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bluebird bio and Celgene Corporation Present Initial Data from Ongoing Phase 1 Clinical Study of Next-Generation Anti-BCMA CAR T Cell Therapy bb21217 in Patients with Relapsed/Refractory Multiple Myeloma at ASH Annual Meeting

On December 2, 2018 bluebird bio, Inc. (Nasdaq:BLUE) and Celgene Corporation (NASDAQ:CELG) reported initial data from the ongoing Phase 1 clinical study of bb21217 (CRB-402), an investigational next-generation anti-BCMA CAR T cell therapy being studied in patients with relapsed/refractory multiple myeloma (Press release, bluebird bio, DEC 2, 2018, View Source [SID1234531796]). The data were presented by Nina Shah, M.D., University of California, San Francisco, as an oral presentation at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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bb21217 is an investigational anti-BCMA CAR T cell therapy that uses the bb2121 chimeric antigen receptor (CAR) molecule with a manufacturing process designed to improve CAR T cell functional persistence. bb21217 has exhibited improved functional persistence and increased anti-tumor activity in preclinical animal studies.

"Anti-BCMA CAR T therapy with bb2121 has shown clinical responses in a substantial proportion of patients with relapsed/refractory multiple myeloma. With the bb21217 program we are pursuing an approach intended to improve the in vivo persistence of functional CAR T cells with the hope that this provides a more durable benefit for patients," said David Davidson, M.D., chief medical officer, bluebird bio. "The safety results and promising response rate in the initial dose cohort, as well as the observation of detectable CAR T cells in the first three patients with follow up to the month 6 study visit and beyond, support advancing to a higher dose to further characterize the potential of bb21217 as a treatment option for patients with relapsed/refractory multiple myeloma."

"The initial results of bb21217 are encouraging in terms of the adverse event profile, as well as the instances of ongoing, deep responses shown in these heavily pre-treated patients," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "We look forward to further results from this next-generation agent in this area of continued medical need."

bb21217 is being evaluated in the ongoing dose escalation part of the Phase 1 CRB-402 study in adults with relapsed/refractory multiple myeloma who have received at least three prior treatments, including a proteasome inhibitor and immunomodulatory agent (or are double refractory).

"Patients with multiple myeloma often undergo multiple cycles of treatment because there is currently no known cure for this aggressive cancer," said Nina Shah, M.D., University of California, San Francisco, San Francisco, Calif. "The early clinical data from this Phase 1 study show manageable safety findings, and most patients in this initial group achieved an objective response. Future study is needed to assess durability of response at the current dose, as well as safety and activity at higher doses of bb21217."

Patients included in these preliminary Phase 1 results (n=12) had a median age of 63 years (min; max: 44 – 69 years). They had received a median of seven prior lines of therapy (min; max: 4 – 17 lines) and 83 percent of patients received a prior autologous stem cell transplant. Fifty-eight percent (n=7) of patients had high-risk cytogenetics.

All treated patients received a dose of 150 x 106 CAR+ T cells. The median follow-up after bb21217 infusion was 26 weeks (min; max: 4 – 51 weeks). The primary endpoint is safety measured by frequency of adverse events (AEs), dose limiting toxicity (DLT) and changes in laboratory results. Secondary endpoints include disease specific response criteria based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma.

Safety Results

The safety results, reported as of the data extract of October 18, 2018, were manageable and consistent with known toxicities of CAR T therapies.

Eight of the 12 patients (67 percent) treated with bb21217 developed cytokine release syndrome (CRS); four Grade 1, three Grade 2, one Grade 3 case and no Grade 4 cases. Additionally, three of the 12 patients (25 percent) experienced neurotoxicity, including one Grade 1, one Grade 2 and one Grade 4 case. All CRS and neurotoxicity events resolved and no deaths occurred on study. Following the Grade 4 neurotoxicity event, patients were divided into two groups based on tumor burden and dosing continued at 150 x 106 CAR+ T cells for a total of 12 subjects treated at this dose level.

