On February 26, 2018 Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) has approved VerzenioTM (abemaciclib) in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (Press release, Eli Lilly, FEB 26, 2018, View Source [SID1234524179]). This additional FDA approval marks the third indication for Verzenio within five months. In September 2017, Verzenio became the first and only cyclin-dependent kinase (CDK)4 & 6 inhibitor approved in combination and as a single agent in metastatic breast cancer. Specifically, Verzenio was approved for use in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy, and as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

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The recommended dose of Verzenio in combination with an AI is 150 mg orally twice daily, continued until disease progression or unacceptable toxicity. Verzenio is available in four tablet strengths (200 mg, 150 mg, 100 mg, and 50 mg).

This approval of Verzenio as initial therapy in combination with an AI is based on the efficacy and safety demonstrated in the pivotal MONARCH 3 clinical trial. MONARCH 3 is a Phase 3, randomized, double-blind, placebo-controlled trial evaluating Verzenio in combination with an AI as initial endocrine-based therapy that enrolled 493 postmenopausal women with HR+, HER2- advanced breast cancer who had no prior systemic treatment for advanced disease. In patients who received neoadjuvant/adjuvant endocrine therapy, a disease-free interval of more than 12 months since completion of endocrine therapy was required. This Verzenio new drug application was given Priority Review as part of the FDA’s Expedited Programs for Serious Conditions, a program used for therapies that address an unmet medical need in the treatment of serious or life-threatening conditions, such as metastatic breast cancer. Verzenio was also granted Breakthrough Therapy Designation in 2015 based on the Phase 1 JPBA trial.

In MONARCH 3, Verzenio dosed orally at 150 mg twice daily on a continuous schedule with an AI demonstrated a greater than 28-month median progression-free survival (PFS) in patients who received initial endocrine-based therapy for metastatic disease (28.2 months [95% CI: 23.5-NR] vs 14.8 months [95% CI: 11.2-19.2] with placebo plus an AI [HR: 0.54; 95% CI: 0.418-0.698, P < 0.0001]). In patients with measurable disease who received Verzenio plus an AI (n=267), an objective response rate of 55.4 percent was achieved (ORR; defined as complete response plus partial response [CR + PR], and based upon confirmed responses; PR defined as ≥30% reduction in target lesions)1 (n=148; 95% CI: 49.5-61.4), with 52.1 percent of patients having achieved a PR (n=139) and 3.4 percent having achieved a CR (n=9).2 In comparison, in the placebo-plus-AI group of patients with measurable disease (n=132), ORR was 40.2 percent (n=53; 95% CI: 31.8-48.5), with all women being partial responders. Median duration of response (DoR) was 27.4 months with Verzenio plus an AI (95% CI: 25.7-NR) versus 17.5 months with placebo plus an AI (95% CI: 11.2-22.2).3,4

"This approval is an important milestone, as it shows that Verzenio plus an aromatase inhibitor substantially reduced tumor size and delayed disease progression in women with HR+, HER2- metastatic breast cancer. Notably, the MONARCH 3 trial included patients with certain concerning clinical characteristics, such as a pattern of disease that spread to the liver," said Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, Texas Oncology and U.S. Oncology, Dallas, TX. "This information will help inform treatment decisions for each patient, which can be complicated in advanced breast cancer."

The labeling for Verzenio contains warnings and precautions for diarrhea, neutropenia, hepatotoxicity, venous thromboembolism, and embryofetal toxicity. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. Perform complete blood counts and liver function tests prior to the start of Verzenio treatment, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. Based on results, Verzenio may require dose modification. Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. Advise patients of potential risk to a fetus and to use effective contraception. See full Prescribing Information for further management instructions. The most common adverse reactions in the MONARCH 1, 2, and 3 trials (all grades, ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

"The speed with which our team has been able to work with the FDA to gain approval for this additional Verzenio indication underscores Lilly’s commitment to delivering meaningful medicines that can help more people living with advanced breast cancer," said Sue Mahony, Ph.D., senior vice president and president of Lilly Oncology. "Verzenio has now been developed, studied and clinically proven in three key trials to be effective for women with HR+, HER2- metastatic breast cancer – helping to ensure we are providing support to those who need it most."

"For those facing a diagnosis of metastatic breast cancer or learning that their disease has spread further, each new indication and clinical development is critical," said Marc Hurlbert, Ph.D., chairman, Metastatic Breast Cancer Alliance. "Today’s news represents continued progress towards helping more people living with this devastating disease."

