On November 6, 2019 ALX Oncology, a clinical-stage immuno-oncology company developing therapies to block the CD47 checkpoint mechanism, reported that it will present clinical and pharmacodynamic biomarker data from the solid tumor combination cohorts of the ongoing ALX148 Phase 1 clinical program at the SITC (Free SITC Whitepaper) 34th Annual Meeting [Abstract P449] (Press release, ALX Oncology, NOV 6, 2019, View Source [SID1234550524]).

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As of September 23, 2019, eighty-two patients with advanced malignancies were administered ALX148 in combination with standard regimens of either trastuzumab (n=30) or pembrolizumab (n=52). Objective responses were observed in expansion cohorts for response-evaluable patients with gastric/gastroesophageal junction cancer (G/GEJ) and squamous cell carcinoma of the head and neck (HNSCC). A summary of results is described below.

Patients with HER2 positive G/GEJ (n=19) whose tumors had progressed on prior systemic therapy, including HER2-targeted therapy, demonstrated an objective response rate (ORR) of 21% and a disease control rate (DCR) of 26%.
Patients with HNSCC (n=20) whose tumors had progressed on prior platinum therapy, demonstrated an ORR of 20% and a DCR of 30%. In checkpoint inhibitor-naïve subjects (n=10), an ORR of 40% and a DCR of 40% were observed.
ALX148 was well tolerated with no maximum tolerated dose reached. Treatment-related adverse events were mostly of low grade and frequency.

Complete CD47 target occupancy was observed throughout the dosing interval with no impact on circulating immune cell populations following ALX148 combination treatments.
Immunohistochemistry analysis using paired pre- and on-study tumor biopsies showed a statistically significant increase in intratumoral macrophages in pembrolizumab and trastuzumab combinations, and an increase in intratumoral CD8+ cells in combination with pembrolizumab.

RNA expression analysis from paired tumor biopsies suggest increased dendritic cells, cytotoxic cells, as well as gene signatures associated with antigen presentation, myeloid cell activity and tumor inflammation following ALX148 in combination with pembrolizumab.

"These exciting clinical responses and pharmacodynamic changes within the tumor microenvironment observed with ALX148 combinations support our hypothesis that blocking CD47 with an Fc-inactive molecule can enhance the anti-cancer innate and adaptive immune response in patients with advanced solid tumor malignancies," said Jaume Pons, Ph.D., President and Chief Executive Officer of ALX Oncology. "ALX148 as a myeloid checkpoint inhibitor has the potential to become a new cornerstone of immune therapy. We continue to advance ALX148 development in populations in need of novel treatments."

On November 6, 2019 Moderna, Inc., (Nasdaq: MRNA) a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients,reported financial results for the third quarter of 2019 (Press release, Moderna Therapeutics, NOV 6, 2019, View Source [SID1234550523]).

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New updates and recent progress include:

Infectious Diseases

Positive interim results announced from Phase 1 CMV vaccine (mRNA-1647) study; Moderna is advancing mRNA-1647 to a dose-confirmation Phase 2 study in the near term while planning for a pivotal Phase 3 study
First participant dosed in Phase 1b age de-escalation study of hMPV+PIV3 vaccine (mRNA-1653)
FDA granted Fast Track designation for Zika vaccine (mRNA-1893)
Immuno-Oncology

First patient dosed in Phase 2 PCV (mRNA-4157) study in patients with resected melanoma
OX40L (mRNA-2416) Phase 2 expansion cohort in ovarian cancer to focus only on the combination with durvalumab (IMFINZI)
Rare Diseases

Positive interim results announced from Phase 1 chikungunya antibody (mRNA-1944) study; dosing of two additional cohorts planned to begin in the near term
Phase 1/2 MMA (mRNA-3704) study is actively recruiting patients at U.S. sites following a protocol amendment expanding the eligibility criteria to patients 8 years and older
FDA granted Fast Track designation for PA program (mRNA-3927); study start-up is ongoing for the open-label, multi-center Phase 1/2 study of multiple ascending doses of mRNA-3927 in pediatric patients with PA in the U.S.
Research

Moderna announced a multi-year mRNA immunotherapy research collaboration with Harvard University to explore fundamental immunological processes and identify potential therapeutic opportunities
"The positive Phase 1 cytomegalovirus vaccine results announced this quarter represent an important step toward the prevention of congenital CMV infections. These data resulted from investment in our mRNA technology platform, which has now generated six positive infectious disease vaccine clinical readouts. Additionally, the recent positive Phase 1 chikungunya antibody results help de-risk a delivery technology shared by our rare disease programs, further validating our approach into new areas where mRNA medicines have the potential to treat a wide range of diseases," said Stéphane Bancel, Moderna’s chief executive officer. "We ended the quarter with a strong cash balance of $1.34 billion and up to $187 million in additional untapped grant funding, giving us up to $1.5 billion to invest in the Company moving forward. We expect investment levels in 2020 to be approximately $500 million, similar to 2019. We intend to expand our group of biopharmaceutical partners and bring in additional non-dilutive grant and government funding as we advance our development pipeline and create new modalities."