Efficacy Results

Of the 12 patients who received treatment with bb21217, 83 percent (n=10) achieved an objective clinical response by IMWG criteria. As of the data extract, responses are ongoing in nine of 10 patients, including three with a complete response (CR) or stringent complete response (sCR), two with a very good partial response (VGPR) and four with a partial response (PR).

Evidence of myeloma in the bone marrow, known as minimal residual disease (MRD), was undetectable at a minimum of two time points, by next-generation sequencing at a sensitivity level of 10-5 or better in all responders who had evaluable bone marrow samples (n=4) with some as early as day 15.

CAR+ T cell expansion was observed during the first 30 days following treatment in all evaluable patients (n=11) with anti-BCMA CAR+T cells showing sustained persistence in all patients (3/3) with six or more months of follow-up.

The ongoing Phase 1 CRB-402 study is assessing a higher dose of 300 x106 CAR+ T cells in both high and low tumor burden cohorts.

About bb21217

bb2121 and bb21217 are bluebird bio’s lead investigational anti-BCMA CAR T therapies being developed in collaboration with Celgene.

Chimeric antigen receptors (CAR) are receptor proteins that have been engineered to give T cells the ability to target a specific protein. bb2121 and bb21217 are designed to recognize and kill plasma cells, notably malignant myeloma cells, that express the B cell maturation antigen (BCMA).

bluebird bio’s clinical development program for bb21217 includes the ongoing Phase 1 CRB-402 two-part (dose escalation and dose expansion), non-randomized, open label study with sites in the United States. For more information visit: clinicaltrials.gov using identifier NCT03274219.

bb21217 is not approved for any indication in any geography.

About Multiple Myeloma

Multiple myeloma is a cancer of certain cells in the blood, called plasma cells. The cause of multiple myeloma is not known, and currently there is no cure. However, there are a number of treatment options available that can lead to remission. For some people with multiple myeloma, remission can last many years. Patients who have already been treated with some available therapies but continue to have progression of their disease have "relapsed" or "refractory" multiple myeloma, meaning their cancer has reoccurred after they have received initial treatments. Patients with relapsed/refractory multiple myeloma have fewer treatment options.

Pfizer Presents Positive 26-Week Data For PF-05280586, A Potential Biosimilar To Rituximab, At The American Society Of Hematology Annual Meeting

On December 2, 2018 Pfizer Inc. (NYSE:PFE) reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting that the REFLECTIONS B328-06 study, a comparative safety and efficacy study of PF-05280586 versus Rituxan/MabThera (rituximab-EU)i, met its primary endpoint of overall response rate (ORR) at Week 26 of the 52-week study.1

"It is encouraging to see new data supporting a potential rituximab Biosimilar. If approved this may help provide a more cost-effective treatment option and expand access for patients and physicians," said Dr. Jeff Sharman, medical director, US Oncology Hematology Research. "The data presented today will help us understand the nuances of the medicine without the confounding influence of additional concurrent treatments."

26-week data from the ongoing 52-week REFLECTIONS B328-06 study (n=394) demonstrated no clinically meaningful differences in efficacy, in terms of ORR at Week 26, between PF-05280586 and MabThera, for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma (LTB-FL).1 ORR at Week 26 was 75.5% (PF-05280586) vs 70.7% (rituximab-EU), and was within the pre-specified equivalence margin. ORR is defined as the percentage of patients achieving complete response (CR) or partial response (PR), based on central review. Additionally, estimated rates of one-year progression-free survival were similar across groups (76.4% vs. 81.2% in the PF-05280586 and MabThera groups, respectively).1 The results also show that PF-05280586 had a similar safety profile to MabThera.1

"With a patient centered approach and over a decade of experience globally,2 Pfizer remains dedicated to developing and delivering high quality biosimilars with similar efficacy and safety profiles to originator medicines that help have a meaningful impact on people living with various conditions including cancer," said Joe McClellan, vice president, Biosimilars Development at Pfizer. "We have also been a committed global partner to the oncology community for almost 20 years, and the continued growth of our oncology and supportive care presence, through both novel therapies and biosimilars, means we are able to provide patients, physicians and healthcare systems with a wider range of treatment options."

