On December 1, 2018 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported a presentation of the first interim data with melflufen (Ygalo) from the ongoing phase I/II study ANCHOR at the 60th ASH (Free ASH Whitepaper) meeting in San Diego, California, USA (Press release, Oncopeptides, DEC 1, 2018, View Source [SID1234531775]).

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Overall conclusions

The combinations of melflufen and dexamethasone (dex) with either bortezomib or daratumumab in relapsed-refractory multiple myeloma (RRMM) patients are well tolerated
No dose limiting toxicity has been observed at the melflufen 30 and 40 mg dose levels in either regimens. The 40 mg dose level is still recruiting patients
An Overall Response Rate (ORR) of 86% was observed with melflufen and dexamethasone in combination with daratumumab (CD38-directed monoclonal antibody)
An Overall Response Rate (ORR) of 100% was observed with melflufen and dexamethasone in combination with bortezomib (proteasome inhibitor)
The data are presented in a poster that can be found at: www.oncopeptides.com / presentations / 60th ASH (Free ASH Whitepaper)

CEO comments

"Although, these are early data and small patient samples, it is encouraging to see that melflufen is well tolerated and has a very high level of activity with no cross resistant pattern in combination regimens. These patients have undergone 2-3 prior lines of therapy and have developed resistant disease. The interim data show a very good efficacy profile for melflufen in combination with either bortezomib or daratumumab. In a cross-study comparison in RRMM patients treated with combination regimens our interim data with an ORR in the range 86-100% stand out positively. The treatment landscape changes over time and there is a high need of new treatment options with a novel mechanism of action like melflufen" said Jakob Lindberg, CEO of Oncopeptides.

About the ANCHOR study

The study recruitment is ongoing. ANCHOR is a phase I/II study where melflufen and dexamethasone (dex) is dosed in combination with either bortezomib or daratumumab. All patients must have 1-4 prior lines of therapy and be refractory (or intolerant) to an immunomodulary agent (IMiD) or a proteasome inhibitor (PI) or both.

In combination with bortezomib (Regimen A) patients cannot be refractory to a PI and in combination with daratumumab (Regimen B) patients cannot be previously exposed to any anti-CD38. Patients will be treated until documented disease progression or unacceptable toxicity. The primary objective of the phase I part of the study is to determine the optimal dose of melflufen and dex, up to a maximum of 40 mg, in combination with bortezomib or daratumumab. An additional 20 patients per regimen will be recruited in the phase II part of the study where the primary objective is ORR.

Summary of the ANCHOR interim data

Melflufen in combination with bortezomib – Regimen A

At the time of the data cut-off November 12, 2018, 3 patients had been treated with 30 mg melflufen and dex in combination with bortezomib. Median age was 81 years with a median of 3 prior lines of therapy. All patients were relapsed-refractory and 2 out of 3 patients were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off with a median treatment duration of 5.8 months.

The patients received a total of 17 cycles of treatment with a median of 7. All 3 patients achieved partial response (PR). No dose limiting toxicities were observed at the 30 mg melflufen dose level and the melflufen 40 mg has been opened for enrollment. The regimen was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

Melflufen in combination with daratumumab – Regimen B

At the time of the data cut-off, November 12, 2018, 9 patients had been treated with melflufen in combination with daratumumab and dex. Median age was 63 years with a median of 2 prior lines of therapy. No patient had achieved CR in any previous line of therapy, 67% were IMiD refractory and 56% were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off.

All 9 patients were still ongoing with a median treatment duration of 3.9 months. They received a total of 39 cycles of treatment with a median of 4.

Overall response rate N/A*
ORR CR VGPR PR MR SD PD
total, N=9 86% 0 4 2 0 1 0 2
*2 of the 9 patients were still in their first cycle of treatment and were therefore not evaluable for response as described at time for data cut.

4 patients were treated with 30 mg melflufen and 5 patients were treated with 40 mg melflufen with no dose limiting toxicity observed. The combination of melflufen, dexamethasone and daratumumab was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

About Melflufen

Melflufen (Ygalo), a peptide conjugated alkylator belonging to a novel class of peptidase-enhanced compounds, targets multiple myeloma (MM) cells with a unique mechanism of action. Aminopeptidases are enzymes found in all cells but are over-expressed in several cancers including MM. Ygalo selectively targets MM cells through aminopeptidase-driven accumulation. In vitro experiments show a 50-fold enrichment of the active substance in MM cells compared with administration of equal amount of an alkylator not enriched by aminopeptidases. The enrichment results in selective cytotoxicity (increased on-target potency and decreased off-target toxicity), and that resistance pathways of existing myeloma treatments (including alkylators) is overcome. Melflufen also demonstrates strong anti-angiogenic properties.

