On June 23, 2017 Novartis reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Kisqali (ribociclib) in combination with an aromatase inhibitor for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer as initial endocrine-based therapy (Press release, Novartis, JUN 23, 2017, View Source [SID1234519671]). The CHMP recommendation of combining Kisqali with any aromatase inhibitor means that, if approved, oncologists could prescribe Kisqali with letrozole, anastrozole or exemestane, giving them the discretion to select the therapy they believe is most appropriate for each individual patient.

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"This positive CHMP opinion brings us one step closer to improving the lives of women diagnosed with advanced or metastatic breast cancer throughout Europe," said Bruno Strigini, CEO, Novartis Oncology. "There is currently no cure for advanced breast cancer, and approximately 30 percent of those affected by early-stage breast cancer will go on to develop advanced disease. We look forward to working with European health authorities to make Kisqali available to those who may benefit from it as quickly as possible."

The positive CHMP opinion is based on superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which globally enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus the aromatase inhibitor letrozole reduced the risk of progression or death by 44% over letrozole alone at interim analysis[1]. Most adverse events in the MONALEESA-2 trial were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and/or reduction[1].

A subsequent, pre-planned analysis of overall survival with an additional 11 months of follow-up demonstrated a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone (HR=0.568 (95% CI: 0.457-0.704; p<0.0001))[2]. More than half of women with measurable disease taking Kisqali plus letrozole saw their tumor size shrink by at least 30% (overall response rate (ORR) in patients with measurable disease = 55% vs 39%, p=0.00025)[2],[4]. Follow-up to measure overall survival is ongoing as data remain immature[4].

The European Commission will review the CHMP recommendation and usually delivers its final decision within two months. The decision will be applicable to all 28 European Union member states plus Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

In March 2017, Kisqali was approved by the US Food and Drug Administration (FDA) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer. Kisqali can be taken with or without food as a once-daily oral dose of 600 mg (three 200 mg film-coated tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor.

Globally, an estimated 250,000 women will be diagnosed with advanced breast cancer each year[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease, for which there is currently no cure[5],[6].

About Kisqali (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals. In the European Union, Kisqali is an investigational agent and has not been approved.

About the Kisqali Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7 that are evaluating Kisqali in combination with multiple endocrine therapy partners across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. These trials are fully enrolled.

Novartis is initiating two multi-center, randomized, double-blind Phase III clinical trials, EarLEE-1 and EarLEE-2, to evaluate the safety and efficacy of Kisqali with endocrine therapy as adjuvant therapy in pre- and postmenopausal women who have not previously received treatment with CDK4/6 or aromatase inhibitors. EarLEE-1 will assess Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- high-risk early breast cancer. EarLEE-2 will investigate Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- intermediate-risk early breast cancer.

The CompLEEment study is evaluating the safety and efficacy of Kisqali plus letrozole in men and pre- or postmenopausal women with HR+/HER2- advanced breast cancer with no prior hormonal therapy for advanced disease. The open-label, multicenter, Phase IIIb CompLEEment-1 trial is currently enrolling participants.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali (ribociclib) Important Safety Information FROM THE US PRESCRIBING INFORMATION
KISQALI (ribociclib) is a prescription medicine used in combination with an aromatase inhibitor as the first hormonal-based therapy to treat women who have gone through menopause with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if KISQALI is safe and effective in children. KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. KISQALI can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking KISQALI and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking KISQALI, patients should tell their health care provider if they are pregnant, or plan to become pregnant as KISQALI can harm an unborn baby. Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with KISQALI. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking KISQALI. The most common side effects (incidence >=20%) of KISQALI when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the KISQALI + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see full Prescribing Information for KISQALI, available at www.kisqali.com (link is external).

