On December 3, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported presentations highlighting updated data from the Phase 2b STORM study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with penta-refractory multiple myeloma, and from two arms of the Phase 1b/2 STOMP study evaluating selinexor and dexamethasone in combination with standard approved therapies, Pomalyst (pomalidomide) or Darzalex (daratumumab), in patients with previously treated multiple myeloma (Press release, Karyopharm, DEC 3, 2018, View Source [SID1234531833]). The data were featured in oral and poster presentations at American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting taking place December 1-4, 2018 in San Diego. A New Drug Application (NDA) seeking accelerated approval for oral selinexor with low dose dexamethasone as a treatment for patients with penta-refractory multiple myeloma is under Priority Review by the U.S. Food and Drug Administration (FDA) with an action date of April 6, 2019, under the Prescription Drug User-Fee Act (PDUFA).

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"As an increasing number of myeloma patients experience progressive disease despite treatment with combination regimens, there is a growing need for new therapies, particularly those with novel mechanisms, to help treat patients with relapsed and/or refractory myeloma. The 26.2% ORR determined by the Independent Review Committee (IRC) in the STORM study is highly compelling and reinforces the potential of selinexor in this difficult to treat patient population," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "Additionally, the Phase 1b/2 STOMP study continues to generate encouraging efficacy and safety data from multiple ongoing arms evaluating once weekly oral selinexor and dexamethasone (dex) in combination with the standard approved therapies in patients with newly diagnosed and relapsed/refractory multiple myeloma. The data presented at this year’s ASH (Free ASH Whitepaper) annual meeting show impressive response rates across several high unmet need patient subgroups, including Darzalex-naïve or Pomalyst-naïve and Revlimid (lenalidomide)-relapsed or -refractory myeloma. Given the synergistic activity observed to date with once weekly oral selinexor plus these approved myeloma therapies, we continue to believe that selinexor holds tremendous potential as a future combination backbone therapy in myeloma."

Updated Phase 2b STORM Results

These clinical results are from Part 2 of the international, multi-center, single-arm Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) study, which enrolled 122 heavily pretreated patients (median of seven prior treatment regiments) with penta-refractory myeloma. Patients with penta-refractory myeloma have previously received the two proteasome inhibitors (PIs), Velcade (bortezomib) and Kyprolis (carfilzomib), the two immunomodulatory drugs (IMiDs), Revlimid and Pomalyst, and the anti-CD38 monoclonal antibody Darzalex, as well as alkylating agents, and their disease is refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex and their most recent therapy. Each patient started 80mg oral selinexor twice weekly in combination with low-dose dexamethasone (dex; 20mg twice weekly).

For the STORM study’s primary objective, oral selinexor achieved a 26.2% ORR, which included two stringent complete responses (sCRs), six very good partial responses (VGPRs) and 24 partial responses (PRs). The two sCRs were negative for minimal residual disease, one at the level of 1×10-6 and one at 1×10-4; this is particularly significant in this penta-refractory population. Both patients who had relapsed after CAR-T therapy achieved PRs. The ORR in patients who had previously received Darzalex combination therapy (n=86) was 29.1%. The disease control rate for patients who had achieved stable disease or better was 78.7%. All responses were confirmed by an IRC. Median progression-free survival (PFS) was 3.7 months and the median duration of response (DOR) was 4.4 months. Median overall survival (OS) across the study was 8.6 months. Median OS in the approximately 40% of patients with at least a minimum response (MR) on selinexor + dex was 15.6 months compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable (p<0.0001). The short median OS of patients with no response to selinexor is consistent with the lack of available effective therapies for the very heavily pretreated population who entered the study. Real world OS data were also obtained from the Flatiron Health Analytic Database (FHAD). These results further highlight the limited life-expectancy in patients with highly refractory multiple myeloma. OS data from the FHAD indicate that patients with triple-class refractory myeloma (n=69) had a median OS of 3.5 months, also consistent with previously reported data from the literature.

The most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from Part 1 of this study (Vogl et al., J Clin Oncol, 2018) and from other selinexor studies. Most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (69%), fatigue (56%), anorexia (52%), and weight loss (47%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 treatment-related AEs were thrombocytopenia (54%), anemia (29%), neutropenia (19%) and fatigue (19%). No significant major organ toxicities were observed, and bleeding and infection rates were low.

Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. A NDA seeking accelerated approval for oral selinexor with low dose dexamethasone as a new treatment for patients with penta-refractory multiple myeloma was accepted and filed with Priority Review by the U.S. FDA. The FDA assigned an action date of April 6, 2019 under the Prescription Drug User-Fee Act (PDUFA). Provided marketing approval is granted by the FDA, Karyopharm plans to commercialize selinexor in the U.S. in the first half of 2019. The Company also plans to submit a Marketing Authorization Application to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval.

Updated Phase 1b/2 STOMP Study (Selinexor plus Darzalex and Low-dose Dexamethasone (SDd))

In this arm of the Phase 1b/2 STOMP (Selinexor and Backbone Treatments of Multiple Myeloma Patients) study, oral selinexor (dose escalated using either 100mg once weekly or 60mg twice weekly) is being evaluated in combination with Darzalex (16mg/kg intravenously once weekly) and low dose dexamethasone (dex; orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a PI and an IMiD, or patients with myeloma refractory to both a PI and an IMiD. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SDd Patients as of 15-Nov-20182
Category N3 ORR VGPR PR4
Darzalex naïve 24 19 (79%) 7 (29%) 12 (50%)
All 26 19 (73%) 7 (27%) 12 (46%)
Key: ORR=Overall Response Rate (VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Two patients were not evaluable for response withdrew consent prior to disease follow up
4 Two unconfirmed PR

Despite the heavily pretreated nature of the patients in the study, with 100% of the patients having dual- (PI and IMID) refractory disease, only 19% of patients did not respond (≤stable disease). Median PFS and DOR have not been reached. Based on published data the expected ORR for Darzalex therapy without selinexor in the Darzalex-naïve population is ~30%. Thus, the ORR of 79% provides a basis for further evaluation of the SDd combination.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (60%), fatigue (48%), diarrhea (32%), vomiting (24%) and anorexia (28%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 treatment-related AEs were thrombocytopenia (44%), anemia (28%), leukopenia (28%) and neutropenia (24%). No Grade 5 AEs were reported. The maximum tolerated dose was not reached. Two dose-limiting toxicities (DLTs) (Grade 3 thrombocytopenia and Grade 2 fatigue) were observed in patients receiving selinexor 60mg twice weekly. No DLTs were reported in the 100mg once weekly cohort. The longest duration of therapy is over 60 weeks. Based on these preliminary tolerability and efficacy data, the RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dex (40mg orally, weekly).

Updated Phase 1b/2 STOMP Study (Selinexor plus Pomalyst and Low-dose Dexamethasone (SPd))

In this arm of the Phase 1b/2 STOMP study, oral selinexor is being evaluated in combination with Pomalyst (3 or 4mg orally, once daily) and low dose dex (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a PI and an IMiD, or patients with myeloma refractory to both a PI and an IMiD. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 15-Nov-20182
Prior Therapy Status N3 ORR VGPR PR4 Median PFS
Pomalyst-naïve and Revlimid refractory or relapsed 26 14 (54%) 5 (19%) 9 (35%) 12.2 months
Pomalyst and Revlimid refractory 8 3 (38%) - 3 (38%) 5.5 months
All 34 17 (50%) 5 (15%) 12 (35%) 12.2 months
Key: ORR=Overall Response Rate (VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Four patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, two withdrawal of consent before disease follow up
4 One unconfirmed PR

Responses tended to occur rapidly with a median of one month to onset. Median PFS among all evaluable patients was 12.2 months, with a follow up of 9.4 months. Median PFS in Pomalyst and Revlimid-refractory myeloma was 5.5 months. Among patients with a PR or better (n=17), the median time on treatment was 9.4 months.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (53%), fatigue (50%) and weight decreased (34%). As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (55%), thrombocytopenia (34%), anemia (29%) and leukopenia (18%). There were three Grade 5 treatment-related events (febrile neutropenia, intracranial hemorrhage and pneumonia). Based on these tolerability and efficacy data, doses of oral selinexor 60-80mg 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.

In parallel with the ongoing Phase 1b/2 STOMP study, Karyopharm is conducting the pivotal, randomized Phase 3 BOSTON study evaluating once weekly selinexor in combination with the proteasome inhibitor Velcade and dex (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. The Company expects to complete enrollment in the BOSTON study by the end of 2018, with top-line data anticipated at the end of 2019. Assuming a positive outcome, Karyopharm plans to use the results from the BOSTON study to support an application for full approval of selinexor in relapsed/refractory multiple myeloma.