PF-05280586 has been accepted for review by the FDA, the BsUFA goal date for a decision by the FDA is in second-quarter 2019. Pfizer is also working towards making PF-05280586 available for patients in Europe. Further results on the safety and efficacy from this ongoing 52-week study in LTB-FL are expected to be presented next year.

About PF-05280586

PF-05280586 is a monoclonal antibody (mAb) that is in development as a potential biosimilar to Rituxan/MabThera. Rituxan/MabThera is indicated for the treatment of patients with certain types of CD20-positive non-Hodgkin lymphoma; CD20-positive chronic lymphocytic leukemia; rheumatoid arthritis; granulomatosis with polyangiitis and microscopic polyangiitis; and other region-specific indications.3, 4

PF-05280586 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities.

About the REFLECTIONS B328-06 Study

REFLECTIONS B328-06 is a randomized, 52-week double-blind clinical trial evaluating the efficacy, safety and immunogenicity, pharmacokinetics and pharmodynamics of PF-05280586 versus MabThera for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma.

More information about the PF-05280586 REFLECTIONS B32806 study can be found at www.clinicaltrials.gov.

Syros Announces Promising Clinical Data from Ongoing Phase 2 Trial of SY-1425 in Genomically Defined AML and MDS Patients at ASH Annual Meeting

On December 2, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported initial clinical data from cohorts in its ongoing Phase 2 trial evaluating SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacitidine and with daratumumab in genomically defined patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS) (Press release, Syros Pharmaceuticals, DEC 2, 2018, View Source [SID1234531794]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

"AML and MDS are complex diseases, and we need therapies that can be used in combination to help patients live longer and with a better quality of life," said Rachel J. Cook, M.D., M.S., Assistant Professor of Medicine and Site Director for Acute Leukemia at the Knight Cancer Institute, Oregon Health and Science University and a clinical investigator in the Phase 2 study of SY-1425. "These data provide early clinical evidence that SY-1425 may be a meaningful treatment option for defined subsets of AML and MDS patients that is generally well-tolerated in combination with other therapies. I look forward to continuing to investigate SY-1425 to fully understand its potential to benefit patients."

"These initial combination data from our ongoing Phase 2 trial of SY-1425 are promising," said David A. Roth, M.D., Syros Chief Medical Officer. "SY-1425 in combination with azacitidine showed both a high response rate and rapid onset of clinical responses in AML patients selected with our RARA or IRF8 biomarkers that we have not seen to date in the biomarker-negative cohort. The combination was generally well-tolerated with no evidence of increased toxicities beyond what would be expected with each agent alone, including myelosuppression that can sometimes be seen when combining drugs to treat leukemia. These data speak to the combination potential of SY-1425 as well as to the potential of our platform to identify patients most likely to respond to gene control medicines. We look forward to further characterizing the clinical activity of SY-1425 in combination with azacitidine as we continue to enroll and follow patients in the trial."

SY-1425 in Combination with Azacitidine
The ongoing Phase 2 trial cohort is evaluating the safety and efficacy of SY-1425 in combination with azacitidine, a standard-of-care hypomethylating agent, in RARA or IRF8 biomarker-positive patients with newly diagnosed AML who are not suitable candidates for standard chemotherapy. The trial also includes a cohort evaluating SY-1425 in combination with azacitidine in biomarker-negative newly diagnosed, unfit AML patients, with the aim of supporting the development of a commercial companion diagnostic. Patients in these cohorts were treated with azacitidine administered at standard daily doses of 75 mg/m2 intravenously or subcutaneously for seven days, followed by SY-1425 administered at 6 mg/m2 orally divided in two daily doses for the remainder of the 28-day cycle.

