On December 7, 2020 CIBMTR reported that Initial results from a recent study indicate that for patients between the ages of 50 and 75, overall survival nearly doubled when patients with myelodysplastic syndrome (MDS) received allogeneic hematopoietic cell transplantation (alloHCT) when compared to other treatments (Press release, CIBMTR, DEC 7, 2020, View Source [SID1234572361]). Additionally, patients age 65 and older saw a similar benefit to overall survival as those between the ages of 55 and 64. The majority of patients received transplant using matched unrelated donors, and outcomes were similar to those of patients using matched related donors.

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These findings from a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study were presented during the 62nd ASH (Free ASH Whitepaper) Annual Meeting & Exposition.

The initial results of a separate observational study currently being run by the CIBMTR (Center for International Blood and Marrow Transplant Research)—which is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin—also demonstrate the patients 65 and older experience similar benefit from allogeneic HCT to patients 55-64 years of age. In addition, the initial analysis of the CIBMTR observational study showed similar non-relapse mortality between these two age groups. The initial results were published in JAMA Oncology.

"In both studies of older adults with MDS, we found that transplantation using either an HLA-matched related or HLA-matched unrelated donor is feasible even in older patients and in the BMT CTN study, provides significant survival benefit relative to non-transplant therapies. This supports the early referral of all patients with MDS to a transplant center for consultation, regardless of age," said Steven Devine, MD, Chief Medical Officer, NMDP/Be The Match, and Associate Scientific Director, CIBMTR.

Early referral to a transplant center for all patients is critical as it allows the search for a donor to start early for those patients who are eligible for transplant. This increases the likelihood a patient will find a suitable donor and proceed to transplant earlier in their disease, which can lead to better outcomes.

"While alloHCT is the only known cure for MDS, many older adults did not receive HCT in the past because the benefits for older adults had not been sufficiently proven for CMS to provide payment coverage. Taken together, these studies support allogeneic HCT for older patients with MDS based on survival improvements," said J. Douglas Rizzo, MD, MS, Senior Scientific Director, CIBMTR.

Currently, the Centers for Medicare and Medicaid Services (CMS) does not cover alloHCT for adults over age 65 unless the patient is enrolled in a qualified Coverage with Evidence Development (CED) study. The NMDP/Be The Match and CIBMTR will provide CMS with the data from these two studies for its use in making coverage policy decisions.

In the meantime, the current CIBMTR observational study meets CED requirements and qualifies for payment under CMS. The study remains open for enrollment for a broad range of clinically eligible Medicare recipients. By enrolling patients in this study, more older patients across the U.S. with MDS will have access to HCT.

Access the BMT CTN study abstract presented by senior study author Corey Cutler, MD, MPH, Dana-Farber Cancer Institute, during the ASH (Free ASH Whitepaper) Annual Meeting:

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Access the initial results of the CIBMTR observational study published in JAMA Oncology:

Comparison of Patient Age Groups in Transplantation for Myelodysplastic Syndrome: The Medicare Coverage With Evidence Development Study

About the BMT CTN

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts rigorous multi-institutional clinical trials of high scientific merit, focused on improving survival for patients undergoing hematopoietic cell transplantation and/or receiving cellular therapies. The BMT CTN has completed accrual to 43 Phase II and III trials at more than 100 transplant centers and enrolled over 12,800 study participants. BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, a part of the National Institutes of Health (NIH) and is a collaborative effort of 20 Core Transplant Centers/Consortia, the CIBMTR (Center for International Blood and Marrow Transplant Research), the National Marrow Donor Program/Be The Match and the Emmes Company, LLC, a clinical research organization.

On December 7, 2020 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported an oral presentation highlighting data related to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, was presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting taking place virtually December 5-8, 2020 (Press release, Karyopharm, DEC 7, 2020, View Source [SID1234572380]). The presentation featured new data from a randomized, investigator-sponsored Phase 2 study evaluating combination chemotherapy with or without XPOVIO in newly diagnosed older adults with acute myeloid leukemia (AML).

