On June 24, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) reported new efficacy and safety data from the ongoing Phase 1/2 dose-escalation and expansion study evaluating investigational oral IDHIFA (enasidenib) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-2 (IDH2) mutation (Press release, Agios Pharmaceuticals, JUN 24, 2017, View Source [SID1234519654]). IDHIFA, being developed in collaboration with Celgene Corporation, is an investigational first-in-class, oral, targeted inhibitor of the mutant IDH2 enzyme. Data in an oral session at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) demonstrated an overall response rate (ORR) of 37 percent, including a complete response (CR) rate of 20.1 percent in 214 patients with R/R AML who received enasidenib at 100 mg daily, which was the recommended starting dose in the expansion phases of the trial.

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"With data from an additional 105 patients and the first look at data from the Phase 2 expansion in R/R AML patients treated at the recommended Phase 2 starting dose of 100 mg once daily, these updated results underscore the consistency and durability of response for enasidenib as a potential first-in-class therapy for patients with relapsed or refractory AML and an IDH2 mutation," said Chris Bowden, M.D., chief medical officer of Agios. "We are working with our partner Celgene to quickly bring this oral, targeted therapy to patients with limited treatment options."

As of October 14, 2016, a total of 345 patients with advanced hematologic malignances and an IDH2 mutation were enrolled into the Phase 1/2 study, which includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion. In the study, 281 patients had R/R AML and 214 of the R/R AML patients were treated at 100 mg daily. This is the first presentation of data from the Phase 2 expansion. Data reported include patients receiving enasidenib at total daily doses ranging from 50 mg to 650 mg in the dose-escalation arm and 100 mg daily in the Phase 1 and Phase 2 expansion arms. A maximum tolerated dose was not reached. The median age of the R/R AML patients enrolled in the study is 68 (ranging from 19-100). Patients with R/R AML received a median of two prior lines of therapy (ranging from one to 14).

The overall safety profile observed for enasidenib was consistent with previously reported data. The most common treatment-emergent AEs were nausea (48%), diarrhea (41%), fatigue (41%), decreased appetite (34%) and blood bilirubin increased (33%). For all patients in the study, 26.1 percent had treatment-related serious adverse events (SAEs), notably IDH differentiation syndrome (7%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%).

Data from 214 of the R/R AML patients with an IDH2 mutation who were treated at the recommended Phase 2 starting dose of 100 mg daily demonstrated a 37 percent (79 of 214 patients) overall response rate, which was the primary endpoint of the study. Further, the complete response rate was 20.1 percent (43 of 214 patients). Median duration of response was 5.6 months [95% CI 4.6, 7.4] for all patients who responded and 8.8 months [95% CI 5.6, NR] for patients who achieved a CR. Median time to first response was 1.9 months (0.5-11.1) and median time to CR was 3.7 months (0.7-11.2). At the time of the data cut-off, median overall survival (OS) as observed in the study was 8.3 months [95% CI 7.5,9.4]. Additional results including qualitative improvement in response over time, improvement in hematological parameters over time, OS for patients achieving a CR and transfusion independence were also reported.

"Enasidenib’s unique profile as a targeted differentiation agent distinguishes it in a field that has seen few new medicines in decades," said Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "Even in the absence of CR, some patients became transfusion independent with enasidenib treatment, suggesting a proportion of patients on study are deriving clinical benefit from an oral, single agent therapy in the relapsed/refractory setting."

Clinical Development

Enasidenib continues to be studied in the following ongoing clinical trials:

Phase III IDHENTIFY study evaluating the efficacy and safety of enasidenib versus conventional care regimens in older patients with R/R AML with an IDH2 mutation (NCT02577406)
Phase 1b study of either enasidenib or ivosidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML (NCT02632708)
Phase 1/2 study of either enasidenib or ivosidenib in combination with azacitidine in newly diagnosed AML (NCT02677922)
The New Drug Application (NDA) for IDHIFA is currently under Priority Review with the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory AML with an IDH2 mutation. The NDA has been given a Prescription Drug User Fee Act (PDUFA) action date of August 30, 2017.

Ivosidenib (AG-120, wholly owned by Agios) is an investigational, oral, targeted inhibitor of the mutant IDH1 enzyme.

About AG221-C-001
Study AG221-C-001 includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion.

