New Data at EAN Show Genentech’s Ocrevus (Ocrelizumab) Significantly Reduced Multiple Measures of Disease Progression in Relapsing and Primary Progressive Multiple Sclerosis
OCREVUS increased the number of patients with relapsing MS (RMS) and primary progressive MS (PPMS) who maintained No Evidence of Progression or Active Disease (NEPAD) versus Rebif® (interferon beta-1a) in RMS and placebo in PPMS OCREVUS significantly reduced the risk of RMS and PPMS patients’ requiring mobility aids versus comparators In PPMS patients, OCREVUS reduced the risk of more severe forms of disability progression versus placebo June 23, 2017 01:00 AM Eastern Daylight Time SOUTH SAN FRANCISCO, Calif.--(EON: Enhanced Online News)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that new post-hoc analyses from the OCREVUSTM (ocrelizumab) Phase III clinical trial program in people with relapsing and primary progressive forms of multiple sclerosis (RMS and PPMS) will be presented at the 3rd Congress of the European Academy of Neurology (EAN) from June 24 to June 27 in Amsterdam, Netherlands.“Slowing disability progression, or preventing people with MS from having to use a cane or wheelchair, makes a great difference to their daily lives. It is particularly exciting to see these benefits in people with PPMS, a disabling form of MS without approved treatments in Europe.” OCREVUS significantly reduced disease activity and disability progression in patients with RMS and PPMS, as measured by No Evidence of Progression or Active Disease (NEPAD), a novel composite endpoint in MS. In RMS, OCREVUS significantly increased the proportion of patients maintaining NEPAD by 82 percent compared with Rebif® (interferon beta-1a) at 96 weeks in a pooled exploratory analysis of the Phase III OPERA I and II studies (p<0.0001). In PPMS patients, OCREVUS more than tripled the proportion of those who maintained NEPAD compared with placebo at 120 weeks in an exploratory analysis of the Phase III ORATORIO study (29.9 percent with OCREVUS versus 9.4 percent with placebo, p<0.001).NEPAD is considered a clinically meaningful endpoint because it signifies a patient has no relapses, no confirmed disability progression measured by the Expanded Disability Status Scale (EDSS), no progression equal to or above 20 percent on the timed 25-foot walk (T25-FW) and the nine-hole peg test (9-HPT), no gadolinium-enhancing T1 MRI lesions and no new or enlarging T2 MRI lesions.“These results underline that the significant effects of OCREVUS on disability progression are clinically meaningful,” said Ludwig Kappos, M.D., Chair of the Department of Neurology, University Hospital, Basel, Switzerland. “Slowing disability progression, or preventing people with MS from having to use a cane or wheelchair, makes a great difference to their daily lives. It is particularly exciting to see these benefits in people with PPMS, a disabling form of MS without approved treatments in Europe.”In separate post-hoc analyses of the OPERA I and II studies, OCREVUS significantly reduced the risk of patients with RMS losing the ability to walk long distances unassisted (EDSS ≥4) or requiring a cane or crutch (EDSS ≥6) compared with interferon beta-1a at 96 weeks (p≤0.005). In the ORATORIO study, OCREVUS significantly reduced the risk of becoming wheelchair-bound (EDSS ≥7) compared with placebo at 120 weeks in PPMS patients with baseline EDSS ≤6 (p≤0.028).Furthermore, in a post-hoc analysis of the placebo-controlled ORATORIO study, OCREVUS consistently reduced the risk of 12- and 24-week confirmed disability progression (CDP) across three different definitions of the measure meant to capture more severe disability worsening than traditionally assessed in PPMS patients.In addition, interim results from FLOODLIGHT, a sensor-based digital monitoring study to determine adherence and correlation with in-clinic testing in people with and without MS, will be presented. Pregnancy outcomes in all female patients treated with OCREVUS will also be presented.The most common side effects associated with OCREVUS in all Phase III studies were infusion reactions and upper respiratory tract infections, which were mostly mild to moderate in severity.
Acceleron Provides Updated Results from Phase 2 Studies of Luspatercept in Beta-Thalassemia at the 22nd Congress of the European Hematology Association
CAMBRIDGE, Mass.--(BUSINESS WIRE)--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, today announced preliminary results from the ongoing Phase 2 study of luspatercept in patients with beta-thalassemia during an oral presentation at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain. Luspatercept is being developed to treat a range of hematologic diseases including beta-thalassemia, myelodysplastic syndromes (MDS), and myelofibrosis as part of a global collaboration between Acceleron and Celgene.