About MONARCH 3
MONARCH 3 is a Phase 3, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of Verzenio (abemaciclib), a CDK4 & 6 inhibitor, in combination with an AI (anastrozole or letrozole), as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. If neoadjuvant/adjuvant endocrine therapy was administered, a disease-free interval of more than 12 months since completion of endocrine therapy was required. A total of 493 patients were randomized 2:1 to receive 150 mg of Verzenio or placebo orally twice a day, without interruption, given in combination with either 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with key secondary endpoints of ORR, DoR, overall survival and safety.

About Advanced Breast Cancer
Breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012.5 An estimated 266,120 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S. in 2018.6 Advanced breast cancer includes metastatic breast cancer, meaning cancer that has spread from the breast tissue to other parts of the body, and locally or regionally advanced breast cancer, meaning the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.7 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic and an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being metastatic.8 Survival is lower among women with a more advanced stage at diagnosis: 5-year relative survival is 99 percent for localized disease, 85 percent for regional disease, and 26 percent for metastatic disease. Other factors, such as tumor size, also impact 5-year survival estimates.9

About VerzenioTM (abemaciclib)
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious.3 Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.3,10

Verzenio is Lilly’s first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

INDICATION

Verzenio is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
in combination with fulvestrant for women with disease progression following endocrine therapy
as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

IMPORTANT SAFETY INFORMATION

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade > 3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in < 1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade < 3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade < 3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs < 1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs < 1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs < 1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs < 1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs < 1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs < 1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs < 1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (98%; < 1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

Strong CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of other strong CYP3A inhibitors. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of other strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.

Avoid concomitant use of strong CYP3A inducers and consider alternative agents. Coadministration of Verzenio with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr < 30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

On February 26, 2018 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported that Reshma Kewalramani, M.D., has been appointed Chief Medical Officer and Executive Vice President, Global Medicines Development and Medical Affairs, effective April 1, 2018 (Press release, Vertex Pharmaceuticals, FEB 26, 2018, View Source [SID1234524171]). Dr. Kewalramani currently serves as Senior Vice President, Clinical Development and Medical Affairs at Vertex and will succeed Jeffrey A. Chodakewitz, M.D., who is retiring from his role as Chief Medical Officer and Executive Vice President, Global Medicines Development and Medical Affairs. Dr. Chodakewitz will remain with Vertex as a senior advisor through early 2019.

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Since joining Vertex in 2014, Dr. Chodakewitz has been an inspirational senior medical leader and has played an instrumental part in the company’s advances in cystic fibrosis (CF) and in expanding Vertex’s development pipeline. Prior to Vertex, Dr. Chodakewitz had an outstanding 20-year career at Merck, where he led the successful development of multiple medicines and vaccines across a number of therapeutic areas.

"I would like to personally thank Jeff for his leadership and dedication to improving the lives of people with cystic fibrosis and other serious and life-threatening diseases," said Jeffrey Leiden, M.D., Ph.D., Chairman, President and Chief Executive Officer of Vertex. "He has played a critical role in leading multiple successful clinical development efforts at Vertex, and I’m pleased that we will continue to benefit from his guidance as a senior advisor over the next year as he transitions to retirement. I’m also delighted that Reshma has agreed to succeed Jeff as our Chief Medical Officer. Reshma’s depth of medical knowledge, paired with her experience and proven track record as a clinical leader at Vertex, makes her an ideal successor to Jeff. I look forward to working with Reshma to continue to advance our clinical development pipeline in cystic fibrosis and other serious diseases."

"It has been an honor to lead Vertex’s clinical development efforts and to be a part of the significant advancement in treatments for cystic fibrosis patients over the last four years," said Dr. Chodakewitz. "I have enjoyed working closely with Reshma since she joined the Company last year and am confident that Vertex will continue its success in pursuing innovative therapies under her leadership."

"It’s a privilege to work at a company with such a relentless focus on science and deep commitment to improving the lives of patients and their families," said Dr. Kewalramani. "I am excited to assume the role of CMO and continue our important work to help more people with cystic fibrosis and other serious diseases alongside the talented team at Vertex."