On June 23, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data from multiple studies of Venclexta/Venclyxto (venetoclax), presented at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 22-25 June, in Madrid (Press release, Hoffmann-La Roche, JUN 23, 2017, View Source [SID1234519670]). Data presented in relapsed or refractory chronic lymphocytic leukaemia (CLL) confirmed the efficacy of Venclexta/Venclyxto with high and durable response rates and a well-tolerated safety profile in this high-risk population, including people with 17p chromosomal deletion who had previously received treatment. Additionally, phase Ib data demonstrated the anti-cancer activity of Venclexta/Venclyxto in acute myeloid leukaemia (AML) and relapsed or refractory multiple myeloma (MM), further supporting the potential of this treatment in a broader range of blood cancers. Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

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"Confirmation that Venclexta/Venclyxto achieves a high response rate in relapsed or refractory chronic lymphocytic leukaemia in people with 17p deletion is very promising, as these patients have a particularly poor prognosis," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are also pleased to see early data highlighting the potential central role of BCL-2 in other difficult-to-treat blood cancers and look forward to validating these results in further studies."

The safety and efficacy of Venclexta/Venclyxto is being evaluated in a number of clinical studies in patients with CLL, some of which have led to European Medicines Agency (EMA) conditional marketing authorisation (M13-982 and M14-032) of Venclyxto and Food and Drug Administration (FDA) accelerated approval (M13-982) for Venclexta monotherapy in CLL. Data being presented at EHA (Free EHA Whitepaper) include:

Oral presentation of phase II monotherapy data in high-risk patients with relapsed/refractory CLL with 17p deletion showed an acceptable safety profile and a high response rate of 79%. Minimal residual disease (MRD)-negativity, an exploratory endpoint that is a measure of absence of residual blood cancer in patients’ blood or bone marrow, correlated with a progression-free survival (PFS) rate of 100% at 24 months. [Study M13-982 – Abstract S771, oral presentation Sunday, 25 June, 8:30 CET]. In addition, Venclexta/Venclyxto monotherapy demonstrated improved quality of life (QoL), with sustained and clinically meaningful improvement of several key aspects of functioning and health-related QoL. [Study M13-982 – Abstract S771, oral presentation Sunday 25 June, 8:30 CET and Study M14-032 – Abstract P728, poster presentation Saturday, 24 June, 17:30 CET].

Phase Ib data with Venclexta/Venclyxto in combination with MabThera/Rituxan (rituximab) in patients with relapsed/refractory CLL/small lymphocytic leukaemia (SLL) showed an acceptable safety profile and deep and durable responses, with 51% patients achieving a complete response (CR/CRi), 59% achieving marrow MRD-negativity and an overall response rate (ORR) of 86%. Data in patients achieving MRD-negativity suggested a prolonged treatment-free remission period even after Venclexta/Venclyxto treatment was stopped. [M13-365 study – Abstract P247, poster presentation Friday, 23 June, 17:15 CET].

The safety and efficacy of Venclexta/Venclyxto is also being evaluated in other blood cancers, including AML, an aggressive form of leukaemia that starts in myeloid cells, and MM, a cancer formed from malignant plasma cells.
In AML, Venclexta/Venclyxto has shown an acceptable safety profile in combination with decitabine or azacitidine and a high ORR of 68% in elderly patients with previously untreated AML. [Study M14-358 – Abstract S472, oral presentation Saturday, 24 June, 16:15 CET]. A further open-label phase I/II study in previously untreated elderly patients with AML showed durable efficacy with an acceptable safety profile for Venclexta/Venclyxto in combination with low-dose cytarabine. [Study M14-387 – Abstract E911 to be presented as an Eposter].

In MM, data from a phase Ib study of Venclexta/Venclyxto in combination with bortezomib and dexamethasone demonstrated an acceptable safety profile and anti-myeloma activity. When treated with Venclexta/Venclyxto, an overall response rate of 67% was achieved in patients with relapsed or refractory MM. [Study M12-901- Abstract S460, oral presentation Saturday, 24 June, 17:00 CET].

About Venclexta/Venclyxto
Venclexta/Venclyxto is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in CLL has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct.

Venclexta/Venclyxto is being co-developed by AbbVie and Roche. Together, the companies are committed to research with Venclexta/Venclyxto , which is currently being evaluated in phase III clinical trials for the treatment of relapsed, refractory and previously untreated CLL, along with studies in several other cancers. Venclexta/Venclyxto is commercialised jointly by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of the investigational haemophilia A treatment emicizumab.