The Phase 1 dose escalation study was designed to determine the maximum tolerated dose and recommended Phase 2 dose, and to evaluate efficacy and safety of enasidenib (AG-221/CC-90007) in subjects with advanced hematologic malignancies with an IDH2 mutation. The Part 1 expansion further evaluated the safety, tolerability, and efficacy of enasidenib in subjects with R/R AML, untreated AML, myelodysplastic syndrome or other advanced hematologic malignancies with an IDH2 mutation. Based on the clinical activity observed in R/R AML subjects, the Phase 2 expansion was designed to assess efficacy of enasidenib at recommended 100 mg daily dose and to further evaluate safety in subjects with R/R AML and with IDH2 mutation. The study was not designed or statistically powered to reach a conclusion on OS. A phase 3 randomized controlled trial with OS as a primary endpoint has been initiated.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH2 mutations are present in about 8 to 19 percent of AML cases.

On June 23, 2017 Stemline Therapeutics, Inc. (Nasdaq:STML), a clinical-stage biopharmaceutical company developing novel therapeutics for difficult to treat cancers, reported the presentation today of updated clinical data from Stages 1 and 2 of the ongoing SL-401 pivotal Phase 2 clinical trial in blastic plasmacytoid dendritic cell neoplasm (BPDCN), along with safety data from the entire SL-401 clinical program, at the 22ndCongress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held in Madrid, Spain (Press release, Stemline Therapeutics, JUN 23, 2017, View Source [SID1234519681]).

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A summary of the presentation is as follows:

Stages 1 and 2 enrolled 32 BPDCN patients, of which 19 were first-line and 13 patients were relapsed/refractory.
Median age was 72 years (range 29-85 years).
The most common treatment-related adverse events (TRAEs) with SL-401 across BPDCN and other indications (n=134 patients) were hypoalbuminemia (43%), transaminitis (43%), and thrombocytopenia (26%), by investigator-assessment. TRAEs included capillary leak syndrome (18%), of which 3 cases were grade 5 (2.2%), as previously reported.
The overall response rate (ORR) for Stage 1 and 2 BPDCN patients (n=32) was 84%, with a complete response (CR) rate of 59%, by investigator-assessment.
Eight BPDCN patients who achieved remission on SL-401 (for ~2.5 to ~6 months duration) were subsequently bridged to stem cell transplant, including one relapsed/refractory patient.
In first-line BPDCN patients treated at 12 ug/kg/day (n=16), the median overall survival (OS) has not been reached.
The full presentation will be available on the Stemline website (www.stemline.com), under the "Scientific Presentations" tab, following delivery of today’s presentation at EHA (Free EHA Whitepaper).

Stage 3 is fully enrolled (n=13 first-line BPDCN patients) and data will be reported, along with further updated Stage 1 and 2 data, in 2H17. Depending on the results of this ongoing Phase 2 trial, the largest prospective study ever conducted in this indication (n=45 patients), we intend to file a BLA for SL-401 in BPDCN in 4Q17/1Q18.

On June 23, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported preclinical data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist currently in a Phase 2 clinical trial in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 22nd Congress in Madrid (Press release, Syros Pharmaceuticals, JUN 23, 2017, View Source [SID1234519680]).

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"The data presented at EHA (Free EHA Whitepaper) support our belief that SY-1425 may provide a meaningful clinical benefit as both a monotherapy and a combination therapy for defined subsets of AML and MDS patients and serve as the foundation for our rational combination strategy for SY-1425," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "We are committed to broadly exploring the potential of SY-1425 through our Phase 2 clinical trial, which explores the safety and efficacy of SY-1425 as a single agent and in combination with a standard-of-care therapy, as well as through future clinical investigation of SY-1425 in combination with other targeted agents, including anti-CD38 therapies. We look forward to sharing initial clinical data from the ongoing Phase 2 trial this fall."