Details for the ASH (Free ASH Whitepaper) 2018 presentations highlighting the STORM and STOMP studies are as follows:

Title: Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta-Refractory MM
Presenter: Ajai Chari, Icahn School of Medicine at Mount Sinai, New York, New York
Abstract Number/Publication ID: 598
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Date and Time: Monday, December 3, 2018; 7:45 AM PT
Location: San Diego Convention Center, Room 6F

Title: Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasone (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of SDd
Presenter: Cristina Gasparetto, Duke University Cancer Center, Durham, North Carolina
Abstract Number/Publication ID: 599
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Date and Time: Monday, December 3, 2018; 8:00 AM PT
Location: San Diego Convention Center, Room 6F

Title: Selinexor Plus Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Presenter: Christine Chen, Princess Margaret Cancer Center, Toronto, Ontario
Abstract Number/Publication ID: 1993
Session: 653. Myeloma: Therapy, excluding Transplantation: 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 3, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) and Takeda Pharmaceutical Company Limited (TSE:4502) reported that data from the ECHELON-2 phase 3 clinical trial will be presented today in an oral session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Seattle Genetics, DEC 3, 2018, View Source [SID1234531850]). The data demonstrated that frontline treatment with ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) is effective in extending progression-free survival (PFS) and overall survival (OS) with a safety profile comparable to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), a current standard of care in patients with CD30-expressing peripheral T-cell lymphomas (PTCL). These data were also simultaneously published online in The Lancet. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of PTCL.

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The positive topline results of the ECHELON-2 phase 3 clinical trial were previously reported in October 2018. In November 2018, ADCETRIS was approved by the U.S. Food and Drug Administration (FDA) for adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing PTCL, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with CHP. The ECHELON-2 data were the basis of a supplemental Biologics License Application (BLA), which was reviewed by the FDA under its Real-Time Oncology Review Pilot Program and approved less than two weeks after complete submission of the supplemental BLA.

"As clinicians, we are always searching for new strategies to address unmet needs in aggressive blood cancers, and ADCETRIS has proven to be one of those agents that has shown benefit for patients in multiple types of lymphoma and now in frontline PTCL," said Steven Horwitz, M.D., Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York. "This research is important for patients because clinicians now have a novel approach for treating newly diagnosed patients with CD30-expressing PTCL, a group of aggressive cancers. The ECHELON-2 data demonstrates that ADCETRIS plus CHP is superior in extending both progression-free survival and overall survival compared to a current standard of care, CHOP, a multi-agent chemotherapy regimen we have been using in practice for several decades."

"This is the sixth FDA-approved indication for ADCETRIS in lymphoid malignancies and the second as a frontline treatment in combination with chemotherapy," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "The data presented today at ASH (Free ASH Whitepaper) underscores that the ADCETRIS combination provides clinically meaningful benefit to patients with previously untreated PTCL and has the potential to be practice changing for these patients."

"We are pleased to share these impressive results from the ECHELON-2 trial, which build on the efficacy and safety observed with ADCETRIS in a variety of CD30-positive lymphomas," said Jesús Gómez-Navarro, M.D., Vice President and Head, Oncology Clinical Research and Development, Takeda. "The study demonstrated clinically meaningful outcomes and was the first randomized phase 3 trial in frontline PTCL to show improvement in overall survival. Establishing an optimal therapy for PTCL has been a challenge for physicians, and these findings represent the progress in addressing the unmet needs of people living with this serious disease. We look forward to working with regulatory authorities in our territory to bring a potential new treatment option to patients with PTCL."

The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (Abstract #997, oral presentation on Monday, December 3, 2018 at 6:15 p.m. PT at the San Diego Convention Center, Room 6F)

ECHELON-2 is a global, randomized, double-blind, multi-center trial evaluating ADCETRIS as part of a frontline combination chemotherapy regimen in patients with previously untreated CD30-expressing PTCL. The primary endpoint is PFS per Blinded Independent Central Review (BICR), with events defined as progression, death, or receipt of chemotherapy for residual or progressive disease. Key secondary endpoints include PFS in patients with sALCL, complete remission (CR) rate, OS and objective response rate (ORR). ECHELON-2 enrolled 452 patients (226 in each arm) at 132 sites in 17 countries across North America, Europe, Asia Pacific and the Middle East. The median age of patients was 58 years. The study enrolled patients with advanced disease (80 percent) and most patients had sALCL (48 percent ALK-negative and 22 percent ALK-positive).