Moderna currently has 21 mRNA development candidates in its portfolio with 13 in clinical studies. Across Moderna’s pipeline, more than 1,400 participants have been enrolled in clinical studies. The Company’s updated pipeline can be found at www.modernatx.com/pipeline. Moderna and collaborators have published more than 40 peer-reviewed papers, including 23 over the last 12 months.

The Company has established a wide range of strategic alliances with leading biopharmaceutical companies, as well as government-sponsored and private organizations focused on global health initiatives. Strategic collaborators contribute their therapeutic expertise, help to validate Moderna’s mRNA platform and have provided a quarter of the Company’s total capital to date. As of September 30, 2019, Moderna had up to $187 million in additional funding available from grants (including amounts not yet committed)1.

Summary of Program Highlights by Modality

Prophylactic vaccines: Moderna is developing vaccines against viral diseases where there is unmet medical need – including complex vaccines with multiple antigens for common diseases, as well as vaccines against epidemic and pandemic threats to global public health.

Cytomegalovirus (CMV) vaccine (mRNA-1647): At the Company’s annual R&D Day, Moderna announced positive data from the three-month interim analysis of safety and immunogenicity of the Phase 1 study of mRNA-1647. Vaccination immunized seronegative participants to levels consistent with or above seropositive titers and boosted baseline titers in seropositive participants. The vaccine was generally well-tolerated; the most common solicited local adverse event was injection site pain, and the most common systemic adverse events were headaches and chills. The next readout from the study will be from a seven-month interim analysis. Moderna also recently announced that it is advancing mRNA-1647 to a dose-confirmation Phase 2 study in the near term. Preparation has also begun for a pivotal Phase 3 study designed to evaluate the efficacy of mRNA-1647 against primary CMV infection. The Phase 2 study will test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle (LNP) used in this Phase 1 study. mRNA-1647 is wholly owned by Moderna.
Human metapneumovirus (hMPV) and parainfluenza type 3 (PIV3) vaccine (mRNA-1653): The first participant in the Phase 1b age de-escalation study of hMPV+PIV3 vaccine (mRNA-1653) has been dosed. Moderna previously announced positive data from the second pre-planned interim analysis of the Phase 1 study of mRNA-1653. mRNA-1653 is wholly owned by Moderna.
Respiratory syncytial virus (RSV) vaccine (mRNA-1172 or V172): The Phase 1 study of mRNA-1172 led by Merck is ongoing.
Zika virus vaccine (mRNA-1893): In August, Moderna announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for mRNA-1893. The Phase 1 study of mRNA-1893 is ongoing.
Presentations of note: Moderna presented data from its prophylactic vaccines at IDWeek, World Vaccine Congress Europe and the International Society of Vaccines Annual Congress, including interim Phase 1 hMPV+PIV3 vaccine (mRNA-1653) data, preclinical Zika vaccine (mRNA-1893) data and interim Phase 1 CMV vaccine (mRNA-1647) data.
Cancer Vaccines: These programs focus on stimulating a patient’s immune system with antigens derived from tumor-specific mutations to enable the immune system to elicit a more effective anti-tumor response.

Personalized cancer vaccine (PCV) (mRNA-4157): The first patients have been dosed in the randomized Phase 2 study investigating a 1 mg dose of mRNA-4157 in combination with Merck’s pembrolizumab (KEYTRUDA), compared to pembrolizumab alone, for the adjuvant treatment of high-risk resected melanoma. The Phase 1 study is ongoing.
PCV (NCI-4650): The National Cancer Institute (NCI) Phase 1 study of NCI-4650 as a monotherapy for patients with advanced metastatic cancers has completed enrollment with five participants. No responses to monotherapy in this heavily pretreated group were observed. NCI-4650 uses Moderna’s mRNA technology but uses a different neoantigen selection process and study design than Moderna’s Phase 1 mRNA-4157 study. Interim results from NCI-4650 were reported at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June and have been submitted for publication.
KRAS vaccine (mRNA-5671 or V941): The Phase 1 open-label, multi-center study to evaluate the safety and tolerability of mRNA-5671 both as a monotherapy and in combination with pembrolizumab, led by Merck, is ongoing.
Intratumoral Immuno-Oncology: These programs aim to drive anti-cancer T cell responses by injecting mRNA therapies directly into tumors.

