On December 10, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported the presentation of four posters highlighting clinical data from the ongoing Phase 1b/2 STOMP study at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 annual meeting held December 9-12, 2017 in Atlanta (Press release, Karyopharm, DEC 10, 2017, View Source [SID1234522492]). The STOMP study is evaluating selinexor, the Company’s lead, novel, oral SINE compound, in combination with backbone therapies for the treatment of patients with heavily pretreated multiple myeloma (MM). Two of the presentations feature updated data from the STOMP arms evaluating selinexor plus low dose dexamethasone (Sd) in combination with either Velcade (bortezomib) (SVd), or Pomalyst (pomalidomide) (SPd). The other two presentations feature new data from the STOMP arms evaluating Sd with Revlimid (lenalidomide) (SRd) and with Darzalex (daratumumab) (SDd).

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"The results from the SVd arm of the Phase 1b/2 STOMP study, particularly the high response rates of 83% in the same patient population eligible for the BOSTON study and 84% in proteasome inhibitor (PI)-naïve or PI-relapsed patients, together with prolonged progression-free survival (PFS), strongly support our ongoing, pivotal Phase 3 BOSTON study," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Overall, the four presentations continue to highlight evidence of strong activity when oral selinexor is combined with the currently available "backbone" myeloma therapies, including PIs, immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies. Oral selinexor continues to demonstrate an expected and manageable tolerability profile, particularly in the SVd regimen where the combination produced higher response rates, paired with lower rates of peripheral neuropathy (PN), compared to the commonly used regimen of Velcade plus dexamethasone. We are delighted to share the results of this research with the medical community at ASH (Free ASH Whitepaper) this year."

Selinexor in Combination with Velcade and Low-dose Dexamethasone (SVd)

In the poster presentation titled, "Selinexor in combination with weekly low dose bortezomib and dexamethasone (SVd) induces a high response rate with durable responses in patients with refractory multiple myeloma," (Abstract #3135) Nizar Bahlis, MD, Southern Alberta Cancer Research Institute, presented updated clinical data from the SVd arm of the STOMP study. The study included patients whose disease was PI naïve, exposed or refractory, provided their disease was not refractory to Velcade as a last therapy. In this study arm, oral selinexor was dose-escalated in once-weekly (80 or 100mg) or twice-weekly (60 or 80mg) regimens. Velcade (1.3mg/m2 subcutaneously) was administered once-weekly or twice-weekly. Dexamethasone (dex) was administered orally either 40mg once-weekly or 20mg twice-weekly. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SVd Patients as of 15-Nov-20172
Category N3 ORR (%) CR VGPR PR4 Median PFS
PI Relapsed/Naïve 19 16 (84%) 2 (11%) 5 (26%) 9 (47%) >13 months
PI Relapse/Naïve, ≤3 Prior Treatments (BOSTON5) 18 15 (83%) 2 (11%) 6 (33%) 7 (39%)
PI Refractory (Velcade, Kyprolis, Ninlaro) 21 9 (43%) 1 (5%) 4 (19%) 4 (19%) 6.4 months
All 40 25 (63%) 3 (8%) 9 (23%) 13 (33%) 9.0 months
Key: ORR=Overall Response Rate (CR+VGPR+PR), CR=Complete Response, VGPR=Very Good Partial Response, PR=Partial Response
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Two patients not evaluable for response: one death unrelated to myeloma and one withdrawal of consent before disease follow up
4One unconfirmed PR
5Patient population eligible for the ongoing Phase 3, randomized BOSTON study evaluating SVd versus Vd

The majority of patients had reductions in M-protein, including 33% with a ≥90% reduction. In the PI Relapsed/Naïve population (N=19), the ORR was 84% and the median PFS was >13 months with similar results in the "BOSTON" population (N=18). This compares favorably to standard Vd regimens (the control arm of the BOSTON study) with ORR 60-65% and PFS 7-9 months across many previous studies.

Adverse events were consistent with those reported previously from the SVd arm of the STOMP study with nausea, anorexia, fatigue, diarrhea and vomiting the most commonly reported for Grade 1/2. Importantly, the reported PN across all patients was Grade 1/2 and limited to six patients (14%), of which five had prior Velcade exposure. Grade ≥3 adverse events were also consistent with those reported previously with thrombocytopenia, neutropenia, fatigue and anemia being the most common. The recommended Phase 2 dose (RP2D) regimen for SVd is oral selinexor (100mg once weekly), Velcade (1.3mg/m2 once-weekly subcutaneously) and oral dex (40mg once weekly), which represents 40% less Velcade and 25% less dex compared to the approved standard Velcade + dex (Vd) regimen.