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"AML is an aggressive form of blood cancer that begins in the bone marrow and is frequently characterized by resistance to currently available therapies, especially in elderly patients," said Timothy S. Pardee, M.D., Ph.D., Associate Professor, Hematology and Oncology, Wake Forest School of Medicine and lead author of the presentation. "The data presented today at ASH (Free ASH Whitepaper) 2020, show that XPOVIO in combination with standard induction and consolidation chemotherapy appears highly active in older patients with de novo AML. Despite the small size of the study, XPOVIO in combination was associated with a significant survival improvement and a higher overall response rate than standard chemotherapy alone. In addition, accompanying preclinical work suggests that XPOVIO may increase response to cytarabine, one of the standard chemotherapy drugs used to treat AML, by interfering with nuclear-mitochondrial communication. As novel approaches to treating patients with AML are desperately needed, we look forward to further evaluating this active regimen."

"AML is the most common form of acute leukemia in adults and unfortunately, very little improvement has been made in recent years in terms of improving long-term patient outcomes," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "We are extremely pleased to see such striking results from the combination of XPOVIO and standard chemotherapy in newly diagnosed older patients with AML. We believe the data presented at ASH (Free ASH Whitepaper) 2020 may encourage interest from the cancer research community to further evaluate the potential use of XPOVIO as a combination drug partner with other standard treatments in older patients with AML."

New Data from Phase 2 Study of XPOVIO in Combination with Chemotherapy in Older Patients with AML

In this randomized Phase 2 study, researchers evaluated standard intensive chemotherapy (the "7+3" regimen because it consists of cytarabine continuously for seven days, along with short infusions of an anthracycline drug on each of the first three days) with or without XPOVIO in newly diagnosed patients with AML who were 60 years of age or older. Responding patients could go on to receive high dose cytarabine consolidation therapy with or without XPOVIO as per initial randomization. Patients in the XPOVIO arm who completed all consolidation could then move to maintenance therapy with XPOVIO alone. Induction therapy consisted of cytarabine (by continuous infusion for seven days) and daunorubicin (on days 1-3). Consolidation consisted of cytarabine therapy. XPOVIO was dosed orally at 60mg twice weekly during induction and consolidation and once weekly during maintenance.

The following table is a summary of the efficacy results:

Cohort

All (n=28)

Standard Arm
(n=7)

XPOVIO Arm

(n=21)

Median overall survival (days)

265

839

Median progression-free survival (days)

108

558

Residual disease on nadir marrow

19% (5/27)

50% (3/6)

10% (2/21)

Complete remission (CR)

68% (19/28)

43% (3/7)

76% (16/21)

MRD negative CR

81% (13/16)

n/a

81% (13/16)

Overall response (CR+CRi)

75% (21/28)

43% (3/7)

86% (18/21)

No CR/CRi

26% (7/28)

57% (4/7)

14% (3/21)

Went on to transplant

29% (8/28)

14% (1/7)

33% (7/21)

Relapsed after CR

24% (5/21)

33% (1/3)

22% (4/18)

Key: CR=complete remission; CRi=complete remission with incomplete count recovery)

Diarrhea was the most common treatment-related adverse event (AE), resulting in dose modifications and dose holding. Additionally, seven patients (33%) on the XPOVIO arm experienced prolonged thrombocytopenia. Sixty-day mortality was 10% (2/21) of patients on the XPOVIO arm compared to 14% (1/7) of patients on the standard of care arm.

These results suggest that a 7+3 regimen in combination with XPOVIO has a manageable safety profile and is highly active in patients aged 60 and older. XPOVIO provided a statistically significant survival benefit (839 days versus 265 days; p=0.0472) in this small, randomized trial; ORR was also significantly improved on the XPOVIO arm.

In addition to the Phase 2 clinical research, preclinical studies were also conducted with murine AML cell lines to assess the mechanisms of chemo-sensitization. The results of this preclinical research showed that XPOVIO induces retention of topoisomerase II in the nucleus increasing sensitivity to anthracyclines (which block topoisomerase II), and significantly sensitizes cell lines to cytarabine. Existing research shows that AML cells increase mitochondrial oxygen consumption in response to cytarabine, which in turn leads to resistance. The ability of XPOVIO to interfere with this response was assessed. When co-treated with both cytarabine and XPOVIO, the treated AML cells showed a diminished mitochondrial oxygen response.