OX40L (mRNA-2416): Based on available data, the Company has decided to focus its development of mRNA-2416 for the treatment of patients with ovarian cancer in combination with durvalumab (IMFINZI), a PD-L1 inhibitor. The safety cohort of the combination arm (mRNA-2416 and durvalumab) of this Phase 1/2 study is ongoing and will be followed by a Phase 2 expansion cohort in patients with advanced ovarian carcinoma. The Company will not move forward with the mRNA-2416 monotherapy ovarian cancer arm of this study.
OX40L + IL23 + IL36γ (Triplet) (mRNA-2752): The Phase 1 trial evaluating mRNA-2752 as a single agent and in combination with durvalumab in patients with accessible solid tumors and lymphomas is ongoing. mRNA-2752 is an investigational mRNA immuno-oncology therapy that encodes a novel combination of three immunomodulators.
IL12 (MEDI1191): The Phase 1 open-label, multi-center study of intratumoral injections of MEDI1191 alone and in combination with durvalumab in patients with advanced solid tumors, led by AstraZeneca, is ongoing. MEDI1191 is an mRNA encoding for IL12, a potent immunomodulatory cytokine.
Systemic Secreted Therapeutics: In this modality, mRNA is delivered systemically to create proteins that are secreted outside the cell with the aim of producing pharmaceutically active proteins with therapeutic effects across the human body.

Antibody against the chikungunya virus (mRNA-1944): Moderna recently announced positive interim data from the first analysis of safety and activity in the Phase 1 study evaluating escalating doses of mRNA-1944 administered via intravenous infusion in healthy adults. mRNA-1944 successfully encoded for functional antibody (CHKV-24) in humans at all dose levels tested (0.1, 0.3 and 0.6 mg/kg). Antibody level predicted to protect against chikungunya infection was achieved within hours and was projected to be maintained for at least 16 weeks at the middle and high doses. No significant adverse events were observed at the low and middle doses; infusion-related adverse events were observed at the high dose, which resolved spontaneously without treatment. These results mark the first systemic mRNA therapeutic to show production of therapeutic levels of a secreted protein in humans, demonstrating predictable translation from preclinical species. mRNA-1944 uses the same proprietary LNP delivery technology as the systemic intracellular therapeutics targeting MMA and PA. The safety and pharmacology of mRNA-1944 will continue to be explored in two additional cohorts: one cohort with steroid premedication at the 0.6 mg/kg dose and a second cohort with two doses of 0.3 mg/kg (without steroid premedication) given one week apart.
Presentation of note: In October, Moderna presented data from the Phase 1 study of its chikungunya antibody (mRNA-1944) at the Annual Meeting of the Oligonucleotide Therapeutics Society.
Systemic Intracellular Therapeutics: These programs aim to deliver mRNA into cells within target organs as a therapeutic approach for diseases caused by a missing or defective protein.

Methylmalonic acidemia (MMA) (mRNA-3704): The Phase 1/2 open-label, dose escalation study is actively recruiting patients for the first cohort at U.S. sites following a protocol amendment expanding the eligibility criteria to patients 8 years and older. This study is evaluating mRNA-3704 for the treatment of MMA due to methylmalonyl-CoA mutase (MUT) deficiency. The Company is planning to initiate several sites outside the U.S. and recently received Medicines and Healthcare products Regulatory Agency (MHRA) approval in the U.K. The objectives of this study are to evaluate safety and tolerability, assess the pharmacodynamic response and characterize the pharmacokinetic profile of mRNA-3704. This is Moderna’s first rare disease program to advance into clinical testing. The mRNA-3704 program uses the same LNP formulation as mRNA-1944.
Propionic acidemia (PA) (mRNA-3927): This quarter, Moderna announced an open Investigational New Drug (IND) and FDA Fast Track designation for mRNA-3927. Study start-up is ongoing for the open-label, multi-center Phase 1/2 study of multiple ascending doses of mRNA-3927 in pediatric patients with PA in the U.S. The objectives of this study are to evaluate the safety and tolerability of mRNA-3927 administered via IV infusion, assess the pharmacodynamic response as assessed by changes in plasma biomarkers and characterize the pharmacokinetic profile of mRNA-3927. The mRNA-3927 program uses the same LNP formulation as mRNA-1944.
MMA and PA Natural History Study (MaP): As of October 2019, a total of 87 patients have been enrolled in the study (37 MMA, 50 PA). This is a global, multi-center, non-interventional study for patients with confirmed diagnosis of MMA due to MUT deficiency or PA and is designed to identify and correlate clinical and biomarker endpoints for these disorders.
Information about each development candidate in Moderna’s pipeline, including those discussed in this press release, can be found on the investor relations page of its website: View Source

