On November 21, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to VENCLEXTA (venetoclax tablets) in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy (Press release, AbbVie, NOV 21, 2018, View Source [SID1234531555]). This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.7

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Intensive chemotherapy may not be appropriate for all patients diagnosed with AML.8 An analysis of 446 older (≥70 years of age) AML patients concluded that intensive chemotherapy can be delivered but may not be beneficial to most.8 There are a number of factors why AML patients may be unable to tolerate intensive chemotherapy, such as age, performance status and comorbidities.8 Median survival in patients not eligible for intensive chemotherapy is five to 10 months.1

"AML is an extremely aggressive and debilitating blood cancer, and outcomes for patients ineligible for intensive chemotherapy are very poor," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "This new approval for VENCLEXTA marks a significant milestone for AbbVie and, more importantly, for patients diagnosed with this deadly disease. We look forward to continuing our work developing VENCLEXTA and advancing treatment options in other aggressive cancers."

The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy: M14-358, a trial evaluating VENCLEXTA in combination with azacitidine (n=67) or decitabine (n=13), and M14-387, a trial of VENCLEXTA and LDAC (n=61).7 Efficacy was established based on the rate of complete remission (CR) and duration of CR.7

The M14-358 trial showed that VENCLEXTA in combination with azacitidine resulted in a CR rate of 37 percent and a CR with partial hematologic recovery (CRh) rate of 24 percent. The median follow-up of patients included in the study was 7.9 months (range: 0.4 to 36 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.7 to 8.9 months). For patients taking VENCLEXTA in combination with decitabine, the CR rate was 54 percent and the CRh rate was 7.7 percent. The median follow-up of patients taking this combination was 11 months (range: 0.7 to 21 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1 to 18 months), with patients achieving a first CR or CRh at a median of 1.9 months (range: 0.8 to 4.2 months).7

The M14-387 trial showed that patients receiving VENCLEXTA in combination with LDAC achieved a CR rate of 21 percent and a CRh rate of 21 percent. The median follow-up of patients was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was six months (range: 0.03 to 25 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.8 to 9.4 months).7

For patients taking VENCLEXTA in combination with azacitidine, serious ARs were reported in 75 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome. For those taking VENCLEXTA and decitabine, serious ARs were reported in 85 percent of patients. The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.7

For patients taking VENCLEXTA in combination with LDAC, serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.7

The challenges of treating AML, including in older adults who are more likely to be ineligible for intensive chemotherapy, are an ongoing topic of discussion among the medical community. Dr. Daniel Pollyea, clinical director of leukemia services at University of Colorado Hospital reflected on his experience treating patients with AML here: "A Physicians View: Facing the Challenges of Treating AML in Older Adults."

"Many of my patients are ineligible for the intensive treatment for AML, which typically involves intensive chemotherapy. Only a minority of AML patients older than 60 are able to tolerate the standard chemotherapy required to achieve optimal results," said Dr. Pollyea. "Having a new medicine to treat AML is encouraging for my patients and their families. VENCLEXTA’s approval is a true breakthrough for AML patients ineligible for intensive chemotherapy."

VENCLEXTA, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.3,4,5,6 The FDA approved VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.7

The approval of VENCLEXTA in AML marks the third approval granted under priority review by the FDA for VENCLEXTA.7 VENCLEXTA is being studied in two ongoing Phase 3 studies in the AML patient population ineligible for intensive chemotherapy.9,10

Venetoclax is being studied in several other hematologic malignancies including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and myelodysplastic syndrome (MDS).11,12,13 Venetoclax is being developed by AbbVie and Roche and is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the Clinical Trials that Supported Accelerated Approval in AML

The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr <45 mL/min or other comorbidity. Efficacy was established based on the rate of complete remission (CR) and duration of CR.7

Study M14-358 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly-diagnosed AML. Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients received VENCLEXTA via a daily ramp-up to a final 400 mg once daily dose.7

Azacitidine (N=67):
The CR rate was 37 percent (95% confidence interval [CI]: 26, 50), and the CRh rate was 24 percent (95% CI: 14, 36). The median follow-up was 7.9 months (range: 0.4 to 36 months) for VENCLEXTA in combination with azacitidine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.7 to 8.9 months).7

Of patients treated with VENCLEXTA in combination with azacitidine, 7.5 percent (5/67) subsequently received stem cell transplant.7

The study enrolled 17 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 35 percent (95% CI: 14, 62) and the CRh rate was 41 percent (95% CI: 18, 67). Seven patients subsequently received stem cell transplant.7