Key findings, which will be presented by Dr. Steven Horwitz and published in The Lancet, include:

The ECHELON-2 study met its primary endpoint with ADCETRIS plus CHP demonstrating a statistically significant improvement in PFS as assessed by a BICR (hazard ratio [HR]=0.71; p-value=0.0110). This corresponds to a 29 percent reduction in the risk of progression, death or need for additional anticancer therapy for residual or progressive disease.
After a median follow-up time of 36.2 months, the median PFS in the ADCETRIS plus CHP arm was 48.2 months (95% CI, 35.2-not evaluable) compared to 20.8 months (95% CI, 12.7-47.6) in the control arm per BICR assessment. The three-year PFS was 57.1 percent for ADCETRIS plus CHP compared to 44.4 percent in the control arm.
Per investigator assessment, ADCETRIS plus CHP demonstrated a statistically significant improvement in PFS (HR=0.70; p-value=0.0096).
OS in the ADCETRIS plus CHP arm was statistically significant compared to CHOP (HR=0.66; p-value=0.0244). This corresponds to a 34 percent reduction in the risk of death.
After a median follow-up of 42.1 months, the median OS was not reached for either arm of the study. The estimated three-year OS was 76.8 percent for ADCETRIS plus CHP compared to 69.1 percent for CHOP.
All other key secondary endpoints, including CR rate and ORR, in addition to PFS in patients with sALCL, were statistically significant in favor of the ADCETRIS plus CHP arm. Per BICR assessment, the CR rate (68 percent versus 56 percent, respectively) and ORR (83 percent versus 72 percent, respectively) for the ADCETRIS plus CHP arm were significantly higher than those treated with CHOP (p-value=0.0066 and p-value=0.0032, respectively). Per investigator assessment, the CR rate and ORR showed a similar benefit for the ADCETRIS plus CHP arm versus CHOP (p-value=0.0043 and p-value=0.0018, respectively).
Excluding consolidative stem cell transplant or radiotherapy for consolidation of response to initial therapy, 74 percent of patients in the ADCETRIS plus CHP arm versus 58 percent of patients in the CHOP arm did not require subsequent anticancer therapies for residual or progressive disease. Of the 226 patients who received CHOP, 49 patients (22 percent) received subsequent treatment with an ADCETRIS-containing therapy.
The safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
The most common treatment-related adverse events of any grade occurring in 20 percent or more of patients in the ADCETRIS plus CHP and CHOP arm were: nausea (46 and 38 percent, respectively), peripheral sensory neuropathy (45 and 41 percent, respectively), neutropenia (38 percent each), diarrhea (38 and 20 percent, respectively), constipation (29 and 30 percent, respectively), alopecia (26 and 25 percent, respectively), pyrexia (26 and 19 percent, respectively), vomiting (26 and 17 percent, respectively), fatigue (24 and 20 percent, respectively) and anaemia (21 and 16 percent, respectively).
The most common Grade 3 or higher adverse events occurring in the ADCETRIS plus CHP and CHOP arms were neutropenia (35 and 34 percent, respectively) and anaemia (13 and 10 percent, respectively).
The incidence and severity of neutropenia was similar between study arms, and lower in the subset of patients who received primary prophylaxis with granulocyte-colony stimulating factor. Febrile neutropenia was reported in 41 patients (18 percent) in the ADCETRIS plus CHP arm and 33 patients (15 percent) in the CHOP arm.
New or worsening treatment-emergent peripheral neuropathy events occurred in 117 patients (52 percent) in the ADCETRIS plus CHP arm and 124 patients (55 percent) in the CHOP arm, with a majority at a maximum severity of Grade 1 (64 and 71 percent, respectively). At last follow-up, peripheral neuropathy returned to baseline or lower in 50 percent of the patients in the ADCETRIS plus CHP arm versus 64 percent in the CHOP arm, and the median time to resolution was 17 weeks and 11.4 weeks, respectively.
Adverse events leading to death occurred in seven patients (three percent) in the ADCETRIS plus CHP arm and nine patients (four percent) in the CHOP arm.
Please see Important Safety Information, including Boxed Warning, at the end of this press release.

About T-Cell Lymphomas

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). PTCL accounts for approximately 10 percent of non-Hodgkin lymphoma cases in the U.S. and Europe and may be as high as 24 percent in parts of Asia.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include the completed phase 3 ECHELON-2 trial in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed phase 3 ECHELON-1 trial in previously untreated Hodgkin lymphoma, the completed phase 3 ALCANZA trial in cutaneous T-cell lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 3, 2018 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the presentation of the efficacy and safety results of oral rigosertib in combination with azacitidine (Vidaza) in patients with HR-MDS reported at an oral presentation during the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego (Press release, Onconova, DEC 3, 2018, View Source [SID1234531818]). Rigosertib, the Company’s lead compound, is being evaluated in both intravenous and oral forms.