Takeda Presents Data from Phase 1/2 Studies for NINLARO™ (ixazomib) in Newly Diagnosed Multiple Myeloma Patients and in the Maintenance Setting
CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that data from two Phase 1/2 clinical trials evaluating NINLARO™ (ixazomib) in patients with newly diagnosed multiple myeloma will be presented during oral sessions at the 2017 European Hematology Association (EHA) annual meeting on Saturday, June 24, 11:45 a.m. – 12 p.m. CEST and Sunday, June 25, 8:15 a.m. – 8:30 a.m. CEST. Both studies evaluated NINLARO plus lenalidomide and dexamethasone in newly diagnosed patients with multiple myeloma who did not undergo stem cell transplant (SCT), followed by maintenance with single-agent ixazomib. NINLARO is currently not approved for the treatment of newly diagnosed multiple myeloma or in the maintenance setting.“Despite recent progress, multiple myeloma remains a rare, devastating and incurable hematologic cancer. Data being presented at EHA demonstrate Takeda’s ongoing commitment to exploring new ways to provide effective and sustainable treatment for patients with multiple myeloma, both at the time of diagnosis and for long-term use,” said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “These Phase 1/2 data demonstrate the potential use of ixazomib in combination with lenalidomide-dexamethasone in newly diagnosed multiple myeloma and as a single-agent maintenance therapy, which resulted in patients achieving deepening responses with continual use of the treatment. Ixazomib’s efficacy and safety profile – coupled with its administration as a completely oral regimen – potentially can reduce some logistical burdens, and help patients be able to sustain a multiple myeloma therapy.”Deep and Durable Responses with Weekly Ixazomib, Lenalidomide and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of Patients who did not Undergo SCT (Abstract S408, oral presentation at 11:45 a.m. CEST on June 24, 2017 at IFEMA Madrid, Hall A)In this Phase 1/2 study, patients with newly diagnosed multiple myeloma received weekly oral ixazomib (1.68 - 3.95 mg/m2 in Phase 1 and 4.0 mg in Phase 2) plus lenalidomide and dexamethasone for up to twelve, 28-day induction cycles. Of the 65 enrolled patients, 42 continued on study treatment without withdrawing early for SCT. After initial therapy, 25 patients went on to receive weekly, single-agent ixazomib at the last tolerated dose given during induction until disease progression or unacceptable toxicity.Key findings, which will be presented by Dr. Shaji Kumar of the Mayo Clinic, Rochester, Minnesota, include:Patients who did not undergo SCT and were treated with ixazomib plus lenalidomide and dexamethasone at induction achieved high response rates, demonstrate the activity of this regimen At a median follow-up of 55.2 months, the confirmed overall response rate (ORR) was 80%, complete plus very good partial response (CR+VGPR) rate was 63% and CR rate was 32% Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 6 of 7 (86%) were MRD-negative. Median progression-free survival (PFS) was 29.4 months Median overall survival (OS) was not reached at a median follow-up of 55.2 months; four-year landmark OS estimate was 82% A total of 86% of patients had grade ≥ 3 adverse events (AEs) and 52% of patients had serious AEs. The most common grade ≥ 3 AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, rashes, eruptions and exanthems, peripheral neuropathy and nausea. Of the two patients who died on study, one was considered to be treatment-related and was due to respiratory syncytial viral pneumonia After completing 12 cycles of induction therapy with lenalidomide and dexamethasone, 25 patients went on to receive maintenance single-agent ixazomib Increased depth of response occurred in a number of patients who received maintenance therapy with single-agent ixazomib; 32% of patients improved their response during maintenance The occurrence of the most common grade ≥ 3 AEs and adverse drug reactions (ADRs), which included neutropenia, thrombocytopenia, back pain and rashes, eruptions and exanthems, was confined almost exclusively to the induction period Less toxicity was reported during the maintenance versus induction periods “Based on an increasing body of evidence that long-term therapy may improve clinical outcomes, this Phase 1/2 trial focused on continuous treatment of patients with newly diagnosed multiple myeloma,” said lead investigator Shaji Kumar, M.D., Mayo Clinic, Rochester, Minn. “The trial evaluated patients who received weekly ixazomib plus lenalidomide and dexamethasone as an induction regimen followed by maintenance with single-agent ixazomib. Data showed that patients had deep responses on single-agent therapy and median progression-free survival of more than two years. We remain committed to gathering additional data of ixazomib in this investigational, maintenance setting.”Twice Weekly Ixazomib Plus Lenalidomide-Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Data for Patients who did not Undergo Stem Cell Transplant (SCT) (Abstract S780, oral presentation at 8:15 a.m. CEST on June 25, 2017 at IFEMA Madrid, Hall D)This Phase 1/2 study evaluated twice-weekly oral ixazomib (3.0 or 3.7 mg) plus lenalidomide and dexamethasone for up to sixteen, 21-day cycles followed by maintenance therapy with single-agent twice weekly ixazomib (at last tolerated dose). Of the 64 patients enrolled, 41 continued on study treatment without early withdrawal for SCT.Key findings, which will be presented by Deborah Berg, Senior Scientific Director, Oncology Clinical Research, Takeda, on behalf of Dr. Paul Richardson, Dana-Farber Cancer Institute, Boston, Mass., include:In patients who did not undergo SCT, initial treatment with twice-weekly ixazomib plus lenalidomide and dexamethasone was associated with deep responses At median follow-up of 47 months, the ORR was 92%, the CR + VGPR rate was 69% and the CR rate was 31% Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 8 of 9 (89%) were MRD-negative Median PFS for patients was 24.9 months and median OS was not estimable; three-year landmark OS estimate was 86% A total of 85% of patients had grade ≥ 3 AEs and 54% of patients had serious AEs. The most common grade ≥3 AEs included rash, eruptions and exanthems, hyperglycemia, peripheral neuropathy, peripheral edema, thrombocytopenia and neutropenia. There was one on-study treatment-related death due to cardio respiratory arrest. After completing induction therapy, 18 patients went on to receive maintenance with twice-weekly single-agent ixazomib Patients on maintenance therapy received a median of 31.5 treatment cycles 22% patients improved their responses during maintenance 44% of patients who received maintenance therapy had an onset of a grade ≥ 3 AE and ADRs in cycle 17 or beyond. The most common grade ≥ 3 AEs and ADRs were hyperglycemia, rashes, eruptions and exanthems, diarrhea, vomiting, peripheral neuropathy, nausea and neutropenia. “The addition of ixazomib – a first in class oral proteasome inhibitor – to doublet therapy has been shown to substantially improve efficacy in newly diagnosed multiple myeloma patients,” said lead investigator Paul Richardson, M.D., Dana-Farber Cancer Institute. “In this Phase 1/2 trial in newly diagnosed multiple myeloma, ixazomib plus lenalidomide and dexamethasone resulted not only in high quality of responses using a twice a week schedule but also in an encouraging deepening of responses over time in patients who did not receive a stem cell transplant. In addition, impressive durable clinical benefit was seen as patients went on to receive maintenance therapy with single-agent ixazomib after successful induction/remission therapy using this all oral approach.”
FDA granted regular approval to the combination of rituximab and hyaluronidase human (RITUXAN HYCELA, Genentech Inc.) for adult patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. The approval provides patients a subcutaneous route of rituximab administration that shortens the administration time to 5 to 7 minutes as compared to intravenous infusion that can take several hours. This new product also provides for flat dosing.The approval specifies the combination is indicated for the following previously approved indications for Rituxan:Relapsed or refractory, follicular lymphoma (FL) as a single agent. Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC). Rituxan Hycela is not indicated for the treatment of non-malignant conditions. Approval was based on multiple randomized clinical trials demonstrating the following: (a) non-inferior rituximab trough concentrations (Ctrough) levels for Rituxan Hycela 1,400 mg/23,400 Units compared to a intravenous rituximab 375 mg/m2 (b) non-inferior rituximab Ctrough levels for Rituxan Hycela 1,600 mg/26,800 Units compared to intravenous rituximab 500 mg/m2 and (c) comparable efficacy and safety results of the two products. Trial results are provided in the drug prescribing information.The most common adverse events (≥20%) observed in patients with FL include infections, neutropenia, nausea, constipation, cough, and fatigue. The most common adverse events (≥20%) observed in patients with DLBCL include infections, neutropenia, alopecia, nausea, and anemia. The most common adverse events (≥20%) observed in patients with CLL were infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema.The recommended doses are 1400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1600 mg rituximab and 26,800 units hyaluronidase human for CLL. Refer to the prescribing information for specific dosing schedules. Rituxan Hycela treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion.
H. Lundbeck A/S (Lundbeck) and Takeda Pharmaceutical Company Limited (Takeda) today announced that after providing additional analysis, the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the supplemental new drug application (sNDA) to include new data in the clinical trials section of the U.S. prescribing information of Trintellix (vortioxetine) for treating aspects of cognitive dysfunction in adults with major depressive disorder (MDD).