SY-1425 in Combination with Hypomethylating AML and MDS Therapies
Syros presented data showing that hypomethylating agents (HMAs) increase the activity of SY-1425 in in vitro and in vivo models of AML with high levels of RARA expression. HMAs including azacitidine, a therapy used as a standard-of-care in AML and MDS, prime the DNA for gene activation, thus enhancing SY-1425’s gene activation and differentiation properties. In patient-derived xenograft (PDX) models of AML with high RARA expression, SY-1425 in combination with azacitidine shows:

Greater clearance of tumor cells in bone marrow and other tissues, compared to either azacitidine or SY-1425 alone.
Greater duration of response, compared to either azacitidine or SY-1425 alone.
Based on these data, Syros expanded its ongoing Phase 2 clinical trial to include an arm assessing the safety and efficacy of SY-1425 in combination with azacitidine in newly diagnosed AML patients 60 years or older who are not suitable candidates for standard chemotherapy and who are positive for the Company’s biomarkers of high expression of the RARA-pathway associated genes RARA and IRF8. The treatment regimen for patients in the combination arm uses full doses of both agents and is consistent with the one identified in preclinical studies to maximize tumor suppression and tolerability.

SY-1425 Sensitizes RARA-High AML Cells to Anti-CD38 Therapeutic Antibody
Syros presented data demonstrating that SY-1425 induces the cell surface protein CD38 in AML cells from patient samples with high levels of RARA expression. By inducing CD38, SY-1425 sensitizes the cells to daratumumab, an anti-CD38 monoclonal antibody that targets CD38-positive tumor cells for immune cell-mediated killing. Daratumumab is approved to treat various multiple myeloma (MM) populations. The preclinical studies show SY-1425:

Induces levels of CD38 expression in RARA-high AML cells comparable to those in MM cells that are known to be responsive to daratumumab; notably, AML cells do not normally express high levels of CD38.
Triggers robust activation of natural killer cells when combined with daratumumab in RARA-high AML cells.
Leads to robust immune cell-mediated tumor cell death in RARA-high AML cells when combined with daratumumab.
Induces higher levels of CD38 expression in vivo than ATRA, a non-selective agonist of the retinoic acid receptor family.
Based on these data, Syros believes SY-1425 in combination with an anti-CD38 antibody represents a potentially promising immunotherapy approach for defined subsets of AML patients and plans to pursue clinical development of the combination in these patients.

Mechanism of Action of SY-1425
Syros presented data showing that SY-1425 regulates genes known to be associated with the proliferation of AML cells and normal myeloid differentiation. Using its proprietary gene control platform to analyze regulatory regions of the genome, Syros scientists identified changes in enhancer landscapes, gene expression and transcription factor distribution in AML cells treated with SY-1425. These changes show that SY-1425 pushes AML cells with high expression of the RARA and IRF8 genes into a more differentiated state. RARA and IRF8 code for transcription factors that work together to induce differentiation of blood and bone marrow cells and reduce proliferation of blast cells. The data show that:

In AML cells with high RARA and IRF8 expression, treatment with SY-1425 triggers a differentiation program in which a critical set of transcription factors bind to various sites on the genome to either activate or inactivate enhancers. In doing so, these transcription factors create an enhancer profile in RARA-high and IRF8-high AML cells that is similar to the enhancer profiles of normal differentiated cell types.
In RARA-high and IRF8-high AML cells treated with SY-1425, enhancers that were downregulated are enriched for binding sites for JUN and FOS, which are transcription factors known to drive proliferation, and enhancers that were upregulated are enriched for binding sites for RARα and IRF8, which are transcription factors known to be critical for differentiation.
The ongoing Phase 2 trial of SY-1425 is assessing the safety and efficacy of SY-1425 as both a monotherapy and in combination with azacitidine in subsets of AML and MDS patients who are positive for the Company’s RARA and IRF8 biomarkers. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

On June 23, 2017 Takeda Pharmaceutical Company Limited (TSE: 4502) reported 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) (Free EHA Whitepaper) 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 (Press release, Takeda, JUN 23, 2017, View Source [SID1234519679]). 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.

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"Despite recent progress, multiple myeloma remains a rare, devastating and incurable hematologic cancer. Data being presented at EHA (Free EHA Whitepaper) 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."

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with approximately 114,000 new cases globally per year.

About NINLAROTM (ixazomib) capsules
NINLAROTM (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.

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 in 2014.

The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT; this study is currently enrolling
TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
TOURMALINE-MM5, investigating ixazomib plus dexamethasone vs. pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide
TOURMALINE-MM6, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with multiple myeloma transitioning from a bortezomib-based triplet induction regimen
In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLAROTM (ixazomib): 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.

For European Union Summary of Product Characteristics: View Source

For US Prescribing Information: View Source

For Canada Product Monograph: View Source

About Takeda