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ORAL PRESENTATION:

Phase 2 Expansion Study of Oral Rigosertib Combined with Azacitidine treatment in Patients with Higher-Risk (HR) Myelodysplastic Syndromes (MDS): Efficacy and Safety Results in HMA Treatment Naïve & Relapsed (Rel)/Refractory (Ref) Patients

Session Name: 637. Myelodysplastic Syndromes — Clinical Studies: Novel Therapeutics I

Date: Saturday, December 1, 2018

Presentation Time: 4:15 PM PST

Seventy-four (74) patients were treated with a median age of 69 years (range 42-90) at 9 clinical sites, and received either 840 mg or 1,120 mg of oral rigosertib daily divided into two doses, in combination with a standard dose of injectable azacitidine. Of the 55 evaluable patients, 29 patients were treated with a daily dose of 1,120 mg of oral rigosertib, either 560 mg twice daily (12 patients) or 840 mg in the a.m. and 280 mg in the afternoon (17 patients). Twenty-six patients were treated with 560 mg in the AM and 280 mg in the PM (daily dose of 840 mg) for the first three weeks of a four-week cycle. All patients also received 75 mg/m2/day SC or IV azacitidine during the second week of the four-week cycle. The median duration of treatment for the HMA naïve and HMA failed patients was 7.8 and 4.9 months respectively. The median duration of response in these groups was 12.2 and 10.8 months, respectively.

The overall response rate (ORR) using the IWG 2006 criteria, in 29 HMA naïve patients, was 90%; including 10 patients (34%) with Complete Remission (CR). Among the 26 evaluable HMA-

failed patients the ORR was 54% including 8% CR or PR. The median time to initial and best response were 1 and 4 cycles in the HMA naïve group and 2 and 5 cycles in the HMA failed group.

The safety population (n = 74) received at least 1 dose of oral rigosertib. The combination was well tolerated. Other than genitourinary adverse events (AEs), the AE profile was similar to those described for azacitidine alone in this patient population. Genitourinary AEs, including hematuria (45% incidence of all grades, including 9% grade 3, and dysuria (38% all grades and 9% grade 3) were observed. A Safety Optimization Strategy was implemented for the higher dose cohort of 1,120 mg of oral rigosertib. These strategies included earlier in the day administration of the PM dose, oral hydration, monitoring of urinary pH and mandatory bladder emptying at night. Collectively these strategies resulted in mitigation of the target genitourinary AEs, including reduction of genitourinary grade 3 AEs reported from an earlier cohort despite receiving a higher dose of oral rigosertib.

In conclusion, oral rigosertib in combination with azacitidine was well tolerated in HMA naïve and HMA failed HR-MDS patients. The combination produced an encouraging rate of overall response and complete remission in both groups. The safety optimization strategies and increased dose exploration of oral rigosertib in the combination is leading to the development of a pivotal Phase 3 trial in HMA and chemotherapy naïve patients.

Drs. Lewis Silverman and Guillermo Garcia Manero, the lead investigators of the study at Mount Sinai Medical Center and MD Anderson Cancer Center, respectively, commented, "This multi-institutional collaborative study based on earlier laboratory research showing synergistic activity of rigosertib in combination with azacitidine led to a clinical trial of this combination in higher-risk MDS patients for both HMA naive and failed patients. The high overall response rate reported today is impressive, as is the durability and rate of achieving complete remission. We are excited about progressing these studies to a randomized pivotal placebo-controlled Phase 3 trial. The overall tolerability of the combination and convenience of administration of oral rigosertib could be key advantages for these future studies."

Dr. Steve Fruchtman, President of Onconova Therapeutics, Inc, sponsor of this study and developer of rigosertib commented, "We are most grateful to the patients, their families and our dedicated collaborating investigators for their participation in this study. The impressive results presented here have led to our plan for a pivotal trial for these patients ultimately hoping to improve upon their current therapeutic options. Based on End of Phase 2 Meetings with the Health Authorities, we have developed a randomized controlled pivotal trial. We expect to start the regulatory process for the approval of this trial plan very shortly. We are hopeful that both intravenous and oral formulations of rigosertib will be useful in serving the needs of higher risk MDS patients".