Melflufen in clinical development

Melflufen (Ygalo) has been used to treat late-stage RRMM patients in both phase I and phase II clinical studies (O-12-M1) with favorable results. Currently, melflufen is being studied in four clinical trials for the treatment of multiple myeloma. The current studies are OCEAN, HORIZON, ANCHOR and BRIDGE.

The current clinical study program is intended to demonstrate better results from treatment with melflufen compared to established alternative drugs for patients with multiple myeloma. Melflufen could potentially provide physicians with a new treatment option for patients suffering from this serious disease.

Melflufen has been investigated in the treatment of late-stage relapsed refractory multiple myeloma (RRMM) patients. This was done in the clinical study O-12-M1 where strong final results were reported in December 2017. Currently, four clinical studies are ongoing with melflufen.

OCEAN is Oncopeptides pivotal Phase III study where melflufen is compared directly with current standard of care, pomalidomide, in late-stage RRMM patients.

HORIZON is a Phase II study that studies the effect of melflufen in late-stage RRMM patients with few or no remaining established treatment options. Updated interim data from this study will be presented at ASH (Free ASH Whitepaper) in December 2018.

ANCHOR is a phase I/II study where melflufen is administered in combination with either bortezomib or daratumumab in RRMM patients. The results of this study aim to create understanding and knowledge among treating physicians for how melflufen can be used in combination with these drugs. In addition, the results could open up for the use of melflufen in earlier lines of treatment.

BRIDGE is a phase II study, where melflufen is used in RRMM patients with impaired renal function. This is a positioning study to show melflufen’s treatment profile in these patients.

On December 1, 2018 MaaT Pharma reported the results from its ODYSSEE (NCT02928523) Phase 1b/2a clinical trial demonstrating that the Company’s proprietary MaaT Microbiome Restoration Biotherapeutic (MMRB) therapeutic is able to restore a functional microbiome in acute myeloid leukemia (AML) patients after having undergone intensive chemotherapy and multiple courses of antibiotics (Press release, MaaT Pharma, DEC 1, 2018, View Source [SID1234531791]). The study was designed to investigate the safety and feasibility of reestablishing a functional microbiome using MaaT Pharma’s therapeutic as well as evaluating initial signs of efficacy including reduction of intestinal inflammation and the control of detrimental antibiotic-resistant bacteria. Due to the harsh treatment regimens, AML patients lose their functional microbiome and experience a variety of severe complications that dramatically impact outcomes and quality of life. MaaT Pharma’s MMRB therapeutic aims to restore microbiome function and improve clinical outcomes in these patients. The data were presented at 6:15 pm Pacific Time on December 1st, 2018 at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held in San Diego, California.

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In total 25 AML patients were treated in the clinical trial. At the time of admission, fecal microbiota was collected from each patient, conditioned, processed and frozen according to GMP conditions. Following the first round of chemotherapy and antibiotic treatment, patients were administered two doses of the collected fecal microbiota as an enema 24 hours apart after hematopoietic recovery and before undergoing the second round of chemotherapy. Blood and fecal samples were collected on three separate days, (1) on day 0, at the time of patient inclusion in the trial, (2) on day 29, following hematopoietic recovery after the first round of intensive treatments and (3) on day 40, before the start of the consolidation chemotherapy. Microbiome profile evolution was analyzed using high-resolution metagenome sequencing and patient follow-up was scheduled for 6 months and 12 months after inclusion.

"The results from the ODYSSEE clinical trial are impressive and demonstrate proof-of-concept for the ability of our approach to restore a functional microbiome, following antibiotics and chemotherapies, in AML patients and that reestablishing the microbiome has the potential to improve survival outcomes," commented Professor Mohamad Mohty, MD, PhD, Professor of Hematology at Sorbonne University and Head of the Hematology and Cellular Therapy Department at the Saint Antoine Hospital in Paris. "Acute myeloid leukemia patients have limited treatment options and the intensive chemotherapy and antibiotic therapy regimens they have to endure significantly contribute to poor quality of life and low survival outcomes. Given these positive results, we look forward to our planned randomized trial with the off-the-shelf capsule formulation MaaT033, as the next step."