Dr. Kewalramani is an accomplished leader and physician who has a track record of building strong teams, putting patients first, leading change and delivering results. Prior to joining Vertex in February 2017, Dr. Kewalramani spent over 12 years at Amgen where she most recently served as Vice President and Head of the U.S. Medical Organization. During her tenure at Amgen, Dr. Kewalramani held roles with increasing responsibility across Clinical Development and Medical Affairs and served in leadership positions involving research and development and commercialization activities across a variety of therapeutic areas. Dr. Kewalramani is the industry representative to the Food and Drug Administration (FDA) Endocrine and Metabolic Drug Advisory Committee and was on the inaugural Board of Directors of the Kidney Health Initiative. She completed her internship and residency in Internal Medicine at the Massachusetts General Hospital and her fellowship in Nephrology at the Massachusetts General Hospital and Brigham and Women’s Hospital combined program. Dr. Kewalramani received her medical degree, with honors, from the Boston University School of Medicine and is also an alumnus of the Harvard Business School.

On February 26, 2018 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that its 6-month study on storage of the frozen encapsulated cells necessary for the determination of an "initial shelf life" has been successfully completed by Austrianova (Press release, PharmaCyte Biotech, FEB 26, 2018, View Source [SID1234524167]). This work involved the removal of samples of encapsulated cells from -80o Celsius (C) storage at various intervals up to six months, thawing the encapsulated cells and testing them for various functional parameters as well as for sterility.

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Regulatory agencies, including the U.S. Food and Drug Administration (FDA), require that studies be conducted to determine an initial shelf life for a medicinal product before an advanced phase clinical trial can begin. This shelf life can then be extended with further testing as the product is being used in the clinical trial. Austrianova Singapore already has data demonstrating storage life of frozen encapsulated cells for over six years; however, these studies were done with a slightly different cell line than the cell line that will be used for PharmaCyte’s planned clinical trial. The current completed study uses the Research Bank of cells that will be used in the final product for PharmaCyte’s trial and from which Eurofins has already generated PharmaCyte’s Master Cell Bank.

The stability test results show that there are no significant changes in the viability or the enzymatic activity of the cells upon thawing after a 6-month storage period at -80oC. These results will allow an initial shelf life of six months to be set for the product; this will be extended as the product is tested further.

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, stated, "We are pleased with this significant result which will enable us to apply to the FDA for an initial shelf life of six months. This study, one of many being performed for us by Austrianova, is an essential part of the Investigational New Drug Application (IND) that we will be submitting to the FDA."

PharmaCyte is working on an IND to submit to the FDA so that it can begin a clinical trial involving locally advanced, inoperable, non-metastatic pancreatic cancer and expects to submit its IND later this year.

On February 26, 2018 Quentis Therapeutics Inc., a biotechnology company pursuing next-generation immuno-oncology research and drug development, reported that it debuted with the completion of a $48 million Series A financing co-led by founding investor Versant Ventures and by Polaris Partners and the affiliated LS Polaris Innovation Fund (Press release, Quentis Therapeutics, FEB 26, 2018, View Source [SID1234524356]). The syndicate also included AbbVie Ventures, Taiho Pharmaceutical Co., Ltd., Yonghua Capital, Alexandria Venture Investments and New York Ventures, the investment arm of Empire State Development.

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Quentis is pioneering first-in-class cancer immunotherapies that modulate endoplasmic reticulum (ER) stress response pathways in the tumor microenvironment. The Series A proceeds will support the advancement of Quentis’ lead program, a small molecule IRE1α inhibitor, into the clinic in 2019 and through clinical proof-of-concept. Additional uses of the capital include developing a pipeline of preclinical programs and building out Quentis’ team.

The company was enabled by Highline Therapeutics, a Versant Ventures Discovery Engine, under an agreement with Weill Cornell Medicine through its office of Biopharma Alliances and Research Collaborations to establish New York-based spinout companies to advance breakthroughs emerging from Weill Cornell Medicine research.

Quentis’ scientific foundation is based on landmark research conducted by Laurie Glimcher, M.D., previously Dean of Weill Cornell Medicine, now President and Chief Executive Officer of Dana-Farber Cancer Institute and Professor at Harvard Medical School, and Juan Cubillos-Ruiz, Ph.D., Assistant Professor of Microbiology and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. Drs. Glimcher and Cubillos-Ruiz’s research revealed critical roles that the ER stress response plays in compromising the immune system’s ability to detect and fight cancer.

Chronic activation of the ER stress response correlates with poor outcomes in multiple tumor types, including ovarian cancer, triple-negative breast cancer, pancreatic adenocarcinoma and glioblastoma. By modulating ER stress response pathways, Quentis aims to boost a patient’s own anti-cancer immunity and enable more patients to benefit from immunotherapy. The company is pursuing multiple ER stress pathway targets in the tumor microenvironment, as well as in other diseases where ER stress plays an important role.