On June 23, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data from additional analyses of the pivotal phase III GALLIUM study in people with previously untreated follicular lymphoma will be presented at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) annual congress, 22-25 June, in Madrid, Spain (Press release, Hoffmann-La Roche, JUN 23, 2017, View Source [SID1234519668]). The data confirmed that the improvement in progression-free survival (PFS) with Gazyva/Gazyvaro (obinutuzumab)-based treatment over MabThera/Rituxan(rituximab)-based treatment was sustained in an updated analysis with a further six months of follow-up, irrespective of chemotherapy regimen. In addition, health-related quality of life (HRQoL) as reported by people in the Gazyva/Gazyvaro treatment group improved from the baseline assessment, suggesting that lymphoma-related symptoms were reduced by treatment and that this improvement was not diminished by treatment-related side effects. Additional preliminary analyses support the potential use of positron emission tomography (PET) as an early predictor of progression-free survival and overall survival in untreated follicular lymphoma.

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"These data add to the growing body of evidence that Gazyva/Gazyvaro plays an important role in advancing the treatment of follicular lymphoma," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Gazyva/Gazyvaro helped people with follicular lymphoma live longer without their disease worsening compared to MabThera/Rituxan, regardless of chemotherapy regimen. Importantly, this benefit did not come at the expense of health-related quality of life, an important measure of the patient’s treatment experience."
The following new data from the GALLIUM study will be presented:

A subanalysis by chemotherapy regimen showed that improvement in investigator-assessed PFS was superior for Gazyva/Gazyvaro-based treatment vs MabThera/Rituxan-based treatment across CHOP, CVP and bendamustine chemotherapy regimens. The benefit in PFS with Gazyva/Gazyvaro-based treatment was sustained over time. After a further six months of follow-up, for a total follow-up period of 41.1 months, the reduction in the risk of disease progression or death in the Gazyva/Gazyvaro-treated group remained consistent with the previous analysis (HR= 0.68; 95% CI 0.54-0.87; p=0.0016). [Abstract S775, to be presented in an oral presentation on Sunday, 25 June at 08:15 CET].

An additional subanalysis demonstrated that around 50% of people in both the Gazyva/Gazyvaro-based treatment group
and the MabThera/Rituxan-based treatment group reported clinically meaningful improvements in HRQoL from their baseline. This effect underscores the importance of treatment in effect in alleviating symptoms of follicular lymphoma that impact patients’ HRQoL. Importantly, the improvement seen was not diminished by treatment-related side effects. When viewed in the context of longer PFS, these results further support the relative benefit of Gazyva/Gazyvaro-based treatment over MabThera/Rituxan-based treatment in this setting. [Abstract S502 to be presented in an oral presentation on Saturday, 24 June at 16:15 CET].

Data from GALLIUM provides the first large-scale prospective comparison of standard contrast-enhanced CT versus PET scanning. After a median follow-up of 34.5 months, PET status at end of induction, as determined by independent review committee, was highly predictive of PFS (PET-complete remission (CR) vs PET non-CR: HR 0.39; 95% CI 0.25-0.60; p<0.0001) and overall survival (OS) (HR 0.41; 95% CI 0.19-0.86; p=0.018). [Abstract S774, to be presented in an oral presentation on Sunday, 25 June at 08:00 CET].

About the GALLIUM study
GALLIUM (NCT01332968) is a global phase III open-label, multicentre, randomised two-arm study examining the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro alone for up to two years, as compared head-to-head against MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan alone for up to two years or until disease progression (whichever occurs first). Chemotherapies (CHOP, CVP or bendamustine) were selected by each participating study site prior to beginning enrolment. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS 3/5
assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), and safety. The GALLIUM study is being conducted in cooperation with the NCRI (United Kingdom), GLSG (Germany), the East German Study Group Hematology and Oncology (OSHO; Germany).

About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B-cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.

Gazyva/Gazyvaro is currently approved in more than 80 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia (CLL), and in combination with bendamustine for people with certain types of previously treated follicular lymphoma. The approvals in CLL were based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.