Dr. Bahlis commented, "These updated data continue to support the thesis that selinexor combined with once-weekly Velcade and low-dose dex is well tolerated and highly active in relapsed or refractory myeloma. The high response rates and durability observed with SVd are achieved with 40% less Velcade and 25% less dex, with no overt major organ toxicities. The SVd response rates in patients with PI non-refractory myeloma, together with the low rate of PN, compares favorably to the response rates and much higher PN reported from other late-stage Vd trials. In patients with PI refractory myeloma, the response rates reported here support prior preclinical findings suggesting selinexor’s potential to re-sensitize myeloma to PIs."

Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In the poster presentation titled, "Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure," (Abstract #3136) Christine Chen, MD, FRCP, University of Toronto, Princess Margaret Cancer Center, presented updated clinical data from the SPd arm of the STOMP study which includes MM patients who previously received Revlimid and a PI. In this study arm, selinexor was dosed orally either once weekly (60 or 80mg) or twice weekly (60 or 80mg) with Pomalyst (4mg orally, once daily) and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 15-Nov-20172
Category N3 ORR (%) VGPR PR4 Median PFS
Pomalyst Naïve and Revlimid Refractory or Relapsed 19 12 (63%) 2 (11%) 10 (53%) 11.6 months
Pomalyst and Revlimid Refractory 8 3 (38%) - 3 (38%) 4.8 months
All 27 15 (56%) 2 (7%) 13 (48%) 11.6 months
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Four patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, two withdrawals of consent before disease follow up
4One unconfirmed PR

Responses tended to occur rapidly with a median of one month to onset. Median PFS of 11.6 for SPd compares favorably with the PFS of ~4 months reported for Pomalyst-dex in the Revlimid refractory or relapsed population.

Among the 31 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (52%), anorexia (45%), fatigue (45%) and diarrhea (32%). The most common Grade ≥3 adverse events were neutropenia (55%), thrombocytopenia (32%) and anemia (29%). Gastrointestinal adverse events were generally manageable with antiemetics. There were two Grade 5 treatment-related events (febrile neutropenia and intracranial hemorrhage). Five DLTs (Grade 3 fatigue, neutropenia and febrile neutropenia) were observed in patients receiving selinexor 60mg twice weekly and 80mg once weekly. Based on the activity and tolerability observed in this study arm, 60-80mg of oral selinexor 60mg once weekly are being evaluated in combination with Pomalyst (3mg orally, once daily) and low dose dex to determine the RP2D for this combination regimen.

Dr. Chen commented, "Myeloma patients whose disease is refractory to a PI and an IMiD would typically move to the currently approved regimen of Pomalyst and dex, which carries an expected ORR of up to 30% and PFS of approximately four months in this patient population. The 56% ORR reported here shows the significant clinical activity of this novel, all oral, SPd regimen in patients with heavily pretreated myeloma. These data continue to build upon the body of clinical data suggesting that once-weekly selinexor is generally well tolerated and can rapidly induce durable responses when combined with Pomalyst and dex in patients with PI- and Revlimid-exposed myeloma, including patients whose disease was refractory to prior therapy with Pomalyst. This SPd regimen has the potential to provide a new therapeutic option for myeloma patients where a significant unmet need remains."

Selinexor in Combination with Revlimid and Low-dose Dexamethasone (SRd)

In the poster presentation titled, "A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma," (Abstract #1861) Darrell White, MD, Dalhousie University and QEII Health Sciences Center, presented new clinical data from the SRd arm of the STOMP study evaluating patients who received at least one prior therapy, which may include prior Revlimid, as long as the patient’s MM was not refractory to prior Revlimid. Patients whose MM was refractory to Revlimid maintenance regimens were also allowed in this cohort. In this study arm, oral selinexor was dose-escalated starting at either 60mg once weekly or 60mg twice weekly, with Revlimid (25mg orally, once daily), and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SRd Patients as of 15-Nov-20172
Category N3 ORR VGPR PR4
Revlimid Naïve (All) 12 11 (92%) 3 (25%) 8 (67%)
Revlimid Naïve, ≤2 Prior Treatments 10 10 (100%) 3 (30%) 7 (70%)
Revlimid Relapsed or Refractory 4 2 (50%) - 2 (50%)
All 16 13 (81%) 3 (19%) 10 (63%)
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Three patients not evaluable for response: two deaths unrelated to myeloma, one withdrawal of consent before disease follow up
4Three unconfirmed PRs

Median PFS for the overall study population and for patients with Revlimid-naïve disease was not reached. The median time on treatment for the overall study population was not reached.