Research Update

In September, Moderna announced a multi-year research collaboration with Harvard University with the goal of identifying and developing novel therapeutic approaches that could improve the lives of patients with immunological diseases. Additional funding from Moderna to Harvard Medical School (HMS) has established an initiative at HMS called the Alliance for RNA Therapies for the Modulation of the Immune System (ARTiMIS), which will enable basic science research in the field of immunology using Moderna’s mRNA and nanoparticle delivery technology.
Corporate Updates

Moderna appointed Tracey Franklin as Chief Human Resources Officer.
Moderna was named a top biopharmaceutical employer by Science for the fifth consecutive year.
The Company will host its Manufacturing and Digital Day on March 4, 2020 at its Norwood, MA facility.
Financial Guidance

The Company expects to end 2019 with approximately $1.20 billion in cash, cash equivalents and investments.
For 2019, the Company expects net cash used in operating activities and purchases of property and equipment to total approximately $500 million.
In 2020, the Company expects net cash used in operating activities and purchases of property and equipment to be similar to 2019, between $490 million and $510 million.
Third Quarter 2019 Financial Results

Cash Position: Cash, cash equivalents and investments as of September 30, 2019 and December 31, 2018 were $1.34 billion and $1.69 billion, respectively.
Net Cash Used in Operating Activities: Net cash used in operating activities was $363.2 million for the nine months ended September 30, 2019 compared to $239.8 million for the same period in 2018. Net cash used in operating activities includes $22.0 million and $25.0 million for the nine months ended September 30, 2019 and 2018, respectively, of in-licensing payments to Cellscript, LLC and its affiliate, mRNA RiboTherapeutics, Inc., to sublicense certain patent rights. After the first quarter of 2019, we have no further in-licensing payment obligations to Cellscript and its affiliate.
Cash Used for Purchases of Property and Equipment: Cash used for purchases of property and equipment was $24.9 million for the nine months ended September 30, 2019 compared to $92.1 million for the same period in 2018.
Revenue: Total revenue was $17.0 million for the three months ended September 30, 2019 compared to $41.8 million for the same period in 2018. Total revenue was $46.2 million for the nine months ended September 30, 2019 compared to $99.6 million for the same period in 2018. On January 1, 2019, we adopted Accounting Standards Codification (ASC) Topic 606, Revenue from Contracts with Customers (ASC 606), using the modified retrospective transition method applied to those contracts which were not completed as of January 1, 2019. The total revenue decreases in 2019 were due to decreases in collaboration revenue across all our strategic alliances, particularly AstraZeneca and Merck, largely driven by our adoption of ASC 606. Total revenue under the previous revenue recognition standard would have been $24.7 million and $80.2 million for the three months and nine months ended September 30, 2019, respectively.
Research and Development Expenses: Research and development expenses were $119.7 million for the three months ended September 30, 2019 compared to $109.1 million for the same period in 2018. Research and development expenses were $378.8 million for the nine months ended September 30, 2019 compared to $303.7 million for the same period in 2018. The increases were primarily attributable to an increase in personnel related costs, including stock-based compensation, with additional increases for the nine months ended September 30, 2019 being driven by higher clinical trial and manufacturing costs, an increase in lab supplies and materials, and an increase in consulting and outside services.
General and Administrative Expenses: General and administrative expenses were $28.2 million for the three months ended September 30, 2019 compared to $18.5 million for the same period in 2018. General and administrative expenses were $84.0 million for the nine months ended September 30, 2019 compared to $56.2 million for the same period in 2018. These increases were mainly due to the additional costs of operating as a publicly traded company, including an increase in personnel related costs and stock-based compensation, consulting and outside services, legal and insurance related costs.
Net Loss: Net loss was $123.2 million for the three months ended September 30, 2019 compared to $80.3 million for the same period in 2018. Net loss was $390.9 million for the nine months ended September 30, 2019 compared to $243.3 million for the same period in 2018.
Investor Call and Webcast Information

Moderna will host a live conference call and webcast at 8:00 a.m. ET on Wednesday, November 6, 2019. To access the live conference call, please dial 866-922-5184 (domestic) or 409-937-8950 (international) and refer to conference ID 6287715. A webcast of the call will also be available under "Events and Presentations" in the Investors section of the Moderna website at View Source The archived webcast will be available on Moderna’s website approximately two hours after the conference call and will be available for 30 days following the call.