"We’ve witnessed great progress in our ability to harness the immune system to fight cancer. However, despite these advances, the effectiveness of immunotherapy remains limited, and many patients and many types of cancer don’t respond to treatment," said Michael Aberman, M.D., president and CEO of Quentis Therapeutics. "The scientific community continues to learn about important mechanisms, like the ER stress response, that impact cancer immunity. At Quentis, we are excited to be part of the next generation of immuno-oncology companies that are pursuing new therapeutic approaches to hopefully enable more cancer patients to benefit from immunotherapy."

Dr. Aberman continued, "We are thrilled to introduce Quentis today, and we are grateful for the dedication and support of our investors and all those who have helped us reach this important milestone. We look forward to continuing to build out our team in the coming months as we advance toward entering the clinic in 2019."

"It is profoundly gratifying to see our discoveries on the key role played by the ER stress response in inhibiting effective anti-tumor immunity translate into the advancement of potentially meaningful medicines for patients," said Dr. Glimcher, a scientific co-founder of Quentis and chair of the company’s Scientific Advisory Board. "I look forward to continuing to work closely with the Quentis team as they advance development programs toward clinical study."

"Immunotherapy is changing the face of cancer treatment, but harsh conditions within tumors inhibit the protective activity of immune cells and present an impediment to broad efficacy with immunotherapies. We’ve made important strides in understanding how aberrant ER stress responses in cancer promote immune cell dysfunction, and we continue to expand our knowledge of this novel biology," said Dr. Cubillos-Ruiz, a scientific co-founder of Quentis and member of the company’s Scientific Advisory Board. "I look forward to seeing Quentis translate this maturing knowledge in the drug development setting."

"Quentis is assembling all the necessary elements to become a leading company in the ER stress response and immuno-oncology fields," said Carlo Rizzuto, Ph.D., a partner at Versant and a Quentis board member. "We have great confidence in Michael’s ability to build the company and advance its programs to develop new treatments for patients."

In connection with the financing, Amy Schulman, partner with Polaris Partners and LS Polaris Innovation Fund, will join Dr. Rizzuto, Michael A. Foley, Ph.D., Sanders Director, Tri-Institutional Therapeutics Discovery Institute, and Dr. Aberman on Quentis’ Board of Directors.

On February 26, 2018 Alder BioPharmaceuticals, Inc. (NASDAQ:ALDR), a biopharmaceutical company focused on developing novel therapeutic antibodies for the treatment of migraine, reported a corporate update and reported its financial results for the fourth quarter and full year ended December 31, 2017 (Press release, Alder Biopharmaceuticals, FEB 26, 2018, View Source [SID1234524175]).

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"The data from eptinezumab’s Phase 3 pivotal clinical trials in episodic and chronic migraine patients support Alder’s goal to advance the treatment paradigm for migraine prevention. In both trials, eptinezumab’s clinical profile included rapid Day 1 reduction in migraine risk, high levels of efficacy with patients achieving 75% and 100% responder rates and sustained migraine relief for 3 months following a single infusion administration," said Randall C. Schatzman, Ph.D., President and Chief Executive Officer of Alder. "If approved, eptinezumab has the potential to provide a meaningful treatment option for millions of migraine sufferers. Looking ahead to the remainder of 2018 and into 2019, we are focused on our BLA submission, gaining FDA approval and on our commercial readiness activities ahead of eptinezumab’s launch. Our 2017 year-end cash balances, together with the net proceeds of our two successful 2018 financings, total over $600 million, leaving us well-positioned to meet our projected operating requirements into 2020."

Recent 2018 Company Highlights

PROMISE 2 Phase 3 eptinezumab top-line data in chronic migraine patients:
Met the primary endpoint with very high statistical significance vs. placebo (p<0.0001) for both dose levels tested in the trial following the first quarterly infusion.
Met all key secondary endpoints with very high statistical significance vs. placebo including prevention beginning Day One (p<0.0001) and 50 percent (p<0.0001) and 75 percent (p<0.0001) responder rates month one through month three. Furthermore, an average of 15 percent of eptinezumab patients had no migraines (i.e., 100 percent response) for months one to three (p<0.0001 unadjusted).
Safety and tolerability were similar to previously reported eptinezumab studies.

European patent settlement and global license agreement with Teva Pharmaceuticals International GmbH clears Alder’s freedom to develop, manufacture and commercialize eptinezumab in the U.S. and globally.