Among the 19 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (68%), anorexia (42%), fatigue (42%), weight loss (42%), constipation (32%) and vomiting (32%). The most common Grade ≥3 adverse events were thrombocytopenia (68%) and neutropenia (58%). Gastrointestinal adverse events were generally manageable with antiemetics. Five DLTs (thrombocytopenia (n=4) and anorexia (n=1)) were observed in patients receiving selinexor 60mg twice weekly and 80mg once weekly. Thrombocytopenia and anorexia were reduced in the selinexor 60mg once weekly cohort versus the twice weekly groups. Based on the activity and tolerability observed in this study arm, the RP2D of the all-oral SRd is selinexor (60mg orally, once weekly), Revlimid (25mg orally, once daily) and dex (40mg orally, once weekly).

Dr. White commented, "These Phase 1 results suggest that selinexor can be safely combined with Revlimid and dex in an all oral regimen in patients with relapsed or refractory myeloma who have received at least one prior therapy. We were especially pleased to see an encouraging 81% response rate across all patients and a 92% response rate in patients with Revlimid-naïve disease, clear signals of clinical activity, with no new or unexpected toxicities observed. Importantly, this combination shows no evidence of cardiac, pulmonary, liver or renal toxicity. We look forward to continuing our evaluation of selinexor in this SRd regimen in patients with relapsed or refractory myeloma."

Selinexor in Combination with Darzalex and Low-dose Dexamethasone (SDd)

In the poster presentation titled, "A Phase 1b Study to Assess the Combination of Selinexor and Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma Previously Exposed to Proteasome Inhibitors (PI) and Immunomodulatory Drugs," (Abstract #3100) Cristina Gasparetto, MD, Duke University Cancer Center, presented new clinical data from the SDd arm of the STOMP study evaluating MM patients who received at least three prior lines of therapy, including a PI and an IMiD, or patients with MM refractory to both a PI and an IMiD. In this study arm, oral selinexor was dose escalated using either 100mg once weekly or 60mg twice weekly, with Darzalex (16mg/kg intravenously once weekly) and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SDd Patients as of 15-Nov-20172
Category N3 ORR VGPR PR4
Darzalex Naïve 6 5 (83%) 3 (50%) 2 (33%)
All 8 5 (63%) 3 (38%) 2 (25%)
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3One patient not evaluable for response withdrew consent prior to disease follow up due to severe infusion reaction associated with Darzalex
4One unconfirmed PR

Four of nine patients remain on treatment. Responses tended to occur rapidly with a median of one month to onset. Among the nine patients evaluable for safety, the most common Grade 1/2 adverse events were fatigue (44%), nausea (33%) and neutropenia (33%). The most common Grade 3/4 adverse events were thrombocytopenia (56%), leukopenia (44%), anemia (44%) and neutropenia (33%). Gastrointestinal adverse events were generally manageable with antiemetics. The maximum tolerated dose was not reached. Two DLTs (Grade 3 thrombocytopenia and Grade 2 fatigue) were observed in patients receiving selinexor 60mg twice weekly; both patients showed responses. Based on the preliminary tolerability and efficacy data, the RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dex (40mg orally, once weekly).

"Preclinical results have shown that oral selinexor sensitizes patients’ myeloma cells to the anti-CD38 monoclonal antibody, Darzalex," stated Dr. Gasparetto. "These Phase 1b data are early but encouraging, and suggest that selinexor can be safely combined with Darzalex and low-dose dexamethasone in patients with heavily pretreated myeloma. The responses observed occur rapidly within a median one cycle of treatment. We look forward to further evaluating the SDd combination."

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,200 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more 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.

On December 10, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported the presentation of Phase 1/2 clinical data for its novel, second-generation oral SINE compound eltanexor (KPT-8602) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 annual meeting being held December 9-12, 2017 in Atlanta (Press release, Karyopharm, DEC 10, 2017, View Source [SID1234522491]). Clinical and preclinical data for its lead, oral SINE compound selinexor, and other pipeline asset KPT-9274, an oral, dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT) were also presented.