Details for the ASH (Free ASH Whitepaper) 2020 presentations are as follows:

Title: Frontline selinexor and chemotherapy is highly active in older adults with Acute Myeloid Leukemia (AML)
Presenter: Timothy Pardee, Wake Forest School of Medicine
Abstract #: 633
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Commercially Available Therapy, excluding Transplantation II
Date and Time: Monday, December 7, 2020, 11:45 a.m. ET
Location: Channel 12 (Virtual Meeting)

A PDF copy of this presentation are available here.

Virtual Investor and Analyst Event Conference Call and Webcast

Karyopharm will host a conference call and on Tuesday, December 8, 2020, at 1:00 p.m. Eastern Time, to review highlights from the ASH (Free ASH Whitepaper) 2020 data presentations. The event will feature recognized myeloma and leukemia experts James Berenson, MD, Founder, President and Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research, and Dr. Timothy Pardee, MD, PhD, FACP, Wake Forest School of Medicine, along with members of the Karyopharm executive leadership team. To access the event, please dial (877) 870-4263 (local) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor in this same RRMM indication. Karyopharm’s supplemental New Drug Application (sNDA) requesting an expansion of its current indication to include the treatment for patients with multiple myeloma after at least one prior line of therapy has been accepted for filing by the FDA. In June 2020, Karyopharm received accelerated FDA approval of XPOVIO for its second indication in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326
Email: [email protected]

IMPORTANT SAFETY INFORMATION

Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma (MM) and developed or worsened in patients with DLBCL.

Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection. Neutropenia and febrile neutropenia occurred in patients with MM and in patients with DLBCL.

Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction (AR).

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients with MM and DLBCL.

Nausea/Vomiting: Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.

Diarrhea: Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration, and replace electrolytes as clinically indicated.

Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia. Hyponatremia developed in patients with MM and in patients with DLBCL.

Monitor sodium level at baseline and throughout treatment. Monitor more frequently during the first 2 months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose, or permanently discontinue based on severity of the AR.

Serious Infection: XPOVIO can cause serious and fatal infections. Most infections were not associated with Grade 3 or higher neutropenia. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Monitor for signs and symptoms of infection, and evaluate and treat promptly.

Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities.

Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.

Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity: XPOVIO can cause fetal harm when administered to a pregnant woman.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions in ≥20% of patients with MM are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The most common ARs, excluding laboratory abnormalities, in ≥20% of patients with DLBCL are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in ≥15% of patients included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia, lymphopenia, and neutropenia.

In patients with MM, fatal ARs occurred in 9% of patients. Serious ARs occurred in 58% of patients. Treatment discontinuation rate due to ARs was 27%. The most frequent ARs requiring permanent discontinuation in ≥4% of patients included fatigue, nausea, and thrombocytopenia.

In patients with DLBCL, fatal ARs occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal AR was infection (4.5% of patients). Serious ARs occurred in 46% of patients; the most frequent serious AR was infection. Discontinuation due to ARs occurred in 17% of patients.

USE IN SPECIFIC POPULATIONS

In MM, no overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥75 years old had a higher incidence of discontinuation due to an AR than younger patients, a higher incidence of serious ARs, and a higher incidence of fatal ARs.

Clinical studies in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

On December 7, 2020 Boehringer Ingelheim and Proxygen reported they have entered into a collaboration and license agreement to enable the identification of molecular glue degraders against various oncogenic targets (Press release, Proxygen, DEC 7, 2020, View Source [SID1234574446]). The collaboration combines Proxygen’s unique molecular glue degrader discovery platform and its expertise in targeted protein degradation with Boehringer Ingelheim’s long-term strategy to provide first-in-class, breakthrough therapies for cancer patients.