Overall, reintroduction of the patient’s own gut microbiome through MaaT Pharma’s proprietary process was well tolerated and no severe adverse events were reported. Metagenomic analysis of the patient samples collected on days 0, 29 and 40 using MaaT Pharma’s proprietary big data analysis platform, GutPrint showed that the MMRB therapeutic restored significantly greater than 90% of the microbial species diversity and structure at day 40, ten days after treatment, including a 43% reduction of the overall expression of antibiotic resistance genes. Most importantly, gut inflammation was significantly reduced to near-baseline levels following MMRB treatment as measured by fecal neopterin biomarker. These results also correlated with the significant reduction of pro-inflammatory bacterial families and restoration of beneficial species among the Lachnospiraceae and Ruminococcaceae families.

"Our commitment has always been to improve outcomes in patients with life-threatening diseases. The results and experience from this trial support our investment in developing standardized, reproducible and high diversity microbiome biotherapeutic products using our MMRB therapeutic and cGMP production facility to treat patients with blood cancers and the complications arising from its treatment," added Hervé Affagard, Co-founder and CEO of MaaT Pharma. "Our lead product, MaaT013, which is manufactured from pooled donors, was developed based on the positive data we collected from this trial and the scientific and clinical evidence showing that restoring the microbiome has therapeutic potential. MaaT013 is currently being tested in a Phase 2 clinical study to treat acute graft-versus-host-disease, a severe consequence of stem cell transplantation. We are also very pleased to have just been awarded Orphan Drug Designation by the EMA for this product after already receiving the designation by the FDA earlier this year."

The poster is available on the company website under "News" or by accessing the following link View Source

On December 1, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported positive top-line results from the Phase 2b SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue (Press release, Karyopharm, DEC 1, 2018, View Source [SID1234531776]). The data were highlighted in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting in San Diego. For the SADAL study’s primary endpoint, single-agent selinexor achieved a 29.6% overall response rate (ORR), which included a 9.6% complete response (CR) rate in patients with heavily pretreated relapsed or refractory DLBCL. Key secondary endpoints included a median duration of response (DOR, in the responding patients) of 9.2 months and median overall survival (OS, across the entire study) of 9.1 months.

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Selinexor recently received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Karyopharm plans to submit a New Drug Application (NDA) to the FDA during the first half of 2019, with a request for accelerated approval for oral single-agent selinexor as a new treatment for patients with relapsed or refractory DLBCL.

Top-Line Phase 2b SADAL Results

Based on the modified intention-to-treat analysis from the first 115 of 127 patients (median of 2 prior treatment regimens with a range 1-6), as adjudicated by an independent central radiological committee, 34 patients responded (11 patients with a CR and 23 patients with a PR) for an ORR of 29.6%. An additional 8 patients experienced stable disease (SD) for a disease control rate of 36.5%. The median DOR across responding patients was 9.2 months and responses tended to occur rapidly. Patients with a CR had a median DOR of 23.0 months and patients with a PR had a median DOR of 7.8 months. As of the data cutoff date of November 15, 2018, 7 patients who achieved a CR remained on treatment. In addition, 12 patients remain on treatment, but as of November 15th, had not reached their first response assessment and are not included in the top-line efficacy analyses.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were gastrointestinal and constitutional symptoms, along with cytopenias; most manageable with dose modifications and/or supportive care. The most common non-hematologic AEs were nausea (50.0%), fatigue (35.9%), and anorexia (32.0%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 AEs were thrombocytopenia (35.2%), neutropenia (20.3%), and anemia (10.9%) and were generally not associated with clinical sequelae. No significant major organ toxicities were observed, and bleeding and infection rates were low.

The median OS was 9.1 months for all patients in the study. As of the data cutoff date, median survival for the patients with a CR or PR was 29.7 months. The median survival for patients with best response of progressive disease or who were not evaluable for response was 3.2 months.