The most common ARs (≥30 percent) of any grade were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash and anemia.7 Serious ARs were reported in 75 percent of patients.7 The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome.7

Decitabine (N=13):
The CR rate was 54 percent (95% CI: 25, 81), and the CRh rate was 7.7 percent (95% CI: 0.2, 36). The median follow-up was 11 months (range: 0.7 to 21 months) for VENCLEXTA in combination with decitabine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1.0 to 18 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.9 months (range: 0.8 to 4.2 months).7

The study enrolled 18 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 56 percent (95% CI: 31, 79) and the CRh rate was 22 percent (95% CI: 6.4, 48). Three patients subsequently received stem cell transplant.7

The most common ARs (≥30 percent) of any grade were febrile neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis (excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, myalgia, oropharyngeal pain, peripheral edema, pyrexia and rash. Serious ARs were reported in 85 percent of patients.7 The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.7

Low-dose cytarabine (N=61):
Study M14-387 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with low dose cytarabine (N=82) in patients with newly-diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. Of those patients, 61 were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients initiated VENCLEXTA via daily ramp-up to a final 600 mg once-daily dose.7

The CR rate was 21 percent (95% CI: 12, 34), and the CRh rate was 21 percent (95% CI: 12, 34). The median follow-up was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 6.0 months (range: 0.03 to 25 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.8 to 9.4 months).7

The study enrolled 21 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 33 percent (95% CI:15, 57) and the CRh rate was 24 percent (95% CI: 8.2, 47). One patient subsequently received stem cell transplant.7

The most common ARs (≥30 percent) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation and dyspnea. Serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.7

About VENCLEXTA (venetoclax) (US)

VENCLEXTA is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA targets the BCL-2 protein and works to help restore the process of apoptosis.7

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.14 The FDA approved this indication under accelerated approval based on overall response rate.14 Based on the results of the MURANO study, VENCLEXTA was approved in June 2018 for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy.7

Venetoclax is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Use and Important Safety Information (US)

What is VENCLEXTA (venetoclax)?

VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least 1 prior treatment.
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS .You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.

It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS.
Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?
Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome (TLS).

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.
The most common side effects of VENCLEXTA when used in combination with rituximab in people with CLL include low white blood cell counts, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone in people with CLL/SLL include low white blood cell counts; diarrhea; nausea; upper respiratory tract infection; low red blood cell counts; tiredness; low platelet counts; muscle and joint pain; swelling of your arms, legs, hands, and feet; and cough.

The most common side effects of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts, infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit View Source or call 1-800-FDA-1088.

If you cannot afford your medication, contact: www.pparx.org for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

On November 21, 2018 Celyad (Paris:CYAD) (Brussels:CYAD) (NASDAQ:CYAD) (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported its update on key clinical and operational developments for the third quarter ended September 30, 2018 (Press release, Celyad, NOV 21, 2018, View Source [SID1234531539]).

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THIRD QUARTER 2018 HIGHLIGHTS

FDA permitted the IND application for CYAD-101 to go into effect
No toxicity observed in the initial patient treated in the THINK CyFlu cohort evaluating the safety and anti-tumor activity of CYAD-01 after standard preconditioning chemotherapy
Key additions to the Board of Directors and Senior Leadership Team
Cash position of €55.9 million as of September 30, 2018
Dr. Christian Homsy, CEO of Celyad, commented: "We continue to be pleased with the flow of data from our clinical programs for CYAD-01. The data to date for CYAD-01 add to a growing body of evidence showing that our cell therapy has encouraging clinical activity across several indications, including acute myeloid leukemia and metastatic colorectal cancer, and is well-tolerated. In addition, we are excited for our lead allogeneic candidate, CYAD-101, which leverages our understanding of NKG2D biology, to enter the clinic for the treatment of metastatic colorectal cancer by year-end."

THIRD QUARTER 2018 OPERATIONAL AND FINANCIAL REVIEW

Updates to Allogeneic CYAD-101 Program and CYAD-01 THINK CyFlu Cohort

In July 2018, the U.S. Food and Drug Administration (FDA) accepted the Investigational New Drug (IND) application for CYAD-101, the world’s first non-gene edited, allogeneic CAR-T clinical candidate, and permitted it to go into effect. CYAD-101 will initially be evaluated in the alloSHRINK trial. Enrollment in the trial is expected to begin by year-end 2018. In September, Celyad announced the successful injection of the first patient under the amended protocol of the THINK trial, referred to as THINK CyFlu, in patients with metastatic colorectal cancer.