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Molecular glue degraders and PROTACs harness the power of the cell’s recycling machinery to selectively eliminate disease-causing proteins. Molecular glue degraders achieve this by specifically bridging the distance between target proteins and ubiquitin ligases, which consequently flag the target proteins for rapid degradation. Molecular glues orchestrate this protein-protein proximity through highly cooperative binding. They circumvent the need for a defined binding pocket on the surface of the target protein, a requirement for conventional small molecule drugs, allowing pharmaceutical intervention on proteins that were previously considered undruggable.

"Proxygen’s molecular glue degrader platform has the potential to become a valuable component of Boehringer Ingelheim’s cancer research strategy to treat tumors driven by the most frequently mutated cancer-causing proteins that were previously considered undruggable and to further expand our efforts in the area of targeted protein degradation," says Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim. "We are very pleased to partner with Proxygen, complementing our efforts in taking difficult-to-treat cancers on."

The identification of molecular glue degraders has been serendipitous up to this point. Proxygen’s highly scalable and broadly applicable molecular glue discovery platform promises a goal-oriented and comprehensive avenue towards an improved identification of molecular glue degrader candidates.

"We are very excited to join forces with Boehringer Ingelheim," says Bernhard Boidol, Chief Executive Officer of Proxygen. "Working together with a leader in innovative oncological research and development not only validates the broad applicability of our molecular glue degrader platform but also allows us to rapidly develop new therapies for the high unmet medical need of many patients with lung and colorectal cancers."

Proxygen’s new method has recently been recognized by Boehringer Ingelheim through its Grass Roots ‘Innovation Prize’ in Vienna, Austria. The ‘Innovation Prize’ recognizes the innovation power of young life-science companies and bio-entrepreneurs to create and sustain pipelines for the next generation of medicines. Launched in 2015, the Grass Roots programs comprise of ‘Office Hours,’ ‘Academy’ and the ‘Innovation Prize.’ As a company dedicated to improving health and quality of life, these programs give Boehringer Ingelheim the opportunity to lend expertise to the early-stage innovation community and offer guidance around the science to help enable ideas to deliver the next breakthroughs.

Proxygen is entitled to receive up-front payments, research and development support and milestone gated development payments, as well as tiered royalties based on future commercial sales of developed products.

On December 7, 2020 Phosplatin Therapeutics LLC, a clinical stage pharmaceutical company focused on oncology therapeutics, reported that new data showing monotherapy treatment with PT-112, the company’s lead clinical agent, was feasible and well tolerated in heavily pre-treated, relapsed / refractory multiple myeloma patients (Press release, Phosplatin, DEC 7, 2020, View Source [SID1234572331]). The study entitled, "A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma," was presented in a narrated slide presentation on December 5 at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place virtually from December 5-8, 2020.

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"The patients enrolled in this study have exhausted all currently available treatment options," said Taxiarchis Kourelis, M.D., Division of Hematology, Assistant Professor of Medicine, Mayo Clinic College of Medicine Rochester, Minnesota, who presented the study. "We are encouraged by these results, which show a well-tolerated safety profile and preliminary evidence of clinical activity that support further evaluation of PT-112 in a Phase II setting."

The study enrolled 24 patients using a 3+3 dose escalation design to determine the recommended Phase II dose. Patients received PT-112 as a monotherapy on a 28-day dosing cycle. All of the patients enrolled in the study were heavily pre-treated, having exhausted all available therapies. Key findings included the following:

PT-112 monotherapy treatment was feasible and well tolerated in this heavily pre-treated, relapsed / refractory multiple myeloma patient population, with one dose-limiting toxicity (grade 4 neutropenia, 420mg/m2) and no grade 4 non-hematological treatment-related adverse event observed.

The recommended Phase II dose (RP2D) of PT-112 was determined to be 360 mg/m2 given on days 1, 8, and 15 of a 28-day cycle.

Evidence of drug activity included a confirmed partial response in 1 of 4 patients treated at the RP2D, and a confirmed minimal response in a non-responding patient to prior BCMA-CAR-T therapy.

The study (NCT03288480) was designed and launched following translational work conducted in the Cancer Genetics Laboratory of P. Leif Bergsagel, M.D., at the Mayo Clinic in Scottsdale, Arizona.