On November 6, 2019 QIAGEN (NYSE: QGEN; Frankfurt Prime Standard: QIA) reported an expansion of its QIAseq NGS portfolio to offer a one-day workflow for simultaneous preparation of DNA and RNA libraries using next-generation sequencing (NGS) technologies (Press release, Qiagen, NOV 6, 2019, View Source [SID1234550522]).

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The new QIAseq Multimodal Panels are the only solution to offer a consolidated workflow to simultaneously detect DNA variants, RNA fusions and gene expression levels from a single sample, with an input as low as 10 ng of total nucleic acid. This unmatched low-input solution reduces a typical 2-3 day workflow to approximately only nine hours by eliminating the need for two separate time-consuming, inefficient and costly workflows for library preparation from separate DNA and RNA samples. Both libraries are generated from the same sample input, sample utilization and, in turn, sampling-induced bias is also reduced. This enables labs to conserve samples of limited availability for further downstream applications.

The new QIAseq products will be showcased this week together with QIAGEN’s full range of Sample to Insight solutions for molecular oncology research and diagnostics at the Association for Molecular Pathology (AMP) 2019 Annual Meeting in Baltimore, Maryland.

On November 6, 2019 Celgene Corporation (NASDAQ: CELG) reported data from nearly 70 Company-sponsored, global alliance and investigator-initiated clinical studies evaluating Celgene’s investigational and approved therapies will be presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 7-10, in Orlando, Fla (Press release, Celgene, NOV 6, 2019, View Source [SID1234550449]).

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"Celgene has a deep and ongoing commitment to innovative research and development in treatments for serious blood disorders, with the potential to transform patient outcomes," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "We look forward to ASH (Free ASH Whitepaper) as an opportunity to highlight our commitment and leadership in the research and development of novel therapies for the treatment of blood cancers through new insights in both CD19 and BCMA targeted cell therapies and important progress in our myeloid pipeline."

In leukemia and lymphoma, highlighted studies this year include safety and efficacy results from the pivotal TRANSCEND NHL-001 study of an investigational CD-19 targeted chimeric antigen receptor (CAR) T cell therapy lisocabtagene maraleucel (liso-cel) in relapsed/refractory large B-cell non-Hodgkin lymphoma. Additional liso-cel data from three ongoing studies will evaluate the use of the therapy in an outpatient setting, as well as in transplant noneligible patients with relapsed/refractory large B-cell non-Hodgkin lymphoma (PILOT) and in patients with relapsed/refractory chronic lymphocytic leukemia (TRANSCEND CLL-004).

In multiple myeloma, other notable investigational cell therapy abstracts include the first phase 1 clinical data from the bi-specific T-Cell Engager (TCE) CC-93269 and updated phase 1 clinical data from CAR T program, bb21217, both targeting the B-cell maturation antigen (BCMA) in relapsed/refractory disease.

Several abstracts focusing on data in myeloid diseases including longer-term response data from the phase 3 MEDALIST study of luspatercept to treat anemia in patients with IPSS-R very low-, low-, or intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red-blood-cell (RBC) transfusions will be presented. Additionally, the first data from a phase 2 study of luspatercept in myelofibrosis-associated anemia, results from a study of fedratinib in myelofibrosis patients with low platelet counts, and the first data from CELMoD agent CC-90009, a GSPT1 degrader in relapsed or refractory acute myeloid leukemia (AML) will be presented.

Selected abstracts include*:

Lymphoma & Chronic Lymphocytic Leukemia

Abstract #66: Impact of Lisocabtagene Maraleucel (liso-cel) Treatment on Health-related Quality of Life and Health Utility in Patients (pts) with Relapsed/Refractory (R/R) Aggressive B-Cell Non-Hodgkin Lymphoma (NHL): TRANSCEND NHL 001 (Oral presentation; Saturday, December 7, 8:45 a.m., W308 Patrick)
Abstract #202: Multiplexed Immunofluorescence (IF) Analysis and Gene Expression Profiling of Biopsies from Patients with Relapsed/Refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL) Treated with Lisocabtagene Maraleucel (liso-cel) in TRANSCEND NHL 001 Reveal Patterns of Immune Infiltration Associated with Durable Response (Oral presentation; Saturday, December 7, 12:45 p.m., Valencia A (W415A) Reiss)
Abstract #241: Pivotal Safety and Efficacy Results from TRANSCEND NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas (Oral presentation; Saturday, December 7, 2:00 p.m., Hall E2, Abramson)
Abstract #306: Interactome of Aiolos/Ikaros in Diffuse Large B-Cell Lymphoma (DLBCL) Reveals Novel Combination of Cereblon Modulators (CELMoD) and Histone Deacetylase (HDAC) Inhibitors (Oral presentation; Saturday, December 7, 5:15 p.m., Valencia A (W415A), Hagner)
Abstract #347: Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) vs Rituximab Plus Placebo (R-Placebo) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL) (Oral presentation; Sunday, December 8, 8:30 a.m., Tangerine 3 (WF3-4), Trneny)
Abstract #503: Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with liso-cel, a CD19-directed CAR T Cell Product: Updated Results from TRANSCEND CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib (Oral presentation; Sunday, December 8, 5:30 p.m., Hall D, Siddiqi)
Abstract #2868: Outpatient Treatment of Lisocabtagene Maraleucel (liso-cel) in Three Ongoing Clinical Studies in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (NHL), Including Transplant Noneligible Patients: TRANSCEND NHL 001, OUTREACH, and PILOT (Poster presentation; Sunday, December 8, 6:00 p.m., Hall B, Bachier)
Abstract #2882: Lisocabtagene Maraleucel (liso-cel) for Treatment of Transplant-Ineligible Patients with Relapsed/Refractory (R/R) Aggressive Non-Hodgkin Lymphoma (NHL): Initial Results from the PILOT Study (Poster presentation; Sunday, December 8, 6:00 p.m., Hall B, Sehgal)
Abstract #591: Statistical Learning Approaches for Predicting Lisocabtagene Maraleucel (Liso-Cel; JCAR017) Drug Product Composition from Donor-Selected Material Composition (Oral presentation; Monday, December 9, 7:30 a.m., W414AB, Jiang)
Abstract #593: Lisocabtagene Maraleucel (liso-cel; JCAR017) Manufacturing Process Control and Robustness Across CD19+ Hematological Malignancies (Oral presentation; Monday, December 9, 8:00 a.m., W414AB, Teoh)
Abstract #923: Clustering of Transcriptomic Signatures in Newly Diagnosed Diffuse Large B-Cell Lymphoma Identifies Two High-Risk Subgroups Which Increase in Prevalence at Relapse (Oral presentation; Monday, December 9, 7:15 p.m., W414AB, Ortiz)
Multiple Myeloma

Abstract #143: First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T-Cell Engager (TCE) CC-93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial(Oral presentation; Saturday, December 7, 10:30 a.m., Hall E1, Costa)
Abstract #1812: CC-92480 is a Novel CRBN E3 Ligase Modulating Drug (CELMoD) that Shows Enhanced Tumoricidal and Immunomodulatory Activity Against Sensitive and Resistant Multiple Myeloma Cells (Poster presentation; Saturday, December 7, 5:30 p.m., Hall B, Lopez-Girona)
Abstract #1815: CC-92480, a New Generation Cereblon-modulating Agent, is Highly Synergistic in Combination with Standard Care Agents Dexamethasone, Bortezomib, and Daratumamab in Multiple Myeloma (Poster presentation; Saturday, December 7, 5:30 p.m., Hall B, Wong)
Abstract #3119: Preclinical, Translational, and Clinical Evidence of a Differentiated Profile for the Novel CELMoD, Iberdomide (CC-220)(Poster presentation; Sunday, December 8, 6:00 p.m., Hall B, Lonial)
Abstract #927: Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-BCMA CAR T Therapy (Oral presentation; Monday, December 9, 6:45 p.m., Valencia A (W415A), Berdeja)
Myeloid Diseases

