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Karyopharm Presents Positive Phase 1/2 Eltanexor Data at the American Society of Hematology 2017 Annual Meeting

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.

Combination of G100 with KEYTRUDA (pembrolizumab) Triggers Robust Systemic Responses in Follicular NHL Patients

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.

"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.

Phase II data showed Roche’s investigational polatuzumab vedotin plus bendamustine and MabThera/Rituxan (BR) increased complete response rates compared to BR alone in previously treated aggressive lymphoma

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.

"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.

Acceleron Announces Updated Results from Ongoing Phase 2 Trials of Luspatercept in Myelodysplastic Syndromes at the 59th Annual Meeting of the American Society of Hematology

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.

"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.

Bellicum Announces Data Presentation Demonstrating Improved Immune Recovery Following Haploidentical Stem Cell Transplant with BPX-501 in Children with Blood Cancers and Nonmalignant Diseases

On December 9,2017 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported results from a leading European transplant center participating in the BP-004 trial in children with blood cancers and nonmalignant disorders (Press release, Bellicum Pharmaceuticals, DEC 9, 2017, View Source;p=RssLanding&cat=news&id=2321945 [SID1234522457]). Patients were treated with BPX-501 following an alpha/beta T cell and CD19+ B cell depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT). Results demonstrated that donor BPX-501 cells infused after transplant expanded in vivo and persisted over time, contributing to improved immune recovery for patients in the study as compared to historical controls from the same transplant center. The data were reviewed in an oral presentation today during the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

According to study author and presenter Pietro Merli of Ospedale Pediatrico Bambino Gesù in Rome, "These data show that administering BPX-501 cells following a haplo-HSCT may result in improved immune recovery and infection control, addressing significant risks in children undergoing a stem cell transplant who do not have access to a matched donor. Adding BPX-501 to a haplo-HSCT has the potential to improve outcomes and to make the curative benefits of transplants available to more children with cancers and genetic blood diseases."

Study Design and Highlights (Abstract #211)

Investigators evaluated immune recovery and outcomes of 112 pediatric patients who underwent a haplo-HSCT followed by treatment with BPX-501. Children in the study had acute leukemia (n=53), Primary Immune Deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9). All patients were transplanted after depletion of donor alpha/beta T cells and CD19 B cells to prevent graft-versus-host disease (GvHD) and post-transplant lymphoproliferative disorders (PTLD). BPX-501 cells were scheduled to be infused approximately two weeks post-transplant.

Results showed:

BPX-501 cells infused after haplo-HSCT expand and persist in patients, potentially contributing to improved recovery of adaptive immunity.
Peak expansion of BPX-501 cells is reached at nine months after infusion, and BPX-501 cells are consistently detected after two years.
CMV infection is a main driver of BPX-501 cell expansion, suggesting that BPX-501 cells cooperate in clearing the viral infection.
The overall pattern of immune recovery in 112 children studied may be improved when compared to patients who received a similar haplo-HSCT without BPX-501.
"Improved immune recovery and control over infections, as demonstrated in this study, may have a direct impact on treatment-related morbidity and mortality," commented Rick Fair, Bellicum’s President & Chief Executive Officer. "We look forward to reporting on these and other outcomes from our ongoing BP-004 trial in 2018."

A copy of the ASH (Free ASH Whitepaper) presentation will be made available in the "Investors & Media" section of the Company’s website.

About BPX-501
BPX-501 is an adjunct T cell therapy administered after allogeneic HSCT, comprising genetically modified donor T cells incorporating Bellicum’s CaspaCIDe safety switch. It is designed to provide a safety net to eliminate alloreactive BPX-501 T cells (via administration of activator agent rimiducid) should uncontrollable GvHD occur. This enables physicians to more safely perform stem cell transplants by administering BPX-501 engineered T cells to speed immune reconstitution, provide control over viral infections and enhance Graft-versus-leukemic effect without unacceptable GvHD risk. The ongoing BP-004 clinical study of BPX-501 is being conducted at transplant centers in the U.S. and Europe.