This oral presentation was delivered by Shyamala Navada, MD, Mount Sinai Medical Center on Saturday, December 1, 2018.

A copy of the presentation is available by visiting the Scientific Presentations section of Onconova’s website.

Onconova plans to meet with the FDA to discuss the results of the Phase 2 trial and the planned Phase 3 trial, and to seek a Special Protocol Assessment. The Company has partnered rigosertib with SymBio Pharmaceuticals, for Japan and Korea, and with Pint Pharma for Latin American countries. Both partners have indicated their interest in participating in the proposed new pivotal Phase 3 trial by enrolling patients in their respective territories. SymBio is currently conducting Phase 1 studies with oral rigosertib in Japan and also participating in the Phase 3 global INSPIRE trial. The Company is also actively seeking additional collaborations for rigosertib in other geographies.

On December 3, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported the presentation of results from the randomized Phase 3 study TOURMALINE-MM3 to evaluate the efficacy of oral monotherapy with NINLARO (Ixazomib) as a maintenance treatment in adult multiple myeloma patients previously responding to high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 3, 2018, View Source [SID1234531834]).

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The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in progression-free survival (PFS) compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, with assessment by an independent review panel (Independent Review Panel) Review Committee, IRC) (HR 0.72, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and a 39 percent improvement in NINLARO PFS compared to placebo. The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.

"The evidence that multiple myeloma maintenance therapy may extend the duration of disease control is increasing," said Meletios Dimopoulos, MD, professor and chair of the Department of Clinical Therapeutics at the Faculty of Medicine, University of Athens, Athens, Greece. "Because there are currently limited treatment options and no proteasome inhibitor among them, there is a need for additional maintenance therapies that can prolong remission and have an acceptable safety profile. Data from the TOURMALINE-MM3 clinical trial suggest monotherapy with NINLARO as a potential oral treatment option for maintenance therapy with an ASCT proteasome inhibitor. "

"The positive results of this pivotal trial, which is the first and only placebo-controlled Phase 3 trial to test a proteasome inhibitor in this setting, support the use of NINLARO as a potential maintenance therapy in patients undergoing stem cell transplantation," said Jesús Gómez Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is imperative that we continue to assist patients with the development of treatment options that support and deepen remission and delay disease progression. NINLARO-treated patients showed an improvement in progression-free survival compared to the control arm,

"Continuing research efforts are constantly evolving treatment options for multiple myeloma. This message is encouraging for anyone dealing with multiple myeloma, but further efforts are needed to bring us closer to our goal of meeting patients’ unmet medical needs, "said Brian Durie, MD, Chairman of the Board Board, International Myeloma Foundation. "This requires the development of additional safe and effective maintenance therapies."

Maintenance therapy with oral proteasome inhibitor (PI) Ixazomib causes significant progression-free survival (PFS) after autologous stem cell transplantation (ASC) in patients with newly diagnosed multiple myeloma (NDMM): the TOURMALINE-MM3 phase 3 study Sunday, 2. December 2018, 7:30 am – 9:00 am, Marriott Marquis San Diego Marina, Grand Ballroom 7

Among the main results, by Dr. med. Meletios Dimopoulos are presented include:

The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in PFS compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, assessed by an independent review panel (IRC) (HR 0.72, 95% CI: 0.582, 0.890, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and 39 percent improvement in PFS under NINLARO.
According to the IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months for the placebo arm.
The conversion of documented positive finding for minimal residual disease (MRD) at study to MRD negativity was more common in NINLARO-treated patients compared to placebo (12 percent versus 7 percent).
Maintenance therapy with NINLARO resulted in higher rates of deep remission compared to placebo (relative risk 1.41, 95 percent CI: 1.10, 1.80, p = 0.0042).
PFS benefits were broadly distributed across subgroups, including ISS III (HR 0.661), PI pretreated (HR 0.750), PI naive (HR 0.497), and patients with high-risk cytogenetic signs (HR 0.625).
The secondary endpoints, including median PFS2 and OS, have not been reached in either arm. The median follow-up time was 31 months.
Overall quality of life scores (EORTC QLQ-C30) were similar in NINLARO-treated patients compared to the placebo group.
The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.
The discontinuation of treatment due to adverse events (AEs) was low and was 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
A third or higher grade of AEs occurred in 42 percent of patients in the NINLARO arm compared with 26 percent in the placebo arm.
In the NINLARO arm, severe AEs were found in 27 percent of the cases compared to 20 percent in the placebo arm.
Common AEs 3 or higher included infections (15 vs. 8 percent) in both the NINLARO and placebo arm, including pneumonia (6 vs. 4 percent), gastrointestinal disorders (6 vs. 1 percent ), Neutropenia (5 vs. 3 percent), and thrombocytopenia (5 vs. <1 percent).
In the NINLARO arm, peripheral neuropathy was observed in 19 percent of patients compared to 15 percent in the placebo arm. In the NINLARO arm, less than 1 percent of the incidence of peripheral neuropathy was Grade 3 AEs compared to 0 percent in the placebo arm.
The second tumor rate was 3 percent in both arms.
One patient in the NINLARO arm died during the study, whereas no death occurred in the placebo arm. The only death in the study was classified as a treatment-related event and was the result of pneumonia.
About the study TOURMALINE-MM3