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"A key presentation at ASH (Free ASH Whitepaper) this year features updated Phase 1/2 data showing that eltanexor is well tolerated and demonstrates promising durable activity in patients with heavily pre-treated myeloma," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "The recommended Phase 2 dose (RP2D) has now been established. We have now begun enrolling patients into expansion cohorts where we are evaluating eltanexor in patients with advanced colorectal cancer (CRC), castration-resistant prostate cancer (crPC), and myelodysplastic syndrome (MDS)."

Updated Phase 1/2 Clinical Data for Oral Eltanexor

In the poster presentation titled, "Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma," (Abstract #3134) Robert Frank Cornell, MD, Vanderbilt University Medical Center, presented updated clinical data from a Phase 1/2 study evaluating the efficacy, tolerability, pharmacokinetics and pharmacodynamics of oral eltanexor with or without low dose dexamethasone, in patients with relapsed or refractory MM, most with quad- or penta-refractory disease. Using a 3+3 dose escalation design, oral eltanexor (5, 10, 20, 30, 40 and 60mg) was dosed either once daily for five days per week or once every other day for three days each week for a 28-day cycle. Patients with less than a minimal response after one cycle or partial response after two cycles were permitted to add dex. In some patients, dex was added beginning on Day 1. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable Patients as of 3-Nov-20172
N3 ORR VGPR PR MR SD CBR
Patients receiving 20 and 30mg + dex 14 5 (36%) 1 (7%) 4 (29%) 4 (29%) 4 (29%) 9 (64%)
All 34 7 (21%) 1 (3%) 6 (18%) 9 (26%) 12 (35%) 16 (47%)
Key: ORR=Overall Response Rate (VGPR+PR), MR=Minor Response, SD=Stable Disease, CBR=Clinical Benefit Rate (VGPR+PR+MR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Five non-evaluable patients: 1 dose limiting toxicity, 2 patient decisions, 1 lost to follow up, 1 principal investigator decision

Of the 34 evaluable patients, 14 received dex with their eltanexor regimen. Objective responses correlated with longer overall survival and all patients with a VGPR or PR are still alive or censored as of November 24, 2017. Deeper and faster responses were observed when dex was started on Day 1 of Cycle 1 versus delayed dex. Among the 35 patients evaluable for M-protein, 25 patients (71%) had reductions in M-protein. The median time on treatment for the overall study population was greater than 96 days (range, 10-441).

Among the 39 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (54%), fatigue (46%), anemia (38%), diarrhea (38%), dysgeusia (33%), weight loss (33%) and neutropenia (31%). As expected in this patient population, the most common Grade 3/4 adverse events were thrombocytopenia (56%), neutropenia (26%), anemia (15%), leukopenia (15%) and hyponatremia (10%). Importantly, nausea, fatigue, diarrhea and vomiting were nearly all Grade 1, manageable and transient, and bleeding was uncommon. The maximum tolerated dose was not reached; however, dose escalation was halted as responses were achieved. Based on these data, the RP2D has been established as 20mg eltanexor dosed five times per week with 20mg dex dosed twice weekly.

Based on these results, this Phase 1/2 study is being expanded to include patients with advanced CRC, crPC, and high risk MDS. These are indications where selinexor and XPO1 inhibition has shown clear activity, but where side effects such as fatigue and anorexia were problematic for patients due to the underlying malignancies. To date, eltanexor has shown lower levels of these side effects compared to selinexor and Karyopharm believes eltanexor has the potential to control malignancies in these indications with a favorable side effect profile.

"These Phase 1/2 results show that eltanexor, both alone or in combination with dex, induces responses or disease control and is associated with prolonged survival. The combination of eltanexor and low-dose dex was well tolerated and improved the anti-cancer activity, especially if started on Day 1 of Cycle 1. The RP2D regimen has now been established and we look forward to evaluating this promising combination in patients with CRC, crPC and high risk MDS," stated Dr. Cornell.