Abstract #232: Clinical Activity of CC-90009, a Cereblon E3 Ligase Modulator and First-in-Class GSPT1 Degrader, as a Single Agent in Patients with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML): First Results from a Phase I Dose-Finding Study (Oral presentation; Saturday, December 7, 2:45 p.m., Chapin Theater (W320), Uy)
Abstract #405: Elucidating the Mechanism of Action of CC-90009, a Novel Cereblon E3 Ligase Modulator, in AML via Genome-wide CRISPR Screen(Oral presentation; Sunday, December 8, 10:00 a.m., W414AB, Lu)
Abstract #557: A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia (Oral presentation; Monday, December 9, 8:00 a.m., W304EFGH, Gerds)
Abstract #643: Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study (Oral presentation; Monday, December 9, 10:30 a.m., Tangerine 3 (WF3-4), DiNardo)
Abstract #841: Assessment of Longer-Term Efficacy and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled MEDALIST Trial of Luspatercept to Treat Anemia in Patients (Pts) with Revised International Prognostic Scoring System (IPSS-R) Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions (Oral presentation; Monday, December 9, 4:30 p.m., W311ABCD, Fenaux)
Abstract 668: Fedratinib Induces Spleen Responses and Reduces Symptom Burden in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Low Platelet Counts, Who were Either Ruxolitinib-Naïve or were Previously Treated with Ruxolitinib (Oral presentation; Monday, December 9, 10:45 a.m., Room W311 EFGH, Harrison)
Abstract #704 : Health-related Quality of Life (HRQoL) in Patients with Myelofibrosis Treated with Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in the Randomized, Placebo-controlled, Phase III JAKARTA Study (Oral presentation; Monday, December 9, 10:45 a.m., Valencia D (W415D), Mesa)
Beta thalassemia

Abstract #3545: Evaluating Luspatercept Responders on Number of Response Episodes, Duration of Clinical Benefit, and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled BELIEVE Trial of Luspatercept in Adult Beta Thalassemia Patients (Pts) Who Require Regular Red Blood Cell (RBC) Transfusions (Poster presentation; Monday, December 9, 6 p.m., Hall B, Viprakasit)
A complete listing of abstracts can be found at View Source

The safety and efficacy of investigational agents and/or investigational uses of approved marketed products have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

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About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM)

REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)

REVLIMID is indicated for the treatment of adult patients with transfusion-dependent anemia due to low-or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID in combination with a rituximab product is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL)

REVLIMID in combination with a rituximab product is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL)

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

REVLIMID is only available through a restricted distribution program, REVLIMID REMS.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program.

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia.Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Patients may require dose interruption and/or dose reduction. MM: Monitor complete blood counts (CBC) in patients taking REVLIMID + dexamethasone or REVLIMID as maintenance therapy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Monitor CBC inpatients on therapy for del 5q MDS, weekly for the first 8 weeks of therapy and at least monthly thereafter. See Boxed WARNINGS for further information. MCL: Monitor CBC in patients taking REVLIMID for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. FL/MZL: Monitor CBC in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly thereafter

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on the patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first-line treatment of patients with CLL, single-agent REVLIMID therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID and in patients with FL or MZL receiving REVLIMID + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In MM patients, MDS was also observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Increased Mortality with Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with MM with a PD-1-or PD-L1- blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID + dexamethasone. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy

Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L)

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
After at least one prior therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
Follicular Lymphoma/Marginal Zone Lymphoma

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID + rituximab across both trials. Fatal adverse reactions (1 each) included: cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. The most frequent serious adverse reaction that occurred in the REVLIMID/rituximab arm was febrile neutropenia (3.0%).
Grade 3 and 4 adverse reactions reported in ≥5% of patients treated in the FL/MZL trial with REVLIMID + rituximab were: neutropenia (50%) and leukopenia (7%)
Adverse reactions reported in ≥15% of patients with FL/MZL treated with REVLIMID + rituximab were: neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritis (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), thrombocytopenia (15%)
DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin-stimulating agents or estrogen-containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
Lactation: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID
Renal Impairment: Adjust the starting dose of REVLIMID based on the creatinine clearance value and in patients on dialysis
Please see full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

About INREBIC

INREBIC (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

IMPORTANT SAFETY INFORMATION

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S

Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

WARNINGS AND PRECAUTIONS

Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal.

Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia: New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent

Thrombocytopenia: New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated.

Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patient and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed.

Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC.

Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose.

ADVERSE REACTIONS: The most common adverse reactions for INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

DRUG INTERACTIONS: Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC.

PREGNANCY/LACTATION: Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.

RENAL IMPAIRMENT: Reduce INREBIC dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with severe hepatic impairment.

Please see full Prescribing Information, including Boxed WARNING.

On November 6, 2019 Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) reported financial and operational results for the third quarter ended September 30, 2019 (Press release, Vanda Pharmaceuticals, NOV 6, 2019, View Source [SID1234550521]).

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"These results affirm Vanda’s corporate strategy, and continue to demonstrate our ability to grow our commercial assets and expand our pipeline of products," said Mihael H. Polymeropoulos, M.D., Vanda’s President and CEO. "I am proud of the progress we have made in our research and development programs, with several new filings expected to be submitted within the next two years. Furthermore, Vanda has put in place a proactive regulatory strategy to better support our patients and products."