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study in 656 patients to determine the effect of NINLARO (Ixazomib) maintenance therapy on progression-free survival (PFS) versus placebo in patients with multiple myeloma who have a history of disease Remission (complete remission [CR], very good partial remission [VGPR] or partial remission [PR]) on induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) The primary endpoint is progression-free survival (PFS) An important secondary endpoint includes overall survival (OS). For more information, seeView Source .

About NINLARO (ixazomib) capsules

NINLARO (Ixazomib) is an oral proteasome inhibitor that is also being studied in the multiple myeloma therapy continuum and in systemic light chain amyloidosis (AL), the first oral proteasome inhibitor tested in Phase 3 clinical trials and approved. NINLARO was approved by the US Food and Drug Administration (FDA) in November 2015 after a Priority Review and by the European Commission in November 2016. In the US and Europe, NINLARO is used in combination with lenalidomide and dexamethasone in the treatment of patients with multiple myeloma NINLARO has received marketing approval from regulators in more than 60 countries.

In 2011, Ixazomib was granted orphan drug status in multiple myeloma in the US and Europe, and AL amyloidosis in the US and Europe in 2012. In 2014, Ixazomib received breakthrough therapy from the FDA for relapsed or refractory systemic light chain amyloidosis (AL), a related extremely rare disease. The Japanese Ministry of Health, Labor and Social Affairs granted Ixazomib orphan drug status in 2016.

TOURMALINE, the comprehensive Ixazomib clinical development program, includes a total of six ongoing regulatory trials – five investigating all major groups of multiple myeloma patients and one dealing with light chain amyloidosis:

TOURMALINE-MM1 for testing ixazomib over placebo in combination with lenalidomide and dexamethasone in relapsed and / or refractory multiple myeloma
TOURMALINE-MM2 for the testing of ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3 for testing ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem cell transplantation (ASCT)
TOURMALINE-MM4 for the testing of ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma who have not undergone autologous stem cell transplantation (ASCT)
TOURMALINE-AL1 for the testing of ixazomib plus dexamethasone for a physician on the basis of a selection of therapies in patients with relapsed or refractory AL amyloidosis. Patients are currently enrolled in this study.
TOURMALINE-MM5 for the testing of ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and / or refractory multiple myeloma who have become resistant to lenalidomide. Patients are currently enrolled in this study.
For more information on actively recruiting Phase 3 studies, visit View Source

In addition to the TOURMALINE study program, Ixazomib is currently being evaluated in several therapeutic combinations in various patient populations worldwide through investigator-initiated studies (IIT).

NINLARO Ixazomib) Capsules: Important Safety Information Worldwide

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with the use of NINLARO (28% vs. 14% with the NINLARO or placebo regimen). Platelets reached their lowest point between the 14th and 21st day of the 28-day treatment cycle and recovered to baseline by the start of the next cycle. This did not lead to increased bleeding events or platelet transfusions. During treatment with NINLARO, the platelet count should be monitored at least monthly and more frequent monitoring should be considered during the first three cycles. Thrombocytopenia should be treated with dose adjustment and platelet transfusions according to the recommendations of the standard guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens, for example, diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs 11%). These occasionally required the use of medication for vomiting and diarrhea, as well as supportive therapy.

Peripheral neuropathy has been reported in NINLARO (28% vs. 21% with the NINLARO or placebo regimen). The most commonly reported adverse reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO or placebo regimen). Peripheral motor neuropathy has not been reported in any of the two regimens (<1%). Patients should be monitored for signs of peripheral neuropathy and dosing adjusted if necessary.