As of Oct. 29, 2018, 11 biomarker-positive and eight biomarker-negative patients had been enrolled in the trial. Of the biomarker-positive patients, 10 were evaluable for safety and eight were also evaluable for clinical responses. Of the biomarker-negative patients, seven were evaluable for safety and six were also evaluable for clinical responses. The median age of the biomarker-positive patients was 76 and the median age of the biomarker-negative patients was 78, with more than half the patients in both cohorts having poor risk cytogenetics. Target enrollment in both the biomarker-positive cohort and the biomarker-negative cohort is 25, and Syros continues to enroll and follow patients.

Initial Safety Data

SY-1425 in combination with azacitidine was generally well-tolerated with no evidence of increased toxicities.
Adverse events (AEs) were consistent with what has been previously seen with SY-1425 or azacitidine as single agents in AML:
Across all grades and causalities, the most commonly reported AEs were decreased appetite (41%), fatigue (35%) and hypertriglyceridemia (35%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (24%), thrombocytopenia (24%), neutropenia (12%) and fatigue (12%).
Initial Clinical Activity Data

The complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group (IWG) criteria, was 50% in the biomarker-positive cohort.
The overall response rate (ORR), using IWG criteria, was 63%, consisting of:
Three CRs, including one molecular CR.
One CRi.
One morphologic leukemia-free state (MLFS).
Duration of these IWG responses ranged from 29 to 337 days, with four of the five responding patients remaining on treatment as of the data cutoff.
Most of the initial responses were seen at the end of the first treatment cycle.
These data compare favorably to single-agent azacitidine, which shows response rates of 18-29% in newly diagnosed unfit AML patients1 with initial responses generally occurring after four cycles of treatment in most patients who respond2.
In the cohort of biomarker-negative patients, the ORR was 17%, with one of the six response-evaluable patients achieving a cytogenetic CR. While data from this cohort are less mature, the difference in the observed ORR supports the potential predictive value of the RARA and IRF8 biomarkers for identifying patients most likely to respond to SY-1425.
SY-1425 in Combination with Daratumumab
The ongoing Phase 2 trial is characterizing CD38 induction with SY-1425 and evaluating the safety and efficacy of SY-1425 in combination with daratumumab in a pilot cohort of 12 RARA or IRF8 biomarker-positive patients with relapsed or refractory AML or higher-risk MDS. Daratumumab is an anti-CD38 targeted therapy that is approved to treat multiple myeloma. While CD38 is normally expressed at high levels on multiple myeloma cells, AML cells have low CD38 expression. In preclinical studies, SY-1425 induced CD38 expression in AML cells, sensitizing them to treatment with daratumumab. Patients in this cohort were treated with SY-1425 as a single agent administered at 6 mg/m2 orally, divided in two daily doses, for seven days, after which daratumumab was added and administered at 16 mg/kg intravenously weekly for eight doses, then biweekly for eight doses and every four weeks thereafter.

As of Oct. 29, 2018, nine patients had been enrolled in this cohort. All nine were evaluable for safety and CD38 induction, and six were also evaluable for clinical responses. The median age of these patients was 68, with more than half having poor risk cytogenetics. Syros continues to enroll patients to complete the pilot.

Initial Safety Data

SY-1425 in combination with daratumumab was generally well-tolerated with no evidence of increased toxicities.
AEs were consistent with what has been previously seen with single-agent SY-1425 in AML and MDS patients or single-agent daratumumab in multiple myeloma patients:
Across all grades and causalities, the most commonly reported AEs were febrile neutropenia (67%), anemia (44%), nausea (44%), vomiting (44%) and infusion-related reaction (44%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (67%) and anemia (44%).
Initial CD38 Induction and Clinical Activity Data

Eight of the nine patients had increased CD38 expression in myeloid blast cells, with a median 1.57-fold induction as measured by mean fluorescence intensity (MFI), after seven days of treatment with SY-1425.
CD38 expression increased in only two of these patients to levels exceeding those of a multiple myeloma cell line control:
One had an MLFS response.
The other progressed without a clinical response.
The initial clinical data on both combinations presented at the ASH (Free ASH Whitepaper) meeting is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Additional details about the Phase 2 trial of SY-1425 can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