"This evidence is very encouraging and supports our continued development of the PT-112 multiple myeloma program," said Robert Fallon, co-founder and Chief Executive Officer, Phosplatin Therapeutics. "We believe that PT-112’s immunogenic cell death induction, and osteotropic biodistribution, offers a compelling hypothesis for patients who have exhausted available treatment options. We look forward to expanding our study in the near future."

The presentation was part of "Session 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster I" and is available on the ASH (Free ASH Whitepaper) Annual Meeting and Exposition site through the conclusion of the conference.

About PT-112

PT-112 is a novel small molecule conjugate of pyrophosphate that possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents the best-in-class small molecule inducer of this immunological form of cancer cell death and is currently under Phase II development. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The combination Phase Ib study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase I study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase I study of PT-112.

On December 7, 2020 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a pioneer in T-cell immunotherapy, leveraging its novel allogeneic EBV T-cell platform to develop transformative therapies for patients with serious diseases including solid tumors, hematologic cancers and autoimmune disease, reported the presentation of the first preclinical evaluation of ATA3219, a next-generation, off-the-shelf, allogeneic CAR T-cell therapy targeting CD19, as well as data supporting its multicohort Phase II study with tab-cel (tabelecleucel) for the treatment of rare EBV-driven diseases (ATA129-EBV-205) (Press release, Atara Biotherapeutics, DEC 7, 2020, View Source [SID1234572347]). These data are being featured in five poster presentations at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, December 5-8, 2020.

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"Though the current generation of CD19 CAR T immunotherapies has transformed how we treat hematologic malignancies, a significant opportunity remains to improve outcomes and make the power of CAR T accessible to more patients using allogeneic cells with our differentiated EBV T-cell platform," said Jakob Dupont, M.D., Executive Vice President and Global Head of Research and Development at Atara. "As a leader in allogeneic CAR T-cell therapy, Atara is developing ATA3219 to be best-in-class, improving upon established CD19 targeting by leveraging both our EBV T-cell platform and novel 1XX co-stimulation signaling technology. We are pleased to share, for the first time, preclinical data demonstrating the antitumor activity, persistence, polyfunctional phenotype and safety of ATA3219."

Preclinical results presented at ASH (Free ASH Whitepaper) detail findings from in vitro and in vivo evaluations of ATA3219. Specifically, in vitro functional studies demonstrate potent antitumor activity of ATA3219 against CD19-expressing target lines, with durable CD19 antigen-specific and HLA-independent killing of CD19 targets. In addition, both in vivo and in vitro assessments of ATA3219 alloreactivity support a potentially favorable safety profile that would be required for an allogeneic, off-the-shelf CAR-T therapy.

Furthermore, in vivo, ATA3219 demonstrates potent antitumor activity in an established disseminated tumor model of acute lymphoblastic leukemia and is associated with long-term persistence and survival benefit. No treatment-related toxicities were observed in this animal model. Together, these findings support advancing ATA3219 to clinical evaluation.

ATA3219 combines an allogeneic EBV T-cell approach with a CAR signaling domain designed to improve upon current and clinically validated CD19 targeted CAR therapies without the need for gene editing. ATA3219 utilizes next-generation 1XX co-stimulatory domain technology, designed to extend functional persistence without compromising potency.

Following a successful pre-investigational new drug (IND) meeting with the U.S. Food and Drug Administration (FDA) in early Q4 2020, Atara plans to submit an IND for ATA3219 in 2021.

Additionally, Atara will report several data sets related to lead product candidate tab-cel including the first-ever presentation of data on patients with life-threatening complications associated with EBV viremia.

In this heterogeneous group of patients with life-threatening complications stemming from EBV viremia including some with hemophagocytic lymphohistiocytosis (HLH), a condition with poor prognosis for which treatment options are limited, 80 percent (n=4/5) of patients in the EAP-201 study with persistent EBV viremia (not HLH or chronic active EBV (CAEBV) were responders, and 50 percent (n=2/4) of the patients in EAP-901 with EBV viremia and HLH were responders. The overall survival (OS) rate at one year in patients with EBV viremia treated in the EAP-201 study was 100 percent for a median follow-up of 14.6 months (min 12.2, max 17.8).