Selinexor showed robust, single-agent activity in patients with either GCB or non-GCB subtypes of DLBCL: of the 53 patients with the GCB-subtype, 18 responded (5 patients with a CR and 13 patients with a PR) for an ORR of 34.0%. Of the 57 patients with the non-GCB subtype, 12 responded (6 patients with a CR and 6 patients with a PR) for an ORR of 21.1%. In addition, there were 5 patients enrolled whose subtype was unclassified and 4 of these patients achieved a PR.

"The SADAL data presented at ASH (Free ASH Whitepaper) this year demonstrate that oral selinexor, when administered as a single-agent, is clinically active and capable of producing durable responses associated with prolonged overall survival," said Marie Maerevoet, MD, Institute Jules Bordet, "The 60mg twice weekly oral dose continues to be well tolerated with a low incidence of Grade 3 or greater adverse events, which were often manageable with dose modifications and supportive care. We are highly encouraged by the results of this single agent study in patients with heavily pretreated DLBCL who have limited available treatment options."

Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm, said, "In addition to the compelling efficacy and safety data observed with single agent oral selinexor, we were especially pleased to see strong response rates in patients with both the GCB and non-GCB subtypes. This is especially important because the prognosis in patients with refractory disease and the GCB-subtype is particularly poor. We believe that if selinexor is ultimately approved for use in patients with DLBCL, it will provide a meaningful therapeutic option for patients battling refractory disease regardless of DLBCL subtype. We look forward to submitting these data to the FDA during the first half of 2019 as part of a New Drug Application, with a request for accelerated approval."

Details for the Poster Presentation at ASH (Free ASH Whitepaper) 2018:

Title: Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b SADAL Study
Presenter: Marie Maerevoet, Institute Jules Bordet, Brussels, Belgium
Abstract Number/Publication ID: 1677
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster I
Date and Time:Saturday, December 1, 2018; 6:15-8:15 PM PT
Location: San Diego Convention Center, Hall GH

About Selinexor

Selinexor 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 2,800 patients have been treated with selinexor. In April and September 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval. Selinexor is also being evaluated in several other 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), as a potential backbone therapy in combination with approved therapies (STOMP), in diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study 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.

On December 1, 2018 Unum Therapeutics Inc. (NASDAQ: UMRX), reported preliminary results from the ongoing Phase 1 ATTCK-17-01 study, testing ACTR087 in combination with SEA-BCMA in patients with relapsed/refractory multiple myeloma (r/r MM) at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego, CA (Press release, Unum Therapeutics, DEC 1, 2018, View Source [SID1234531761]).

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First-in-human dosing of single agent SEA-BCMA, and of ACTR087 in combination with SEA-BCMA, in the ATTCK-17-01 multi-center, open-label Phase 1 dose-escalation study was well-tolerated, with no dose-limiting toxicities (DLTs) in the first three cohorts. Following infusion, ACTR+ T cells were detectable in these patients and demonstrated expansion post infusion. Furthermore, early disease assessments suggest combination activity of SEA-BCMA with ACTR087. These data support continued dose escalation of ACTR087 and SEA-BCMA in the trial.

"We are pleased with the early data we have observed showing biomarker evidence of antibody-dependent ACTR T cell activation at the lowest doses of SEA-BCMA," said Michael Vasconcelles, Chief Medical Officer of Unum. "Combining ACTR087 with a novel antibody like SEA-BCMA brings together multiple anti-myeloma mechanisms of action that are unique to this combination. Furthermore, this approach provides us the ability to adjust the doses of both the antibody and ACTR087, to optimize the therapeutic index of the combination. We are excited about the potential to develop a meaningful combination for patients with relapsed or refractory myeloma. We look forward to continued dose escalation of the combination in ATTCK-17-01 to further assess its safety and anti-myeloma activity."

The majority of subjects, including at the lowest SEA-BCMA dose levels, demonstrated increasing serum and urine M protein levels during SEA-BCMA single-agent dosing that stabilized or decreased following ACTR087 administration, suggesting combination activity of ACTR087+SEA-BCMA. Subjects exhibited early increases in interferon gamma following ACTR087 administration, and additional elevations following subsequent SEA-BCMA administrations, suggestive of antibody-dependent T cell activation. SEA-BCMA was well-tolerated with no serious adverse events related to SEA-BCMA reported. No DLTs after the SEA-BCMA single-agent dosing period or after the ACTR087 + SEA-BCMA combination were reported across all three cohorts. No severe events of cytokine release syndrome (CRS) or severe neurological events were reported.