Harpoon Therapeutics Presents Preclinical Data Supporting Development of HPN217, a New BCMA-Targeting TriTAC, at the 2018 American Society of Hematology (ASH) Annual Meeting

On December 2, 2018 Harpoon Therapeutics, Inc. ("Harpoon"), a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients with cancer and other diseases, reported its preclinical data supporting the development of HPN217, a new compound targeting B cell maturation antigen (BCMA) (Press release, Harpoon Therapeutics, DEC 2, 2018, View Source [SID1234531793]). Generated from Harpoon’s Tri-specific T cell Activating Construct ("TriTAC") platform, HPN217 is engineered to re-direct a patient’s own T cells to kill BCMA-positive cancer cells. HPN217 is Harpoon’s first TriTAC designed for the treatment of hematologic cancers, such as multiple myeloma. Data were presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, held December 1-4.

"We believe the characteristics of HPN217 – including its structure as a single flexible polypeptide, low molecular weight, and in vitro and in vivo stability with half-life extension – offer advantages over conventional bispecific antibodies targeting BCMA," said Che-Leung Law, PhD, Harpoon’s Vice President, Translational Medicine. "Supported by preclinical data showing tumor growth inhibition in models of multiple myeloma and mantle cell lymphoma, HPN217 is expected to enter a Phase 1 clinical trial for multiple myeloma in 2019."

"Recent clinical data has validated the importance of BCMA as a drug target for T cells in the treatment of multiple myeloma," said Gerald McMahon, PhD, President and Chief Executive Officer of Harpoon. "The introduction of our third TriTAC compound demonstrates the ability of our technology platform to generate new product candidates."

The poster entitled "Preclinical and Nonclinical Characterization of HPN217: A Tri-specific T cell Activating Construct (TriTAC) Targeting B Cell Maturation Antigen (BCMA) for the Treatment of Multiple Myeloma" can be found on the Publications page of Harpoon’s website.

Key information presented includes:

Design of HPN217 TriTAC

The design of HPN217 is based on Harpoon’s novel TriTAC platform. It is a single polypeptide consisting of three domains that recognize human BCMA for myeloma cell targeting, serum albumin for half-life extension, and CD3ε for T cell engagement.

Proof-of-concept In Vitro and In Vivo Preclinical Studies

HPN217 demonstrated BCMA- and T cell-dependent antitumor activity in tissue culture and in xenografts modeling multiple myeloma and lymphoma. Effective preclinical antitumor activities could be observed in models with BCMA receptor copy number as low as approximately 2,200 per cell.

Pharmacokinetics Properties and In Vivo Stability in Nonclinical Studies

In animal studies, HPN217 demonstrated a circulating terminal half-life of 70-84 hours. Importantly, HPN217 remained functionally intact after one week in circulation.

About Multiple Myeloma

Multiple myeloma is the second most prevalent blood cancer after Non-Hodgkin’s lymphoma. There are approximately 229,000 people living with myeloma worldwide, with 114,000 new cases diagnosed and 87,000 deaths each year. The American Cancer Society estimates that approximately 30,700 new cases will be diagnosed and approximately 12,770 deaths are expected to occur from multiple myeloma in the United States in 2018. Despite advances in the treatment of multiple myeloma over the past decade, there remains a significant unmet need.

Takeda to Present Positive Data from TOURMALINE-MM3, First Pivotal Phase 3 Placebo Controlled Trial Evaluating Proteasome Inhibitor Treatment in Maintenance Setting

On December 2, 2018 Takeda Pharmaceutical Company Limited (TSE:4502) reported that data from the Phase 3 randomized, TOURMALINE-MM3 study evaluating the effect of single-agent oral NINLARO (ixazomib) as a maintenance therapy in adult patients diagnosed with multiple myeloma who previously responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT) will be presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 2, 2018, View Source [SID1234531792]). NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.

The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO compared with placebo. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.