Strengthening our Management Team

In August, the Company announced that Dr. Margo Roberts, former Chief Scientific Officer of Kite Pharma Inc., joined Celyad’s Board of Directors and scientific committee. During the quarter, the Company also announced the appointment of Filippo Petti as Chief Financial Officer and Carri Duncan, PhD, as Vice President Corporate Development & Communications.

Financial review

The Company ended the quarter with €55.9 million in cash, cash equivalents and short-term investments. Use of cash over the third quarter of 2018 amounted to €6.7 million, in line with expectations. The Company confirms its previous guidance that existing cash, cash equivalents and short-term investments should be sufficient to fund operating expenses and capital expenditure requirements, based on the current scope of activities, until mid-2020.

HIGHLIGHTS SUBSEQUENT TO QUARTER-END

In October, Celyad announced an exclusive agreement with Horizon Discovery Group plc (LSE: HZD), for the use of its shRNA technology to generate Celyad’s second non-gene-edited allogeneic platform. Details of the agreement can be found on our website.

In early November, Celyad presented updated clinical results for the CYAD-01 program in solid tumors as well as translational research data at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting. Press release highlighting our advancing clinical and technological platforms can be found here.

Celyad is scheduled to present two abstracts detailing updated clinical results from the Phase 1 THINK dose-escalation trial and upcoming clinical trials for the CYAD-01 program at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, December 1-4, 2018. Details can be found on our website here.

On November 21, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) and granted Priority Review for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) (Press release, Daiichi Sankyo, NOV 21, 2018, https://www.prnewswire.com/news-releases/fda-grants-priority-review-for-daiichi-sankyos-new-drug-application-for-flt3-inhibitor-quizartinib-for-treatment-of-patients-with-relapsedrefractory-flt3-itd-aml-300754221.html [SID1234531556]).

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A Priority Review designation is granted by the FDA to drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications. Under Priority Review, the FDA aims to take action on an application within six months as compared to 10 months under standard review. The FDA is expected to make a decision on approval by May 25, 2019.

The NDA is based on results of the pivotal phase 3 QuANTUM-R study of quizartinib, which was the first randomized phase 3 study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD AML. Topline results of the phase 3 QuANTUM-R study were presented during the plenary program at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in June 2018, and new analyses will be presented during an oral presentation at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) on Monday, December 3.

"If approved, quizartinib has the potential to meaningfully advance treatment for patients with relapsed or refractory FLT3-ITD AML. Patients need more treatment options for this type of AML, which is particularly aggressive and difficult to treat. We are pleased that the FDA has filed our application for quizartinib for patients with relapsed or refractory FLT3-ITD AML, and granted priority review," said Arnaud Lesegretain, Vice President, Oncology Research and Development and Head, AML Franchise, Daiichi Sankyo. "Coupled with the recent acceptances of marketing applications for quizartinib in Japan and EU, we look forward to working with regulatory authorities in the U.S., Japan and EU to bring quizartinib to patients."

In addition to FDA priority review, quizartinib is currently under expedited regulatory review with the Japan Ministry of Health, Labour and Welfare (MHLW) and the European Medicines Agency (EMA) for the treatment of adults with relapsed or refractory AML which is FLT3-ITD positive.

About the QuANTUM-R Study
QuANTUM-R is a pivotal, global, phase 3, open-label randomized study that enrolled 367 patients with FLT3-ITD AML who were refractory to or in relapse with duration of remission of six months or less following standard first-line AML therapy with or without hematopoietic stem cell transplantation. Patients were randomized in a 2:1 ratio to receive either single agent oral quizartinib or salvage chemotherapy. The primary objective of the study was to determine whether single agent quizartinib prolonged overall survival compared to salvage chemotherapy. The study met its primary endpoint of improving overall survival.

In the QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count and decreased platelet count. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

About FLT3-ITD Acute Myeloid Leukemia
AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML.2 The five-year survival rate of AML reported from 2005 to 2011 was approximately 26 percent, which was the lowest of all leukemias.1

FLT3 gene mutations are one of the most common genetic abnormalities in AML.3 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML.4,5,6,7 FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML.5,8

Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.9,10

About Quizartinib
Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective FLT3 inhibitor currently in phase 3 development for adults with relapsed/refractory FLT3-ITD AML (QuANTUM-R) in the U.S. and EU; phase 3 development for newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; phase 2 development for relapsed/refractory FLT3-ITD AML in Japan; and, phase 1 development in combination with an investigational MDM2 inhibitor, milademetan, for relapsed/refractory FLT3-ITD AML and newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S., EU and Japan.