About the ATTCK-17-01 Trial
ACTR087 used in combination with SEA-BCMA is being tested in ATTCK-17-01, a Phase I, multi-center, open-label clinical trial designed to test the safety, tolerability, and anti-myeloma activity in patients with r/r MM, currently in the dose escalation phase. Primary study objectives are to characterize the safety of ACTR087 in combination with SEA-BCMA and to determine the recommended Phase 2 dose. Secondary study objectives include assessment of the anti-myeloma activity of the combination, ACTR T cell expansion and persistence, cytokine and SEA-BCMA pharmacokinetics. Immediately following leukapheresis, patients may begin to receive SEA-BCMA as a single agent. Following lymphodepleting chemotherapy, a single ACTR087 infusion is administered. This is the first clinical trial conducted under the Company’s strategic collaboration with Seattle Genetics.

About ACTR087 in combination with SEA-BCMA
ACTR087 is a 4-1BB-containing receptor that also has been evaluated in combination with rituximab in adult patients with relapsed or refractory non-Hodgkin lymphoma (r/r NHL). SEA-BCMA is a novel humanized non-fucosylated antibody that targets the antigen BCMA, developed by Seattle Genetics using the Company’s sugar-engineered antibody (SEA) technology. BCMA is expressed on normal plasma cells, some mature B cells, and at comparatively elevated levels on malignant multiple myeloma cells but is absent from other normal tissues. SEA-BCMA is engineered to enhance its binding to ACTR087, providing additional rationale for this novel-novel combination.

On November 30, 2018 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported the injection of the first patient in the Phase 1 alloSHRINK trial evaluating the Company’s non-gene edited allogeneic CAR-T therapy, CYAD-101, administered concurrently with FOLFOX chemotherapy in the treatment of patients with unresectable metastatic colorectal cancer (mCRC) (Press release, Celyad, NOV 30, 2018, View Source [SID1234531747]).

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"The initiation of the alloSHRINK trial marks a critical milestone for our organization," said Dr. Christian Homsy, CEO of Celyad. "CYAD-101 represents a potential first-in-class approach to allogeneic CAR-T therapy and continues to build up Celyad’s leadership position in the allogeneic field, which is anchored by the Company’s robust allogeneic patent estate in the United States and complemented by our novel shRNA-based non-gene edited platform."

Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented, "CYAD-101 represents Celyad’s second oncology program to enter the clinic for the treatment of metastatic colorectal cancer and balances the Company’s autologous clinical candidate CYAD-01, which has demonstrated encouraging preliminary results in the Phase 1 SHRINK trial. We believe investigating CYAD-101 in the alloSHRINK trial will leverage our clinical experience to date in the treatment of metastatic colorectal cancer as we look to develop novel therapies for this devastating disease."

Celyad also announced that ONO Pharmaceutical Co., Ltd. has given notice to the Company that it will no longer pursue development of CYAD-101 in Japan, Korea and Taiwan. Celyad and ONO Pharmaceutical entered into an exclusive license agreement for the development and commercialization of CYAD-101 in these specified territories in July 2016. Based on the agreement, ONO Pharmaceutical was required to exercise an option following the initiation of the Phase 1 trial for CYAD-101. The agreement has now expired and Celyad controls worldwide development and commercialization rights to CYAD-101.

Press Release

30 November 2018

07:00 am CET

CYAD-101 and alloSHRINK Trial Design

CYAD-101 is an investigational, non-gene edited, allogeneic (donor derived) CAR-T therapy that co-expresses the chimeric antigen receptor NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells and the novel inhibitory peptide TIM (T cell receptor [TCR] Inhibiting Molecule). TCR signaling is responsible for Graft versus Host Disease (GvHD). The expression of TIM reduces signaling of the TCR complex and could therefore reduce or eliminate GvHD in patients treated with CYAD-101.

The alloSHRINK trial (NCT03692429) is an open-label, dose-escalation trial that will assess the safety and clinical activity of CYAD-101 administered concurrently with FOLFOX chemotherapy in patients with unresectable mCRC. Patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-101 every two weeks 48 hours after the initiation of chemotherapy cycles one, two and three. The three dose levels to be evaluated are 100 million, 300 million and 1 billion cells per injection, respectively.