"A growing body of evidence has shown that maintenance therapy in multiple myeloma may prolong the duration of disease control," said Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. "As currently approved options are limited and do not include a proteasome inhibitor, there is a need for additional maintenance treatments that can sustain response and have a tolerable safety profile. Data from the TOURMALINE-MM3 clinical trial supports single-agent NINLARO as a potential oral proteasome inhibitor maintenance therapy option post-ASCT."

"The positive results from this pivotal study – the first and only Phase 3 placebo controlled study evaluating a proteasome inhibitor in this setting – support NINLARO as a potential maintenance therapy for patients who have undergone a stem cell transplant," said Jesús Gómez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is crucial that we continue to support patients by developing treatment options aimed to maintain or deepen response and delay disease progression. According to the findings, patients treated with NINLARO had improved progression-free survival over those in the control arm, which corresponds to a reduced risk of progression or death of nearly one-third."

"As a result of continued research, the multiple myeloma treatment landscape is constantly evolving. While this is encouraging news for the multiple myeloma community, there is still work to be done to further our goal of addressing the unmet needs of patients," said Brian GM Durie, M.D., Chairman of the Board, International Myeloma Foundation. "To that end, the development of additional safe and effective maintenance therapies is essential."

Maintenance Therapy With the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients With Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial Sunday, December 2, 2018, 7:30 – 9:00 a.m., Marriott Marquis San Diego Marina, Grand Ballroom 7

Key findings, which will be presented by Dr. Meletios Dimopoulos, include:

The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in PFS versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; 95% CI: 0.582, 0.890; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO.
Per IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months in the placebo arm.
Conversion from documented minimal residual disease (MRD) positivity at study entry to MRD negativity occurred at a higher rate among patients treated with NINLARO compared with placebo (12 percent versus 7 percent, respectively).
NINLARO maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95 percent CI: 1.10, 1.80; p=0.0042).
PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625).
Secondary endpoints including median PFS2 and OS have not yet been reached in either arm. Median follow-up was 31 months.
Global Quality of Life scores (EORTC QLQ-C30) for patients on NINLARO were similar to those on placebo.
The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.
Discontinuation of treatment due to adverse events (AE) was low, at 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
Grade ≥3 AEs were experienced by 42 percent of patients receiving NINLARO versus 26 percent receiving placebo.
Patients in the NINLARO arm experienced serious AEs at a rate of 27 percent versus 20 percent in the placebo arm.
Common grade ≥3 AEs in both the NINLARO and placebo arms included infections (15 and 8 percent, respectively) including pneumonia (6 and 4 percent, respectively), gastrointestinal disorders (6 and 1 percent, respectively), neutropenia (5 and 3 percent, respectively) and thrombocytopenia (5 and <1 percent, respectively).
On the NINLARO arm, peripheral neuropathy events were observed in 19 percent of patients versus 15 percent on the placebo arm. In the NINLARO arm, <1 percent of peripheral neuropathy events were Grade 3 compared with 0 in the placebo arm.
The rate of second primary malignancies was 3 percent in both arms.
One patient in the NINLARO arm died on study while no patients in the placebo arm did. The single study death was considered to be treatment-related and was due to pneumonia.
About the TOURMALINE-MM3 Trial

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study of 656 patients, designed to determine the effect of NINLARO (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with multiple myeloma who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT). The primary endpoint is progression-free survival (PFS). A key secondary endpoint includes overall survival (OS). For additional information: View Source

About NINLARO (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review and by the European Commission in November 2016. In the U.S. and Europe, NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO has received marketing authorization by regulatory authorities in more than 60 countries.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014. The Japanese Ministry of Health, Labour and Welfare granted Orphan Drug designation to ixazomib in 2016.

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of six ongoing pivotal trials – five, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
TOURMALINE-AL1, investigating ixazomib plus dexamethasone versus physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
TOURMALINE-MM5, investigating ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide; this study is currently enrolling
For more information about actively enrolling Phase 3 studies please visit: View Source

In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLARO (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS

The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.