The approvals in certain types of previously treated follicular lymphoma were based on the phase III GADOLIN study, in people with follicular lymphoma who did not respond to or who progressed during or within six months of prior MabThera/Rituxan-based therapy, showing a significant improvement in PFS and overall survival (OS) with Gazyva/Gazyvaro-based therapy compared to bendamustine alone.

Gazyva is marketed as Gazyvaro in the EU and Switzerland. Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About Follicular Lymphoma
Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), accounting for about one in five cases of NHL.1 It is considered incurable and relapse is common. Every day, more than 50 people in Europe are diagnosed with this type of NHL.2 It is estimated that more than 75,000 people are diagnosed with follicular lymphoma each year worldwide.2

On June 23, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a clinical stage biopharmaceutical company focused on the discovery, development, and commercialization of innovative therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 studies of luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Madrid, Spain (Press release, Acceleron Pharma, JUN 23, 2017, View Source [SID1234519667]). Luspatercept is being developed to treat a range of hematologic diseases including MDS, beta-thalassemia, and myelofibrosis as part of a global collaboration between Acceleron and Celgene.

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"This Phase 2 update further supports our confidence that luspatercept could become a potential first-in-class treatment for lower-risk MDS patients. With some patients continuing on study for more than 26 months, we are very encouraged by both the durability of response and safety profile of luspatercept," said Habib Dable, President and Chief Executive Officer of Acceleron. "With Phase 3 trials across two indications ongoing and new studies planned, we and Celgene remain committed to exploring the full opportunity for luspatercept to transform patients’ lives."

Phase 2 Results

A total of 88 lower-risk MDS patients have been treated with therapeutic dose levels of luspatercept in the ongoing Phase 2 study.

50% (44 of 88) achieved a clinically meaningful erythroid response of an increase in hemoglobin or reduction in red blood cell (RBC) transfusion burden as per the International Working Group’s Hematologic Improvement Erythroid (IWG HI-E) response criteria.
38% (23 of 60 patients with ≥ 2 units RBC / 8 weeks transfusion burden at baseline) achieved RBC transfusion independence (RBC-TI) for ≥ 8 weeks.
Patients with a low transfusion burden ( < 4 units / 8 weeks and hemoglobin < 10 g/dL) demonstrated a clinically meaningful increase in hemoglobin for up to 26 months, with several remaining on treatment.
The results presented at EHA (Free EHA Whitepaper) confirm and extend previously reported results across the lower-risk MDS patient subpopulations, showing erythroid responses regardless of prior use of erythropoiesis-stimulating agents (ESA), baseline erythropoietin (EPO) levels, and ring sideroblast (RS) status.

Phase 2 Safety Summary

A total of 95 lower-risk MDS patients have been treated with luspatercept in the ongoing Phase 2 studies (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. AEs possibly related to study drug that occurred in at least three patients during the studies were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and edema peripheral.
Grade 3 non-serious AEs possibly related to study drug were ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion. These Grade 3 non-serious AEs occurred in six individual patients with one patient accounting for both the ascites and pleural effusion AEs.
Grade 3 serious AEs (SAEs) possibly related to study drug were ataxia, general physical health deterioration, and myalgia; a Grade 2 SAE possibly related to study drug of muscle weakness was reported.
"The longer term results of these Phase 2 studies reinforce the potential of inhibiting ligands in the TGF-beta superfamily for patients with lower-risk MDS," said Michael Pehl, President, Hematology/Oncology for Celgene. "With the Phase 3 study now fully enrolled, we look forward to advancing luspatercept as part of our ongoing commitment to individuals with MDS around the world."

Luspatercept is an investigational product that is not approved for use in any country.

The MEDALIST trial, a global Phase 3 study of luspatercept in patients with lower-risk MDS who require red blood cell transfusions, is fully enrolled and top-line results are expected in mid-2018.

The MDS poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com/.