In addition to the Phase 1/2 eltanexor data, several other abstracts describing Karyopharm’s drug candidates were presented at ASH (Free ASH Whitepaper) 2017, including:

Oral Presentations

Title: PAK4 Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenstrom Macroglobulinemia (WM)
Presenter: Li Na, Dana Farber Cancer Institute
Abstract Number/Publication ID: 648

Title: Selinexor in Combination with Cladribine, Cytarabine and G-CSF for Relapsed or Refractory AML
Presenter: Geoffrey Uy, Washington University School of Medicine in St. Louis
Abstract Number/Publication ID: 816

Title: The Mechanisms by Which Mutant-NPM1 Uncouples Differentiation from Proliferation Are Reversed By Several Drugs, Enabling Rational Multi-Component Non-Cytotoxic Differentiation Therapy
Presenter: Saunthararajah Yogen, Cleveland Clinic
Abstract Number/Publication ID: 878

Poster Presentations

Title: A Phase I/II study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 mutated Acute Myeloid Leukemia (AML)
Presenter: Naval Daver, University of Texas MD Anderson Cancer Center
Abstract Number/Publication ID: 1344

Title: Selective Inhibition of Nucleocytoplasmic Transport Overcomes Ruxolitinib Resistance in Myelofibrosis (MF)
Presenter: Dongqing Yan, Huntsman Cancer Institute
Abstract Number/Publication ID: 1660

Title: XPO1 Inhibition Synergizes with BCR Inhibition, Blocks Tumor Growth and Prolongs Survival in a Bioluminescent Animal Model of Primary Central Nervous System Lymphoma (PCNSL)
Presenter: Marta Crespo, Hall d’Hebron, Barcelona
Abstract Number/Publication ID: 2808

Title: Phase I/II Study of Liposomal Doxorubicin (DOX) in Combination with Selinexor (SEL) and Dexamethasone (Dex) for Relapsed and Refractory Multiple Myeloma
Presenter: Rachid Baz, H. Lee Moffitt Cancer Center and Research Institute
Abstract Number/Publication ID: 3095

Title: Selinexor maintenance is feasible and tolerable after allogeneic stem cell transplant (allo-SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)
Presenter: Hongtao Liu, University of Chicago Medical Center
Abstract Number/Publication ID: 3312

Title: Inhibition of XPO1 by KPT-330 (Selinexor) Enhances Cell Death Induced by the BCL-2 Selective Inhibitor ABT-199 (Venetoclax) through Downregulation of Mcl-1 in Acute Myeloid Leukemia
Presenter: Daniel Luedtke, Wayne State University School of Medicine
Abstract Number/Publication ID: 3819

Title: XPO1 Inhibitor Selinexor Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma (MCL) via Nuclear Retention of IκB
Presenter: Mei Ming, University of Chicago
Abstract Number/Publication ID: 3837

About Eltanexor (KPT-8602)

Eltanexor (KPT-8602) is a second generation oral SINE compound. Eltanexor functions by binding to and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. Eltanexor has demonstrated minimal brain penetration in animals, which has been associated with reduced toxicities in preclinical studies while maintaining potent anti-tumor effects.

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,200 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more 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.

On December 10, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported data from the randomized Phase 2 trial of its investigational intratumoral TLR4 agonist G100 plus low-dose radiation (G100 Monotherapy) with or without KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in follicular non-Hodgkin’s lymphoma (FL) patients (Press release, Immune Design, DEC 10, 2017, View Source [SID1234522489]). The G100 Monotherapy and pembrolizumab combination resulted in a 39% objective response rate (ORR), with a 57% ORR in those patients who expressed a potential predictive biomarker. These data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual meeting in Atlanta, Georgia on Sunday, December 10, 2017.

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"We have been developing two immuno-oncology platforms in parallel: an intratumoral immunization approach with G100 as the lead therapeutic candidate, and novel cancer vaccines from the Dendritic cell-targeting RNA vector platform, ZVex. We believe these data presented at ASH (Free ASH Whitepaper) confirm that G100 is an active and safe agent that results in systemic tumor responses, which are further enhanced in combination with KEYTRUDA," said Carlos Paya, M.D., Ph.D., President and Chief Executive Officer of Immune Design. "In light of the fact that some inhibitors of the anti-PD-1 class are viewed to have limited activity in this type of hematological malignancy, these positive data support further investigation of the potential synergy of G100 with anti-PD-1/L1 agents and the use of TLR4 expression as a potential predictive biomarker."