- H. Lundbeck A/S (Lundbeck) and Takeda Pharmaceutical Company Limited (Takeda) today announced that after providing additional analysis, the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the supplemental new drug application (sNDA) to include new data in the clinical trials section of the U.S. prescribing information of Trintellix (vortioxetine) for treating aspects of cognitive dysfunction in adults with major depressive disorder (MDD). Takeda and Lundbeck are disappointed, but we believe in the strength of the data and plan to continue discussions with the FDA on potential paths forward. The companies remain committed to the depression community and Trintellix as a treatment option for adult patients living with depression, including those who suffer from cognitive dysfunction as part of this disease. The FDA approved Trintellix on 30 September 2013 for the treatment of MDD in adults. The CRL does not change the FDA-approved current prescribing information for Trintellix. About Trintellix (vortioxetine) The mechanism of the antidepressant effect of Trintellix is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to Trintellix's antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this is unknown. Trintellix was discovered by Lundbeck researchers in Copenhagen, Denmark. The clinical trial program in the U.S. was conducted jointly by Lundbeck and Takeda, and Takeda holds the new drug application for the U.S. market. Trintellix is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc. The World Health Organization has issued an Anatomical Therapeutic Chemical (ATC) code for Trintellix that places it in the category of "Other" antidepressants. The most commonly observed adverse events in MDD patients treated with Trintellix in 6-8 week placebo-controlled studies (incidence greater than or equal to 5% and at least twice the rate of placebo) were nausea, constipation and vomiting. Overall, 5% to 8% of the patients who received Trintellix 5 to 20 mg/day in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4 percent of placebo-treated patients in these studies. Trintellix and other antidepressants may cause serious side effects. In clinical studies, Trintellix had no significant effect on body weight as measured by the mean change from baseline in 6-8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12-week, open-label phase, there was no significant effect on body weight between Trintellix and placebo-treated patients. Some reports of weight gain have been received since product approval. Trintellix has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. In the U.S., the recommended starting dose of Trintellix is 10 mg once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the U.S. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses. The available doses provide important flexibility for physicians to help address the variability of patient needs. Trintellix is available as 5 mg, 10 mg and 20 mg tablets in the U.S.
FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation
On June 22, 2017, the U.S. Food and Drug Administration granted regular approvals to dabrafenib and trametinib (TAFINLAR® and MEKINIST®, Novartis Pharmaceuticals Inc.) administered in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. These are the first FDA approvals specifically for treatment of patients with BRAF V600E mutation-positive metastatic NSCLC.The FDA today also approved the Oncomine™ Dx Target Test (Thermo Fisher Scientific), a next generation sequencing (NGS) test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib. This is the first NGS oncology panel test approved by the FDA for multiple companion diagnostic indications.The approvals are based on Study BRF113928 (NCT01336634), an international, multicenter, three-cohort, non-randomized, non-comparative, open-label, trial in patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. Ninety-three patients were treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily). Of these 93 patients, 36 had received no prior systemic therapy for metastatic NSCLC and 57 received at least one platinum-based chemotherapy regimen with demonstrated disease progression. Seventy-eight patients with previously treated BRAF V600E mutation-positive NSCLC received single-agent dabrafenib.In the previously treated group, the overall response rate (ORR) for the combination based on independent radiology review committee assessment per RECIST 1.1 was 63% (95% CI: 49%, 76%) with a median duration of response (DoR) of 12.6 months (95% CI: 5.8, not estimable [NE]). In the treatment-naive group, the ORR for the combination was 61% (95% CI: 44%, 77%) and median DoR was not estimable (95% CI: 6.9, NE); however, 59% of responders had response durations greater than six months. The ORR for patients who received single-agent dabrafenib was 27% (95% CI: 18%, 38%) and the median DoR was 9.9 months.The incidence and severity of adverse reactions occurring in patients with NSCLC were generally similar to those reported in prior approvals for patients with melanoma. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common Grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The majority of laboratory abnormalities were Grade 1-2. The most common (≥5%) Grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively.The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily. The presence of BRAF V600E mutation in tumor specimen should be confirmed by an FDA-approved test prior to initiation of therapy.Full prescribing information for dabrafenibFull prescribing information for trametinibFDA granted Breakthrough Therapy Designation in 2015 for the combination of dabrafenib and trametinib for the treatment of patients with advanced and metastatic BRAF V600E mutation-positive NSCLC who received at least one prior line of platinum-containing therapy. Orphan Drug Designation was granted in 2014 to dabrafenib as a single agent for the treatment of patients with BRAF mutation positive NSLC and in 2015 combination with trametinib. A description of FDA expedited programs is available in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received. HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection."The approval of Haegarda provides a new treatment option for adolescents and adults with Hereditary Angioedema," said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research. "The subcutaneous formulation allows patients to administer the product at home to help prevent attacks."Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks.The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.The FDA granted approval of Haegarda to CSL Behring LLC.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.