About the MDS Phase 2 Studies

Data from two Phase 2 studies were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, lower-risk MDS patients were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The outcome measures for the studies included the proportion of patients who had an erythroid response (IWG HI-E) or achieved RBC transfusion independence (RBC-TI). IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with < 4 units RBC / 8 weeks transfusion burden at baseline and hemoglobin levels below 10 g/dL. For patients with a ≥ 4 units RBC / 8 weeks transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 units RBC sustained for ≥ 8 weeks. RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a ≥ 2 units RBC / 8 weeks baseline transfusion burden.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the transforming growth factor-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the "MEDALIST" study) and in patients with beta-thalassemia (the "BELIEVE" study). For more information, please visit www.clinicaltrials.gov.

On June 23, 2017 Novartis reported that full results from the Rydapt [] (midostaurin) Phase III RATIFY (CALGB 10603 [Alliance]) clinical trial were published in The New England Journal of Medicine (NEJM) [1] (Press release, Novartis, JUN 23, 2017, View Source [SID1234519666]). Top-line data from this study were previously presented during the plenary session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in 2015 [2]. New data include disease-free survival (DFS), further analysis of patients undergoing transplant and expanded safety information.

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"The data from the CALGB 10603/RATIFY trial reinforce the efficacy and safety of Rydapt in patients with FLT3-mutated AML and set the stage for a shift in the way the medical community can approach this difficult-to-treat disease," said Richard M. Stone, MD, Chief of Staff and Director of the Adult Leukemia Program at Dana-Farber Cancer Institute, and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial. "This study has provided critical insights for the AML community and shows the potential of clinical research carried out by international investigators with support from both public and private sources."

Study Results Published in NEJM
In RATIFY, patients aged 18-59 years treated with Rydapt in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy experienced significant improvement in overall survival (OS) with a 22% reduction in the risk of death compared with chemotherapy plus placebo. In patients in the Rydapt arm, OS was 74.7 months [95% CI, 31.5-not reached] vs. 25.6 months [95% CI, 18.6-42.9] in the placebo arm (one-sided stratified log-rank p=0.009, HR=0.78). At four years, OS was 51.4% in the Rydapt arm, compared with 44.3% in the placebo arm [1].

The median event-free survival (EFS) was 8.2 months (95% CI, 5.4-10.7) in the Rydapt arm and 3.0 months (95% CI, 1.9-5.9) in the placebo arm (one-sided stratified log-rank p=0.002, HR=0.78). Median DFS was greater with the addition of Rydapt versus the placebo arm (26.7 months [95% CI, 19.4-not reached] vs. 15.5 months [95% CI, 11.3-23.5], respectively; p=0.01). The complete remission (CR) rate, defined as CR reported within 60 days of protocol therapy initiation, was 58.9% in the Rydapt arm and 53.5% in the placebo arm (p=0.15). The benefit of Rydapt on OS and EFS was consistent across all FMS-like tyrosine kinase 3 (FLT3) mutation subgroups, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) FLT3 mutations [1].

"The Rydapt RATIFY trial is a testament to Novartis’ dedication to exploring opportunities to create therapies for patients with difficult to treat diseases," said Vasant Narasimhan, Global Head of Drug Development and Chief Medical Officer, Novartis. "These results represent the culmination of years of work and dedication from investigators around the world who were driven to find a targeted treatment for these patients."

More patients in the Rydapt arm were able to undergo allogenic hematopoietic stem cell transplantation (HCT) during their first complete response versus placebo (28.1% vs. 22.7%, respectively; p=0.10). When censoring patients at the time of transplant (when protocol therapy was discontinued), OS was numerically better for those in the Rydapt arm versus placebo arm, with a 24.3% reduction in the risk of death at four years (63.7% vs. 55.7% respectively, p=0.08) [1].

The most frequent Grade 3 to 5 non-hematologic adverse events (AEs) (incidence greater than or equal to 20%) in the Rydapt arm were febrile neutropenia and infection. In the placebo arm, the most common AEs were febrile neutropenia, infection and lymphopenia. There were few significant differences (greater than 5%) observed in the overall rate of Grade 3 to 5 AEs between the treatment arms – patients receiving Rydapt experienced higher rates of anemia and rash [1]. Please see below for additional important US safety information [3].

