On June 15, 2015 Karyopharm Therapeutics reported the presentation of positive clinical data for its lead product candidate, selinexor (KPT-330), a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound, at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) 2015 Annual Meeting held June 11-14, 2015 in Vienna, Austria (Filing, 8-K, Karyopharm, JUN 15, 2015, View Source [SID:1234505437]).

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In an ongoing Phase 1b company-sponsored clinical trial evaluating the activity of single-agent selinexor (doses of 3-80mg/m2) in heavily pre-treated patients with diffuse large B-cell lymphoma (DLBCL), selinexor demonstrated a 43% overall response rate (partial response or better) in patients on study greater than one month, and a 31% overall response rate across all doses in the intention to treat population, with a median duration of response (DOR) of greater than nine months. Similar responses were observed in both GCB and non-GCB subtypes. The median overall survival (OS) and progression free survival (PFS) were 4.6 months and 1.7 months, respectively, for the entire study. In patients with a response to selinexor (N=12), the median OS was greater than 10 months (median not reached) and PFS was 24 months, significantly longer than those without a response (N=27; OS 3.5 months, PFS 1.2 months). Adverse events were manageable with standard supportive care and clinically significant cumulative toxicities were not observed, with several patients remaining on selinexor for more than one year.

Additional clinical data on selinexor’s activity in DLBCL, including in patients with double-hit DLBCL, will be provided in an oral presentation on Saturday June 20, 2015, at 10:50 CEST by Dr. Ramiro Garzon from the Ohio State University at the 13th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland.

Initial data from the ongoing Selinexor AraC Idarubicin Leukemia, or "SAIL," study, an investigator-sponsored Phase 2 clinical trial of selinexor with intensive chemotherapy (idarubicin and cytosine arabinoside [Ara-C]) in patients with acute myeloid leukemia (AML) that relapsed after standard intensive induction chemotherapy, were also reported. In 18 evaluable patients, the combination of selinexor (40 mg/m2) with idarubicin/Ara-C demonstrated a 56% overall response rate, including nine patients with complete remission (CR/CRi) and one patient with a partial remission. Adverse events were manageable with standard supportive care and dose adjustments.

"We are excited by these promising data presented at EHA (Free EHA Whitepaper), which continue to demonstrate the vast potential of selinexor across hematologic malignancies and provide further evidence of selinexor’s broad and durable activity, both as a single agent and in combination therapy," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "The correlation between response and prolonged survival demonstrated in heavily pretreated DLBCL patients suggests that responses to selinexor may confer a clinical benefit in this very difficult to treat population and support the ongoing

SADAL study in this group of patients. Moreover, the preliminary clinical data in patients with relapsed/refractory AML suggest that selinexor can be combined effectively with manageable side effects. These findings represent the reported clinical data of selinexor in combination with intensive chemotherapy and suggest that selinexor can enhance the activity of these agents with manageable side effects."

Selinexor data in DLBCL were described during an oral presentation by Dr. Ramiro Garzon of the Ohio State University on Saturday, June 13, entitled "Patients with Heavily Pretreated Diffuse Large B-Cell Lymphoma (DLBCL) who Respond to Oral Selinexor Therapy Show Prolonged Survival: Updated Phase 1 Results." These data from an ongoing Phase 1b clinical study of single-agent selinexor (3-80 mg/m2 oral doses) in patients with DLBCL were as of June 1, 2015 and included the following highlights:

• Among 28 response evaluable patients (per protocol defined as those patients on study for at least one month), the ORR was 43% and the disease control rate (stable disease or better) was 71%. Responses included four patients (14%) who achieved a complete response as confirmed by PET scan, eight patients (29%) who achieved a partial response and 8 patients (29%) with stable disease.

• Among 39 patients treated across all doses, the ORR was 31% and the disease control rate (stable disease or better) was 51%.

• Duration of response was greater than nine months.

• Patients with a response to selinexor (N=12), achieved OS of greater than ten months (median not reached) and PFS of 24 months which were significantly longer than those without a response (N=27; OS 3.5 months, PFS 1.2 months).

• The median overall survival (OS) and progression free survival (PFS) were 4.6 months and 1.7 months, respectively, for the entire study.

• Selinexor showed similar activity in both GCB and non-GCB subtypes of DLBCL.
In a late-breaking poster presented on Saturday, June 13, entitled "Preliminary Phase II Results of Ara-C And Idarubicin in Combination with Selective Inhibitor of Nuclear Export (SINE) Compound Selinexor (KPT-330) in Patients with Relapsed or Refractory AML," Dr. Walter Fiedler of the University Medical Center Hamburg and colleagues described preliminary data from the ongoing Phase 2 SAIL clinical trial demonstrating that selinexor in combination with standard doses of Ara-C and idarubicin is a potentially effective strategy for treating patients with AML that was relapsed or refractory after at least one line of chemotherapy. All data are as of April 27, 2015 and highlights include:

• An overall response rate of 56% was achieved based on 18 evaluable patients with three patients (17%) achieving complete remission (CR), six patients (33%) achieving complete remission with incomplete blood count recovery (CRi) and one patient (6%) achieving partial remission (PR).

• Ten patients (56%) received or were expected to receive either stem cell transplant or donor lymphocyte infusion.

• Adverse events were manageable with standard supportive care and dose adjustments.
An additional poster was presented on Saturday, June 13, entitled "XPO1 Inhibition Using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia (AML) by Targeting DNA Repair Genes" by Dr. Romero Garzon of the Ohio State University. In that preclinical study, Dr. Garzon and colleagues showed that selinexor synergizes with anthracyclines and other topoisomerase 2 inhibitors by preventing AML cells from repairing their DNA after damage by the chemotherapy. This study provides the scientific rationale for the ongoing SAIL study described above and additional studies with topoisomerase 2 inhibitors, as well as mechanistic insights into the use of selinexor with other chemotherapeutic agents.

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, which subsequently reinitiates and amplifies their tumor suppressor function. This is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 900 patients have been treated with selinexor in company- and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four registration-directed clinical trials of selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT) and one in patients with diffuse large B-cell lymphoma (SADAL). A single-arm trial of selinexor in patients with multiple myeloma (STORM) that is also intended to be registration-directed was initiated in May 2015. In solid tumors, Karyopharm plans to initiate a registration-directed trial of selinexor to treat liposarcoma during the second half of 2015. Additional Phase 1 and Phase 2 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 the company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.