Peripheral edema has been reported in NINLARO (25% vs. 18% with the NINLARO or placebo regimen). The underlying causes should be clarified. If necessary, patients should receive supportive care. Dose adjustment should be made with dexamethasone according to the SPC or with NINLARO if severe symptoms occur.

Skin reactions occurred in 19 percent of patients with the NINLARO regimen compared to 11 percent of patients on the placebo regimen. The most common form of rash on both schemes was a maculopapular and macular rash. Rashes should be treated with supportive therapy, dose adjustment or discontinuation of the drug.

Hepatotoxicity, drug-induced liver damage, hepatocellular damage, fatty liver, and cholestatic hepatitis have not been reported commonly in NINLARO-treated patients. Liver values ​​should be monitored regularly and dose adjustments should be made for symptoms of Grade 3 and 4.

Pregnancy – NINLARO can lead to harm to unborn life. For fertile men and women of childbearing potential, contraceptive methods should be used during treatment and for a further 90 days after the last dose of NINLARO. Due to the possible risk to the unborn child, women of childbearing age should be prevented from taking pregnancy while being treated with NINLARO. Women who use hormonal contraceptives should also use a barrier method for contraception.

Breastfeeding – It is not known whether NINLARO or its breakdown products are excreted in breast milk. Due to possible adverse events in breast-fed infants, NINLARO-treated patients should abstain.

SPECIAL PATIENT POPULATIONS

Hepatic impairment: The starting dose of NINLARO should be reduced to 3 mg in patients with moderate or severe hepatic impairment.

Renal impairment: In patients with severe renal impairment or dialysis-dependent patients with end stage renal disease (ESRD), the starting dose of NINLARO should be reduced to 3 mg. NINLARO is not dialyzable and can therefore be administered independently of the dialysis schedule.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS

Simultaneous use of NINLARO and strong CYP3A inducers is foreseeable.

SIDE EFFECTS

The most common adverse reactions reported in at least 20% of NINLARO regimens or more frequently than placebo were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%) and back pain (21% vs. 16%). Serious side effects that occurred in at least 2 percent of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1 percent of patients on NINLARO regimen.

On December 3, 2018 Shenzhen Salubris Pharmaceuticals Co. Ltd. (Salubris, SZSE: 002294) and Viracta Therapeutics, Inc. reported the initial closing of a financing, with Salubris committing $10 million as the lead investor (Press release, Viracta Therapeutics, DEC 3, 2018, View Source [SID1234534657]). New investor Virtus Inspire Ventures, as well as Viracta’s existing investors, NantKwest, Inc., Latterell Venture Partners and Forward Ventures, all participated in the financing. In addition to the financing, Salubris and Viracta have entered into an exclusive Collaboration and License Agreement to bring Viracta’s novel treatment approach for virus-associated malignancies to China.

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Viracta is advancing its innovative approach for viral-associated cancers in a Phase 1b/2 clinical trial for Epstein Barr Virus (EBV)-associated lymphomas in the US and Brazil. The approach is the first targeted, orally administered therapy for EBV-associated malignancies. It incorporates Viracta’s proprietary drug candidate, nanatinostat (VRx-3996) in combination with an antiviral as a targeted treatment to eradicate a range of viral-associated cancers. Viracta plans to initiate a clinical trial for the treatment of EBV-associated solid tumors in the coming year.

EBV-associated nasopharyngeal carcinoma is endemic in Southern China. EBV is also highly associated with the incidence and progression of other solid tumors, including gastric carcinoma, as well as NK/T cell lymphomas found throughout China. Salubris CEO, Kevin Ye highlighted, "EBV-driven cancers disproportionately impact patients in China. We look forward to partnering with Viracta to develop this new treatment option in China. The approach holds the potential to provide a valuable new treatment option for these patients, who currently still face considerable morbidity and mortality."

"We are committed to bringing our treatment approach to cancer patients around the world," commented Viracta CEO, Ivor Royston, MD. "We look forward to developing nanatinostat in collaboration with Salubris to address these major healthcare needs in China."

Under the terms of the license agreement, in addition to the equity investment made by Salubris, Viracta is eligible to receive up to $58 million in pre-commercial milestones as well as significant sales level-triggered commercial milestones and tiered royalties on sales. The Companies will collaborate for clinical development of the treatment approach for viral-associated cancers with Salubris taking on responsibility for development within the Peoples Republic of China (excluding Hong Kong, Macau and Taiwan). Viracta retains development responsibility as well as commercial rights outside of China.