received one prior therapy (Press release, Exelixis, OCT 22, 2015, View Source [SID:1234507763]).

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Cabozantinib was granted Breakthrough Therapy Designation by the FDA in August 2015. Exelixis agreed with FDA that the submission would be a rolling NDA and the company has filed the first component of the application for potential approval of cabozantinib in the United States. The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis. Exelixis plans to complete the NDA submission before the end of 2015.

The rolling NDA submission is based on results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival (PFS); compared with everolimus, cabozantinib was associated with a 42% reduction in the risk of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

"New treatment options are urgently needed for patients with advanced renal cell carcinoma," said Michael M. Morrissey, Ph.D., president and CEO of Exelixis. "The initiation of the NDA submission process for cabozantinib marks an important step forward in our efforts to make a meaningful difference in the lives of people with advanced kidney cancer, and we look forward to working closely with the FDA towards the goal of making cabozantinib available to these patients and their physicians as soon as possible."

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA for advanced RCC.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two therapies have been approved for the treatment of patients who have received prior VEGF receptor TKIs. However, despite the availability of several therapeutic options, currently approved agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.

Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

On October 22, 2015 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious disorders reported the dosing of the first patient in a Phase 1 trial of CYC065, the Company’s novel second generation CDK (cyclin-dependent kinase) 2/9 inhibitor, for the treatment of advanced solid tumors (Press release, Cyclacel, OCT 22, 2015, View Source [SID:1234507762]).

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CYC065 was selected from the Company’s discovery program in Dundee, Scotland and its development was supported in part by a UK government grant. In preclinical studies CYC065 has demonstrated anti-tumor activity as a single agent in hematological malignancies and solid tumors, including drug-resistant models. CYC065 also combined effectively with other targeted anticancer agents in drug-resistant solid tumor in vivo models. The objective of the Phase 1 trial is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of CYC065 in advanced cancer patients. The trial is being conducted at the Dana Farber Cancer Institute in Boston.

"The recent accelerated approval of palbociclib, a CDK4/6 targeted inhibitor, for breast cancer demonstrates that CDK inhibitors can be an effective class of anti-cancer therapeutics," said Geoffrey I. Shapiro, M.D., Ph.D., Associate Professor of Medicine at Harvard Medical School and Director of the Early Drug Development Center, Dana Farber Cancer Institute. "CYC065 works differently from palbociclib, since it targets CDKs 2 and 9. In preclinical models, the drug induces apoptosis, or programmed death, of cancer cells irrespective of retinoblastoma (RB) pathway status and has been shown to reverse drug resistance associated with the addiction of cancer cells to cyclin E, a partner protein of CDK2. CYC065 has also been shown to inhibit CDK9-dependent oncogenic and leukemogenic pathways, such as those driven by MYC amplification or Mixed Lineage Leukemia gene rearrangement. Cancer cells manage to survive and evade other treatments by activating these pathways."

Spiro Rombotis, President and Chief Executive Officer of Cyclacel added, "CDK inhibitors have emerged as an important class of anti-tumor agents. Because these agents can act synergistically with other anti-cancer therapies, they may have utility when used in combination. This is the case with palbociclib, which is approved in combination with letrozole for the treatment of advanced breast cancer. Our first generation CDK2/9 inhibitor, seliciclib, has been administered to approximately 400 patients in several trials. Seliciclib demonstrated clinical evidence of anticancer activity in patients with non-small cell lung cancer and nasopharyngeal cancer. It has also shown durable activity in patients with BRCA mutations, when administered in combination with sapacitabine, another Cyclacel molecule. CYC065, our second generation CDK2/9 inhibitor, is mechanistically similar but has much higher potency and longer patent protection than seliciclib. Data from this study will inform the design of another Phase 1 study of CYC065 in patients with hematological tumors and are also anticipated to provide the basis for proof of concept trials in solid tumors with CYC065 in combination with other anti-cancer agents."

For further information please refer to ClinicalTrials.gov with trial identifier NCT02552953.

About CYC065 & CDK Inhibition

CYC065 is a highly-selective, second generation inhibitor of CDK2 and CDK9 that causes apoptotic death of cancer cells at sub-micromolar concentrations and is bioavailable via oral and intravenous routes. Antitumor efficacy has been achieved in vivo with once a day oral dosing at well tolerated doses. Evidence from published preclinical studies show that CYC065 may benefit patients with adult and pediatric hematological malignancies, including certain Acute Myeloid Leukemias (AML), Acute Lymphocytic Leukemias (ALL), Chronic Lymphocytic Leukemias (CLL), Diffuse Large B-cell Lymphoma (DLBCL), Multiple Myelomas (MM), and certain solid tumors, including breast and uterine cancers.

CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, improved metabolic stability and longer patent protection than seliciclib, Cyclacel’s first generation CDK2/9 inhibitor. Translational biology data support development of CYC065 as a stratified medicine for solid and liquid tumors. CYC065 has been shown to reverse drug resistance associated with the addiction of cancer cells to cyclin E, a partner protein of CDK2, and inhibit CDK9-dependent oncogenic and leukemogenic pathways, e.g. MYC and MLL-r. CYC065 also causes down regulation of the MCL-1-mediated pro-survival pathway, leading to rapid induction of apoptosis in MCL-1 dependent cancer cells.

In 2011, independent investigators published preclinical evidence that CYC065 as a single-agent can induce tumor growth delay to HER2-positive breast cancer cells addicted to cyclin E and resistant to trastuzumab (Herceptin), while administration of CYC065 in combination with trastuzumab resulted in regression or sustained tumor growth inhibition.

MLL gene status and levels of Bcl-2 family proteins correlated with sensitivity of AML cell lines to CYC065. Combination studies revealed the potential to combine CYC065 with available and experimental leukemia therapies, including cytarabine and Bcl-2 inhibitors. Potent anticancer activity of CYC065 was demonstrated in vivo in AML xenograft models resulting in over 90% inhibition of tumor growth. The potent in vitro and in vivo anti-cancer activity, opportunity for patient stratification and the ability to combine with anti-leukemic agents suggest that CYC065 may have therapeutic potential in AML.

A grant of approximately $1.9 million from the U.K. government’s Biomedical Catalyst has supported IND-directed development of CYC065.

CDK enzymes, in particular CDKs 2, 4, 6 and 9, play pivotal roles in cancer cell growth, and repair of DNA damage. Pharmacological inhibition of CDK2/9 has been shown to have potent anticancer effects in certain cancer types, including some that are resistant to conventional treatments. CDK2/9 inhibitors have been shown to induce apoptosis, or programmed death, of cancer cells, whereas CDK4/6 inhibitors, such as palbociclib (Ibrance), induce senescence or dormancy of cancer cells. Senescence may be associated with emergence of resistance.