Key Financial Highlights:

Total net product sales from HETLIOZ and Fanapt were $59.5 million in the third quarter of 2019, a 21% increase compared to $49.1 million in the third quarter of 2018.
HETLIOZ net product sales were $37.6 million in the third quarter of 2019, a 26% increase compared to $29.9 million in the third quarter of 2018.
Fanapt net product sales were $21.9 million in the third quarter of 2019, a 14% increase compared to $19.2 million in the third quarter of 2018.
Cash, cash equivalents and marketable securities (Cash) were $299.6 million as of September 30, 2019, representing an increase to Cash of $59.0 million compared to September 30, 2018.
Key Research and Development Highlights:

Tradipitant

Enrollment in EPIONE, the Phase III clinical study of tradipitant in atopic dermatitis, is complete. Results from EPIONE are expected in the first quarter of 2020.
In October 2019, EPIONE II, a second Phase III clinical study of tradipitant in atopic dermatitis, began enrolling patients.
Enrollment in the Phase III study of tradipitant in gastroparesis is ongoing as Vanda continues to engage with the U.S. Food and Drug Administration (FDA) on tradipitant’s regulatory path.
Vanda plans to initiate the Phase III program of tradipitant in motion sickness in the fourth quarter of 2019. Vanda expects to file a New Drug Application with the FDA for tradipitant for the treatment of motion sickness in 2020.
HETLIOZ (tasimelteon)

Vanda received a complete response letter (CRL) on August 16, 2019 from the FDA related to the supplemental New Drug Application (sNDA) of HETLIOZ for the treatment of Jet Lag Disorder (JLD). Vanda met with the FDA to discuss the CRL in a Post Action meeting and is determining its next steps.
Vanda plans to meet with the FDA in the fourth quarter of 2019 to discuss the HETLIOZ Smith-Magenis Syndrome clinical study results and expects to submit an sNDA by year-end 2019.
An observational study of delayed sleep phase disorder (DSPD) is ongoing. Vanda plans to initiate a Phase III clinical study of HETLIOZ in DSPD patients by year-end 2019.
Fanapt (iloperidone)

A pharmacokinetic study for the once-a-month long acting injectable (LAI) formulation of Fanapt is ongoing.
A study of Fanapt in bipolar disorder is planned to begin by year-end 2019.
VTR-297 (histone deactetylase (HDAC) inhibitor)

Enrollment in the Phase I clinical study (1101) of VTR-297 in hematologic malignancies is ongoing.
Corporate Highlights:

Vanda announced the appointment of Anne Sempowski Ward to its Board of Directors, effective October 28, 2019, increasing the total number of members on the Board to six.
Vanda announced the hiring of Scott L. Howell as its Chief People Officer, Aranthan "AJ" Jones II as its Chief Corporate Affairs and Communications Officer and Joakim "Kim" Wijkstrom as its Chief Marketing Officer, further bolstering the executive leadership team.
GAAP Financial Results

Net income was $100.4 million for the third quarter of 2019, or $1.88 per share, compared to net income of $7.2 million, or $0.14 per share, for the third quarter of 2018.

The income tax benefit of $88.1 million reflected in the financial results for the third quarter of 2019 includes the favorable impact of the release of Vanda’s deferred tax asset valuation allowance.

Income before income taxes was $12.3 million in the third quarter of 2019, a 69% increase compared to $7.3 million in the third quarter of 2018.

2019 Financial Guidance

Vanda reiterates its 2019 net product sales guidance and expects results in the upper half of the range. In addition, Vanda provides an update to Year-end 2019 Cash and expects to achieve the following financial objectives in 2019:

Conference Call

Vanda has scheduled a conference call for today, Wednesday, November 6, 2019, at 4:30 PM ET. During the call, Vanda’s management will discuss the third quarter 2019 financial results and other corporate activities. Investors can call 1-866-688-9426 (domestic) or 1-409-216-0816 (international) and use passcode 5377942. A replay of the call will be available on Wednesday, November 6, 2019, beginning at 7:30 PM ET and will be accessible until Wednesday, November 13, 2019, at 7:30 PM ET. The replay call-in number is 1-855-859-2056 for domestic callers and 1-404-537-3406 for international callers. The passcode number is 5377942.

The conference call will be broadcast simultaneously on Vanda’s website, www.vandapharma.com. Investors should click on the Investors tab and are advised to go to the website at least 15 minutes early to register, download, and install any necessary software or presentations. The call will also be archived on Vanda’s website for a period of 30 days.