The randomized Phase 2 trial was designed to examine intratumoral (IT) administration of G100 Monotherapy vs. G100 Monotherapy + pembrolizumab (G+P) in either treatment naïve or recurrent/refractory FL patients (13 patients/arm). Highlights from the study include:

Clinical Benefit
Patients receiving G+P showed a 39% ORR, as compared to 15% in the G100 Monotherapy arm.
Pembrolizumab monotherapy in a similar recurrent/refractory FL study showed 11% ORR (Ding, ASH (Free ASH Whitepaper) 2017 abstract).
Patients receiving G+P also had more frequent and deeper abscopal tumor shrinkage and a trend toward a better progression free survival (PFS).
Safety: Adverse events considered possibly related to G100 were Grade 1 or 2, with no related serious adverse events. The safety experience in the G+P arm did not suggest any unexpected or worsening toxicity compared to what has been reported previously with pembrolizumab alone.
Potential Predictive Biomarker: A strong association between baseline tumor TLR4 expression and objective clinical response was observed. Reported ORR in patients with a >50% TLR4 expression by IHC (TLR4high) receiving G+P increased to 57%, including patients with recurrent/refractory disease.
Potential Further Development: Because clinical responses were observed in patients with recurrent/refractory disease, treatment failure <2 years after rituximab-containing chemotherapy, and high-risk patients based on GELF criteria, G+P may provide a therapeutic option in this unmet medical need population. Enrichment of patients more likely to respond may be attained by selecting for high expression of TLR4.
Additional subtypes of indolent lymphomas with injectable lesions are known to express TLR4, which expands the potential of this combination of G100 and pembrolizumab in hematological malignancies beyond FL. Likewise, many solid tumors are known to express TLR4.

G100 has been granted orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of FL.

Conference Call Information

Immune Design will hold a conference call on Monday, December 11, 2017 at 8:00 a.m. EST. Ahmad S Halwani, MD, Assistant Professor of Medicine, Huntsman Cancer Institute, University of Utah, and a Principal Investigator on the trial, will join the call.

The live call may be accessed by dialing 844-266-9538 for domestic callers and 216-562-0391 for international callers. The audience passcode is 3258589. A live webcast of the call will be available online from the investor relations section of the company website at View Source and will be archived there for 30 days. A telephone replay of the call will be available for five days by dialing 855-859-2056 for domestic callers or 404-537-3406 for international callers and entering the conference code: 3258589.

ASH Presentation Details:

Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/2 Study Examining G100 Alone and in Combination with Pembrolizumab (Abstract # 2771)

Presenter: Christopher R. Flowers, M.D.
Session Name: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster II
Poster Discussion: Sunday, December 10, 2017, 6:00 PM – 8:00 PM Eastern
Location: Georgia World Congress Center, Bldg A, Lvl 1, Hall A2

About G100

G100 is a product candidate from Immune Design’s GLAAS discovery platform. It contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA), and is the lead product candidate in Immune Design’s Antigen Agnostic approach. G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s preexisting diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control.

About Follicular Non-Hodgkin’s Lymphoma

Follicular lymphoma is a malignancy affecting the lymph nodes and may spread to the bone marrow or spleen. The most common type of slow-growing (indolent) non-Hodgkin’s lymphoma (NHL), it represents approximately 20% of all NHL cases. Despite advances in treatment options in recent decades, FL is considered incurable. Currently, patients who do not respond to initial treatment or whose disease progresses within two years of diagnoses after treatment have a worse survival prognosis and may constitute an unmet medical need population. In 2017, it is estimated that more than 14,000 new cases of FL will be diagnosed in the United States alone.

On December 10, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive results from the randomised phase II GO29365 study that compared polatuzumab vedotin in combination with bendamustine plus MabThera/Rituxan (rituximab) (BR) against BR alone in people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant (Press release, Hoffmann-La Roche, DEC 10, 2017, View Source [SID1234522488]). The study met its primary endpoint, demonstrating that the addition of polatuzumab vedotin to BR increased complete response (CR) rates from 15% to 40% (p=0.012) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). No unexpected safety signals were observed with the addition of polatuzumab vedotin to BR.

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"As many as forty percent of people with diffuse large B-cell lymphoma do not respond to initial therapy or experience the return of their disease, at which point their treatment options are limited and the prognosis is poor," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The promising efficacy observed for polatuzumab vedotin in this study supports its potential as a new treatment option for people previously treated for this aggressive blood cancer, and we look forward to discussing the results with health authorities."