Alder received approximately $97.7 million in net proceeds from the sale of shares of convertible preferred stock in a committed equity financing with certain institutional and other accredited investors affiliated with or managed by Redmile Group LLC.

Alder received approximately $277.7 million in net proceeds from an underwritten public offering of 2.5% convertible senior notes due 2025 (including approximately $36.3 million from the exercise of an over-allotment option granted to the underwriters in the offering).

Upcoming Corporate Milestones
Planned 2018 Corporate Milestones for eptinezumab Timing
PROMISE 1 12 month data (episodic migraine) 1H 2018
PROMISE 2 6 month data (chronic migraine) 1H 2018
12 month open label safety study 1H 2018
Pharmacokinetic comparability study 2H 2018
BLA submission 2H 2018

Key 2017 Company Highlights

PROMISE 1 Phase 3 eptinezumab data in episodic migraine patients:
Met the primary endpoint with highly statistically significant reductions in monthly migraine days in the trial following the first quarterly infusion.
Significant clinical benefit achieved on Day One post-infusion (p=0.0087 unadjusted) and significant 50 percent (p=0.0001) and 75 percent (p=0.0007) responder rates month one through month three.
Efficacy further improved following a second quarterly infusion; an average of 17% of patients had no migraines following the first administration and that rose to 26% of patients following the second administration.
The safety profile was similar to placebo and consistent with previously reported eptinezumab studies.

Alder completed a public offering of common stock on July 18, 2017 resulting in net proceeds to Alder of approximately $161.5 million, after underwriting discounts, commissions and offering expenses.

Eptinezumab data presentations at top tier medical conferences highlighted Phase 2b (chronic migraine) and PROMISE 1 Phase 3 (episodic migraine) clinical data and analyses:
Three scientific presentations at the 69th Annual American Academy of Neurology (AAN)April 22-28.
Four scientific presentations at the 59th Annual Scientific Meeting of the American Headache Society (AHS) June 8-11.
Seven scientific presentations at the 18th Congress of the International Headache Society (IHC) September 7-10.

Fourth Quarter and Year-End 2017 Financial Results

As of December 31, 2017, Alder had $286.2 million in cash, cash equivalents, short-term investments and restricted cash, compared to $340.9 million as of Sept. 30, 2017 and compared to $351.9 million as of December 31, 2016.

Research and development expenses for the fourth quarter ended December 31, 2017 totaled $44.7 million, compared to $41.8 million for the same period in 2016. For the full year 2017, research and development expenses totaled $252.9 million, compared to $132.8 million for the full year 2016. The increases in spending for both periods were primarily due to manufacturing and clinical trial costs for the company’s eptinezumab program and commercialization preparations.

General and administrative expenses for the fourth quarter ended December 31, 2017 totaled $10.3 million, compared to $7.4 million for the same period in 2016. For the full year 2017, general and administrative expenses totaled $38.1 million, compared to $26.1 million for the full year 2016. The increases in spending for both periods were primarily due to an increase in stock-based compensation expense and salaries due to headcount growth, and an increase in professional fees and other administrative costs, primarily to support commercial readiness activities.

Net loss for the fourth quarter ended December 31, 2017 totaled $54.4 million, or $0.80 per share, compared to net loss of $48.9 million, or $0.97 per share on a fully-diluted basis, for the same period in 2016. For the full year 2017, net loss totaled $288.9 million, or $4.95 per share on a fully-diluted basis, compared to net loss of $156.3 million, or $3.23 per share, for the full year 2016.

Financial Outlook

Alder estimates its available cash, cash equivalents, short-term investments and restricted cash totaling $286.2 million as of December 31, 2017, together with the net proceeds of approximately $97.7 million received in 2018 from the sale of shares of convertible preferred stock in its committed equity financing and approximately $277.7 million received in 2018 in its underwritten public offering of 2.5% convertible senior notes due 2025 will be sufficient to meet projected operating requirements into 2020. These projections assume the BLA filing and approval by the U.S. Food and Drug Administration and the commercial launch of the infusion formulation of eptinezumab in this time period.

Conference Call and Webcast
Alder will host a conference call today at 5:00 p.m. ET to discuss these financial results and recent corporate highlights. The live call may be accessed by dialing (877) 430-4657 for domestic callers or (484) 756-4339 for international callers, and providing conference ID number 6943609. The webcast will be broadcast live and be accessed from the Events & Presentations page in the investors section of Alder’s website at www.alderbio.com. The webcast will be available for replay following the call for at least 30 days.