On October 12, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI) (Karyopharm) and Ono Pharmaceutical Co., Ltd. (ONO), reported their entry into an exclusive license agreement for the development and commercialization of selinexor, Karyopharm’s lead, novel, oral Selective Inhibitor of Nuclear Export (SINE) compound, and KPT-8602, Karyopharm’s second-generation oral SINE compound (Press release, Karyopharm, OCT 12, 2017, View Source [SID1234520877]). The agreement includes the development of selinexor and KPT-8602 for the diagnosis, treatment and/or prevention of all human oncology indications in Japan, South Korea, Taiwan, Hong Kong, and ASEAN countries (the Territory).

Under the terms of the agreement, Karyopharm will receive a one-time upfront payment of ¥2.5 billion (approximately US$22.3 million) from ONO and retains all rights to selinexor and KPT-8602 outside the Territory. Karyopharm is eligible to receive up to an additional ¥19.15 billion (approximately US$170.7 million at the current exchange rate) if specified future development and commercial milestones are achieved by ONO. Karyopharm is also eligible to receive low double-digit royalties based on future net sales of selinexor and KPT-8602 in the Territory. In exchange, ONO will receive exclusive rights to develop and commercialize both compounds in the Territory, at its own cost and expense. ONO will also have the ability to participate in any global clinical study of selinexor and KPT-8602, and will bear the cost and expense for patients enrolled in clinical studies in the Territory.

“We are very delighted to collaborate on the development of selinexor and KPT-8602, an early development stage XPO-1 inhibitor with Karyopharm, a leading pharmaceutical company focused on the research and development of novel first-in-class drugs in the oncology field,” said Gyo Sagara, President, Representative Director of ONO. “We believe both products will present a new treatment option to patients suffering from devastating cancers in Asian countries.”

“Given ONO’s established leadership in oncology, including Opdivo (nivolumab) and Kyprolis (carfilzomib) in Japan, we believe there is no company better suited to advance both selinexor and KPT-8602 in Japan and the other licensed territories,” said Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm. “ONO is well-known and widely respected for its clinical development and commercial expertise, and this partnership provides important validation for both compounds, while allowing us to remain focused on executing our late-phase selinexor trials and pursue regulatory approval in the United States and European Union. We look forward to working with the ONO team to advance both compounds with the goal of rapidly bringing them to patients who are in need of new treatment options.”

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.

About KPT-8602
KPT-8602 is a second generation oral SINE compound. KPT-8602 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. KPT-8602 has demonstrated minimal brain penetration in animals, which has been associated with reduced toxicities in preclinical studies while maintaining potent anti-tumor effects.
About Karyopharm Therapeutics

On October 12, 2017 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported that an abstract describing new data for IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), has been selected as a late-breaking presentation during an oral session at the 2017 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting taking place in National Harbor, MD, November 10 – 12 (Press release, Infinity Pharmaceuticals, OCT 12, 2017, View Source [SID1234520876]). Additionally, a clinical trials in progress poster will also be presented on the Phase 1/1b clinical study which is ongoing to explore the safety and activity of IPI-549 both as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in patients with advanced solid tumors. IPI-549 is believed to be the only PI3K-gamma inhibitor in clinical development.

Details of the presentations are as follows:

Updated Phase 1/1b Data
Title: Monotherapy dose escalation clinical and translational data from first-in-human study in advanced solid tumors of IPI-549, an oral, selective, PI3K-gamma inhibitor targeting tumor macrophages
Abstract number: O43
Oral session: Clinical Trials – New Agents
Oral session date and time: Friday, November 10, 2017, from 1:45 p.m. –3:30 p.m. ET
Lead author: David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Additionally, an identically titled poster will be presented on Friday, November 10, 2017, from 12:30 p.m. – 2:00 p.m. ET and 6:30 p.m. – 8:00 p.m. ET.

Clinical Trials in Progress
Title: Phase 1/1b, first-in-human study of the PI3K-gamma inhibitor IPI-549 as monotherapy and combined with nivolumab in patients with advanced solid tumors
Abstract number: P219
Poster session: Clinical trials in progress
Presentation time: Friday, November 10, 2017, from 12:30 p.m. – 2:00 p.m. ET and 6:30 p.m. – 8:00 p.m. ET
Lead author: Antoni Ribas, M.D., Ph.D., Parker Institute Center Director at the University of California, Los Angeles (UCLA)

About the IPI-549 and the Ongoing Phase 1 Study
IPI-549 is an investigational, orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 reprograms macrophages from a pro-tumor, M2, to an anti-tumor, M1, phenotype and is able to overcome resistance to checkpoint inhibition as well as to enhance the activity of checkpoint inhibitors.1,2 As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

A Phase 1 study of IPI-549 in patients with advanced solid tumors is ongoing to evaluate the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with Opdivo in approximately 200 patients with advanced solid tumors.3 The four-part study includes monotherapy and combination dose-escalation components, in addition to monotherapy expansion and combination expansion components. Patient enrollment is complete in monotherapy dose-escalation, and monotherapy expansion is ongoing. Combination dose-escalation is also ongoing, and combination expansion is expected to begin in the second half of 2017.