The data will be presented in a poster session on Sunday, 10 December at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Laurie Sehn, MD, British Columbia Cancer Agency/University of British Columbia.
The results showed:

Polatuzumab vedotin plus BR significantly improved CR rates from 15% with BR alone to 40% (p=0.012), as measured by PET and assessed by IRC. A CR means no cancer could be detected at that time.
The benefit observed was consistent across secondary endpoints, including improvements in investigator-assessed best objective response (OR; CR and partial response, PR) and CR with polatuzumab vedotin plus BR (70.0% OR, 57.5% CR) compared to BR alone (32.5% OR, CR 20.0%).

Exploratory endpoints also improved with the addition of polatuzumab vedotin to BR:
Patients treated with polatuzumab vedotin plus BR lived longer than those receiving BR alone (median overall survival; 11.8 months vs. 4.7 months; HR 0.35; 95% CI 0.19-0.67; p=0.0008).
The addition of polatuzumab vedotin also increased the time until disease worsening or death (median progression-free survival: 6.7 months vs. 2.0 months; HR 0.31; 95% CI 0.18-0.55; p<0. 0001), and the time between first response to treatment and disease worsening (duration of response: 8.8 months vs. 3.7 months).
No unexpected safety signals were observed with the addition of polatuzumab vedotin to BR. The most common Grade 3-4 adverse events with polatuzumab vedotin plus BR compared to BR alone, respectively, were low white blood cell count (46.2% vs. 35.9%), low white blood cell count with fever (10.3% vs. 5.1%), low platelet count (33.3% vs. 20.5%), anaemia (25.6% vs. 12.8%) and infections (17.9% vs. 17.9%).
Based on results from this study, polatuzumab vedotin was recently granted Breakthrough Therapy Designation by the US Food and Drug Administration and PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of people with relapsed or refractory DLBCL. There are a number of ongoing studies evaluating the efficacy and safety of polatuzumab vedotin for several types of non-Hodgkin lymphoma, including combinations with Gazyva /Gazyvaro (obinutuzumab), MabThera/Rituxan, Venclexta/Venclyxto (venetoclax) and Tecentriq (atezolizumab).

About the GO29365 study
GO29365 is a global, phase Ib/II randomised study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with MabThera /Rituxan (rituximab) or Gazyva /Gazyvaro (obinutuzumab) plus bendamustine in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). The phase II stage randomised 80 patients with heavily pre-treated R/R DLBCL to receive either bendamustine plus MabThera/Rituxan (BR), or BR in combination with polatuzumab vedotin. Patients enrolled had received a median of two prior therapies (a range of 1-7 prior therapies in the polatuzumab vedotin arm and range of 1-5 prior therapies in the BR alone arm). The primary endpoint was complete response (CR) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). Secondary endpoints included objective response (OR; CR and partial response, PR) by investigator assessment and best objective response at the end of treatment by investigator and IRC assessment. Exploratory endpoints included duration of response (DOR), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS).

About polatuzumab vedotin
Polatuzumab vedotin is a first-in-class anti-CD79b antibody drug conjugate (ADC) currently being investigated for the treatment of several types of non-Hodgkin lymphoma (NHL). The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies.1 Polatuzumab vedotin binds to CD79b and destroys these B-cells via a targeted approach, which is thought to minimise the effects on normal cells while maximising tumour cell death. Polatuzumab vedotin is being developed by Roche utilising Seattle Genetics ADC technology.

About diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL.2 DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline.3 However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short.3 Approximately 123,000 people worldwide are estimated to be diagnosed with DLBCL each year.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera /Rituxan (rituximab), Gazyva /Gazyvaro (obinutuzumab), and Venclexta / Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.

On December 10, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 trials with luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Acceleron Pharma, DEC 10, 2017, View Source [SID1234522480]). Luspatercept is being developed as part of a global collaboration between Acceleron and Celgene.

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"As the Phase 2 results in MDS mature, we are excited to see luspatercept achieving a clinically meaningful erythroid response in over 50% of patients. Luspatercept continues to provide long-term benefit to multiple patients now nearing three years on treatment. These results further reinforce luspatercept’s potential to be a transformative treatment option for patients living with lower-risk MDS," said Habib Dable, President and Chief Executive Officer of Acceleron. "We look forward to the upcoming MEDALIST and BELIEVE Phase 3 trial top-line data readouts in mid-2018, and we and Celgene continue to make considerable progress toward initiating the COMMANDS Phase 3 trial during the first half of 2018."