Tab-cel was generally well-tolerated with no new safety signals in this study and data support the continued overall safety profile of the product. The EAP-901 study reported a fatal SAE of chronic hepatic failure that was assessed as unrelated to treatment; one patient experienced a grade 3 TESAE of facial nerve disorder that was assessed as possibly related to treatment and recovered in one month. There were no other fatal or treatment-related TESAEs reported in this patient population.

The Company has now presented clinical data for tab-cel in all six of the patient populations of the multi-cohort study, showing meaningful efficacy and consistent favorable safety profile.

In a poster evaluating the Healthcare Resource Utilization (HRU) and cost for patients with post-transplant lymphoproliferative disease (PTLD) following kidney transplant, it was found that PTLD is associated with substantial HRU and cost (>$200k PPY in the year diagnosed), regardless of the year diagnosed post-transplant, while patients without PTLD and patients who haven’t developed PTLD had a cost of ~$83k per-person year (PPY) in year one, and ~$26k PPY for year two and three post-transplant. Patients who developed PTLD continued to incur higher healthcare costs than patients who did not develop PTLD in years beyond the PTLD diagnosis year.

"We are pleased to see the growing body of evidence showing that tab-cel was well-tolerated and demonstrated strong objective response rates and overall survival in patients with life-threatening EBV-driven diseases beyond EBV+ PTLD," said AJ Joshi, M.D., Senior Vice President and Chief Medical Officer at Atara. "These data support the continued study of tab-cel in the multicohort trial aligned with our mission of bringing potentially transformative therapies to patients with serious diseases of high unmet medical need. Additionally, the characterization of the significant cost burden of PTLD begins to clarify important aspects of the significant value that a transformative treatment could provide to patients and the healthcare system."

Atara Poster Presentations at ASH (Free ASH Whitepaper):

Title: ATA3219: A Potent Next-Generation Allogeneic Off-the-Shelf CD19-CAR T Therapy without the Need for Gene-Editing
Abstract #: 3259
Session: 703. Adoptive Immunotherapy: Mechanisms and New Approaches: Poster III
Time and Location: Monday, December 7, 2020: 7:00 AM-3:30 PM ET, Poster Hall (Virtual Meeting)

Title: Clinical Experience of Tabelecleucel in Patients with Life-Threatening Complications of Epstein-Barr Virus Viremia
Abstract #: 2554
Session: 905. Outcomes Research—Malignant Conditions (Lymphoid Disease): Poster II
Time and Location: Sunday, December 6, 2020: 7:00 AM-3:30 PM ET, Poster Hall (Virtual Meeting)

Title: Clinical Experience of Tabelecleucel in Patients with EBV+ Primary (PID) or Acquired Immunodeficiency (AID) Associated Lymphoproliferative Disease
Abstract #: 1658
Session: 905. Outcomes Research—Malignant Conditions (Lymphoid Disease): Poster I
Time and Location: Saturday, December 5, 2020: 7:00 AM-3:30 PM ET, Poster Hall (Virtual Meeting)

Title: High Healthcare Resource Utilization and Cost for PTLD Patients Following Kidney Transplants
Abstract #: 3482
Session: 905. Outcomes Research—Malignant Conditions (Lymphoid Disease): Poster III
Time and Location: Monday, December 7, 2020: 7:00 AM-3:30 PM ET, Poster Hall (Virtual Meeting)

Title: A Multicenter, Multicohort, Open-Label, Single-Arm per Cohort, Phase II Study to Assess the Efficacy and Safety of Tabelecleucel in Patients with EBV-Associated Diseases Using an Adaptive Two-Stage Study Design
Abstract #: 2551
Session: 905. Outcomes Research—Malignant Conditions (Lymphoid Disease): Poster II
Time and Location: Sunday, December 6, 2020: 7:00 AM-3:30 PM ET, Poster Hall (Virtual Meeting)