RATIFY, the largest clinical trial in FLT3-mutated AML to date, included 3,277 patients screened and 717 study participants from around the world. The full data from the randomized Phase III trial have now been published and include data outside the parameters of the US Prescribing Information and Swiss Product Information. Based on data from the RATIFY clinical trial, The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines []) for AML now include use of midostaurin in FLT3-mutated AML [4].

About AML
AML, a rare and aggressive cancer of the blood and bone marrow, is the most common acute leukemia in adults. It accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the US, Europe and Australia [5]. It also has the lowest survival rate of all adult leukemias [5].

AML prevents white blood cells from maturing, causing an accumulation of "blasts," which do not allow room for the normal blood cells [6]. Mutations in specific genes are found in many cases of AML [7], and genetic testing for mutations in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies [8].

Approximately one-third of AML patients will have a FLT3 gene mutation [7]. FLT3 is a type of cell-surface receptor which plays a role in increasing the number of certain blood cells [9]. The FLT3 gene mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML [7,9,10].

About Rydapt [] (midostaurin)
Rydapt [] (midostaurin) is an oral, multi-targeted inhibitor of multiple kinases, including FLT3 and KIT, which help regulate many essential cell processes, interrupting cancer cells’ ability to grow and multiply [3].

In the US, Rydapt is Food and Drug Administration (FDA)-approved for the treatment of adults with newly diagnosed AML who are FLT3 mutation-positive (FLT3+) as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation [3]. Rydapt is not indicated in the US as a single-agent induction therapy for the treatment of patients with AML. For a description of the experience with single-agent treatment beyond induction and consolidation, healthcare professionals in the US should refer to the Clinical Studies section of the US Prescribing Information (14.1) [3].
The full US Prescribing Information for Rydapt can be found at: View Source

Rydapt is also approved in Switzerland for use in combination with standard induction and consolidation chemotherapy, followed by maintenance monotherapy for treatment of newly diagnosed adult AML patients who have an FLT3 mutation. Novartis has submitted a regulatory application for Rydapt to the European Medicines Agency (EMA) and this application is currently under review.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of Rydapt has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that Rydapt will become commercially available for additional indications anywhere else in the world.

Rydapt Important Safety Information
Patients who are allergic to midostaurin or any of the ingredients in Rydapt should not take Rydapt. If a patient taking Rydapt develops signs of an allergic reaction, they should seek medical help immediately. Signs of an allergic reaction include trouble breathing, flushing, chest pain, throat tightness, and swelling of lips, mouth or throat.

Rydapt should be not be used during pregnancy since Rydapt may harm an unborn baby. Pregnancy testing should be conducted for women who might become pregnant. Effective birth control should be used during treatment and for at least four months after stopping Rydapt. If a patient becomes pregnant or thinks she may be, the patient should tell their doctor right away. Women should not breastfeed during treatment with Rydapt and for at least four months after the final dose. Men taking Rydapt who have female partners that are able to become pregnant should use effective birth control during his treatment with Rydapt and for at least four months after the last Rydapt dose. Rydapt may cause fertility problems in women and men, which may affect their ability to have children.

Rydapt may cause lung problems that may lead to death. Patients on Rydapt who develop a new or worsening cough, shortness of breath, or chest discomfort should get medical help right away. These may be signs of serious lung problems.

Common sides effects reported during Rydapt treatment for AML included low level of white blood cells with fever (febrile neutropenia); nausea; redness, pain or ulcers inside the mouth (mucositis); vomiting; headache; bruising; muscle or bone pain; nose bleeds; device-related infection; high blood sugar levels (hyperglycemia) and upper respiratory infections.

If side effects including nausea, vomiting, and diarrhea occur, get worse or do not go away during treatment with Rydapt, patients should contact their doctor. Depending on the side effect and/or severity of the side effect that occur, their doctor may decrease their dose, temporarily stop, or completely stop treatment with Rydapt.

Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Rydapt may affect how these medicines work or these other medicines may affect how Rydapt works.