Phase 2 Results

A total of 99 lower-risk MDS patients have been treated with therapeutic dose levels of luspatercept (≥ 0.75 mg/kg) in the ongoing Phase 2 trials.

53% (52 of 99 patients) achieved a clinically meaningful erythroid response of an increase in hemoglobin or reduction in red blood cell (RBC) transfusion burden as per the International Working Group’s Hematologic Improvement Erythroid (IWG HI-E) response criteria.
43% (29 of 67 patients) with an RBC transfusion burden at baseline of ≥ 2 units per 8 weeks achieved RBC transfusion independence (RBC-TI) for ≥ 8 weeks.
In an updated analysis of the 23 RBC-TI responders previously reported at EHA (Free EHA Whitepaper) 2017, the median duration of treatment increased to 19.0 months from 14.7 months. The current duration of treatment for RBC-TI responders ranges from 2.8 months to 37.3 months.
Patients with a low transfusion burden at baseline ( < 4 RBC units per 8 weeks and hemoglobin < 10 g/dL) demonstrated a clinically meaningful increase in hemoglobin for up to 34 months, with multiple ongoing.
The results presented at ASH (Free ASH Whitepaper) 2017 confirm and extend previously reported results across the lower-risk MDS patient subpopulations, showing erythroid responses regardless of prior use of erythropoiesis-stimulating agents (ESA), baseline erythropoietin (EPO) levels, and ring sideroblast (RS) status.

Phase 2 Safety Summary

A total of 106 lower-risk MDS patients have been treated with luspatercept in the ongoing Phase 2 trials (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. AEs possibly or probably related to study drug that occurred in at least three patients during the studies were headache, hypertension, fatigue, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and edema peripheral.
Grade 3 non-serious AEs possibly related to study drug were ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, mucosal inflammation, platelet count increase, and pleural effusion. These Grade 3 non-serious AEs occurred in seven individual patients with one patient reporting both the ascites and pleural effusion.
Serious AEs (SAEs) possibly related to study drug were general physical health deterioration, muscular weakness, musculoskeletal pain, and myalgia. These SAEs occurred in three individual patients with one patient reporting both the muscular weakness and musculoskeletal pain.
The MEDALIST trial, a global Phase 3 trial of luspatercept in lower-risk MDS patients, is fully enrolled with top-line results expected in mid-2018. The MEDALIST trial enrolled patients who are RS-positive, RBC transfusion dependent, and are ESA-refractory or ESA-treatment ineligible, based on EPO levels greater than 200 units per liter at baseline. Acceleron and Celgene plan to initiate the COMMANDS Phase 3 trial in first-line, lower-risk MDS patients during the first half of 2018.

The MDS clinical poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com.

Luspatercept is an investigational product that is not approved for use in any country.

Acceleron ASH (Free ASH Whitepaper) Conference Call Information

Acceleron will host a conference call and live webcast to discuss data presented at the ASH (Free ASH Whitepaper) meeting on December 11, 2017, at 7:00 a.m. EST.

Individuals can participate in the conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and refer to the "Acceleron ASH (Free ASH Whitepaper) 2017 Update."

The webcast will be accessible under "Events & Presentations" in the Investors/Media page of the Company’s website at www.acceleronpharma.com.

A replay of the webcast will be available approximately two hours after the event.

About the Ongoing MDS Phase 2 Studies

Data from two Phase 2 trials were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, lower-risk MDS patients were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The outcome measures for the trials included the proportion of patients who had an erythroid response (IWG HI-E) or achieved RBC transfusion independence (RBC-TI). IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with < 4 units RBC / 8 weeks transfusion burden at baseline and hemoglobin levels below 10 g/dL. For patients with a ≥ 4 units RBC / 8 weeks transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 units RBC sustained for ≥ 8 weeks. RBC-TI was defined as receiving no RBC transfusions for ≥ 8 weeks in patients with a ≥ 2 units RBC / 8 weeks baseline transfusion burden.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the TGF-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept is a first-in-class erythroid maturation agent (EMA) that regulates late-stage erythrocyte (red blood cell) precursor cell differentiation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A Phase 3 trial is being planned in first-line, lower-risk, myelodysplastic syndromes patients (the COMMANDS trial). For more information, please visit www.clinicaltrials.gov.