In addition to Priority Review designation, quizartinib has been granted Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the U.S. Food and Drug Administration (FDA). Quizartinib also has been granted accelerated assessment by the European Medicines Agency (EMA) for the treatment of adults with relapsed or refractory AML which is FLT3-ITD positive, and granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of FLT3-mutated AML.

Quizartinib and milademetan are investigational agents that have not been approved for any indication in any country. Safety and efficacy have not been established.

On November 21, 2018 The U.S. Food and Drug Administration reported that it approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy (Press release, US FDA, NOV 21, 2018, View Source [SID1234531586]).

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"Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy," said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of Daurismo was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either Daurismo in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with Daurismo. The median OS was 8.3 months for patients treated with Daurismo plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving Daurismo in clinical trials include low red blood cell count (anemia), tiredness (fatigue), bleeding (hemorrhage), fever with low white blood cell count (febrile neutropenia), muscle pain, nausea, swelling of the arms or legs (edema), low platelet counts (thrombocytopenia), shortness of breath (dyspnea), decreased appetite, distorted taste (dysgeusia), pain or sores in the mouth or throat (mucositis), constipation and rash.

The prescribing information for Daurismo includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. Daurismo should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of Daurismo treatment and effective contraception should be used during treatment and for at least 30 days after the last dose. The Boxed Warning also advises male patients of the potential risk of drug exposure through semen and to use condoms with a pregnant partner or a female partner that could become pregnant both during treatment and for at least 30 days after the last dose. Daurismo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Daurismo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Daurismo to Pfizer.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

On November 21, 2018 C4X Discovery Holdings plc (AIM: C4XD), a pioneering drug discovery company,reported its full year results for the year ended 31 July 2018 (Press release, C4X Discovery, NOV 21, 2018, View Source [SID1234533246]).

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Financial highlights
Revenue increased to £7,064,000 (2017: £143,000), driven entirely by the Indivior licensing agreement.
R&D expenses increased 15% to £6,992,000 (2017: £6,100,000), reflecting the Company’s investment in drug discovery activity and its continued development of lead drug candidates.
Total loss after tax was £1,135,000 or 2.44 pence per share (2017: £6,782,000 or 16.88 pence per share).
Post period end, C4XD completed a £10.1 million fundraise (before expenses) in October 2018 through the placing and open offer of 11,210,674 new ordinary shares in the capital of the Company (Ordinary Shares) at a price of 90 pence (GBX) per Ordinary Share.
Operational highlights
Business model validated

Licensing deal with Indivior in March 2018 for our Orexin-1 antagonist programme; $10 million upfront with up to $284 million in milestone payments.
Discovery Engine progress

C4XD’s proprietary drug asset portfolio has grown from three programmes in 2014 to nine active programmes spread across multiple therapeutic areas.
Disease areas of focus are inflammation, neurodegeneration, immune-oncology/oncology and additional opportunistic areas (e.g., addiction and diabetes).
To date, the Taxonomy3 platform has identified 285 novel, genetically-validated and disease-linked genes that will generate target insights for future discovery programmes in inflammation and neurodegeneration.
Launched Stage 1 of virtual reality-based molecular visualisation tool, 4Sight with the aim of increasing the throughput of the Company’s pre-clinical portfolio by accelerating hit generation and lead optimisation timeframes.
Partnerships

Continued to enhance core, state-of-the-art target identification and drug design capabilities through synergistic strategic partnerships:
o Joint research collaboration with e-Therapeutics plc (AIM:ETX) to identify novel mechanistic insights in Parkinson’s Disease was announced in May 2018.
Senior appointments

Eva-Lotta Allan, Non-Executive Chairman, and Natalie Walter, Non-Executive Director, were appointed to the Board of Directors in July 2018.
Dr Clive Dix, CEO of C4X Discovery, said: "C4X Discovery has had a transformational year in 2018, underlined by the successful completion of our pre-clinical licensing deal with Indivior in March. This pivotal milestone validated our business model. Our pipeline continues to progress, with NRF-2 entering a formal partnering process and excellent in vivo data on IL-17 moving this programme towards partnering. This maturing pipeline, combined with our enhanced commercial capabilities and our innovative collaborations with multiple partners, positions us well to carry out our strategy of becoming the world’s most productive drug discovery engine and delivering returns to our shareholders."

A copy of the final results presentation given by Clive Dix (Chief Executive Officer) will be released later this morning on the Group’s website at www.c4xdiscovery.com.

Analyst conference call today

Dr Clive Dix, Chief Executive Officer, will present the results at 11:30am GMT on 21 November 2018 during a live conference call. A copy of the results presentation will be released later this morning on the Company website at www.c4xdiscovery.com.