The combination expansion component includes multiple cohorts designed to evaluate IPI-549 in patients with specific types of cancer, including patients with non-small cell lung cancer (NSCLC), melanoma, and head and neck squamous cell carcinoma (HNSCC) whose tumors show initial resistance or subsequently develop resistance to immune checkpoint blockade therapy. This combination expansion will also include a cohort of patients with triple negative breast cancer (TNBC) who have not been previously exposed to immune checkpoint blockade therapy. Although there has been great progress in the treatment of cancer, there remains a need for additional treatment options. NSCLC, melanoma, HNSCC and TNBC account for more than 22 percent of all new cancer cases in the U.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

On October 12, 2017 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies, reported that the first patient was dosed in the phase 1 clinical study of its oncology asset MP0274. MP0274 is a proprietary DARPin drug candidate for the treatment of HER2-positive cancer with a new mode of action compared to current standard of care antibodies (Press release, Molecular Partners, OCT 12, 2017, View Source [SID1234520868]).

The phase 1 study of MP0274 is a two part study in patients with advanced HER2-positive solid tumors. Part 1 will be conducted in three sites in Germany, Switzerland and the UK all of which are open to recruitment, and will assess safety, tolerability, pharmacokinetics and establish the recommended dose for further development. Part 2 will be conducted in the initial three sites as well as in additional sites and is designed to confirm safety and to assess preliminary efficacy at the recommended dose. Initial safety data are expected in the first half of 2018 and initial efficacy data towards the end of 2018.

“We are very pleased to have reached this important milestone to dose the first patient in our phase 1 study for patients with advanced HER-2 positive solid tumors with our novel drug candidate MP0274,” commented Dr. Andreas Harstrick, Chief Medical Officer at Molecular Partners. “With this milestone, Molecular Partners significantly expands its clinical portfolio besides the ongoing MP0250 clinical trials.”

Financial Calendar October 26, 2017 Q3 2017 Management Statement October 31, 2017 Extraordinary General Meeting November 9, 2017 R&D Day in New York February 8, 2018 Publication of Full-year Results 2017 (unaudited) March 16, 2018 Expected Publication of 2017 Annual Report April 18, 2018 Annual General Meeting View Source

About the DARPin Difference DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multispecificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan. Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and has entered into Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated T790M-positive NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has just moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

On October 12, 2017 Foundation Medicine, Inc. (NASDAQ:FMI) reported that financial results for the company’s third quarter ended September 30, 2017 will be released on Wednesday, November 1, 2017 (Press release, Foundation Medicine, OCT 12, 2017, View Source [SID1234520898]). The management team will host a conference call on Wednesday, November 1, 2017, at 4:30 p.m. ET to discuss the company’s financial results and recent developments. The call can be accessed by dialing 1-877-270-2148 (domestic) or 1-412-902-6510 (international) five minutes prior to the start of the call. A passcode is not required to access the live call from either number. A replay of the conference call will be available until November 15, 2017 and can be accessed by dialing 1-412-317-0088 and providing the passcode 10113366.

The live, listen-only webcast of the conference call may be accessed by visiting the investors’ section of the company’s website at investors.foundationmedicine.com. A replay of the webcast will be available shortly after the conclusion of the call and will be archived on the company’s website for two weeks following the call.

On October 12, 2017 Two new papers from researchers at Fred Hutchinson Cancer Research Center provide the most comprehensive data yet reported on side effects of the emerging cancer immunotherapy strategy known as CAR T-cell therapy (Press release, EurekAlert!, OCT 12, 2017, View Source [SID1234520875]).

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Based on their data from 133 adult participants in one clinical trial, the researchers identified potential biomarkers associated with the development of the toxic effects, known as cytokine release syndrome and neurotoxicity. They also created algorithms aimed at identifying the rare patients whose symptoms were most likely to turn life-threatening.

The team’s paper on neurotoxicity will be published online in Cancer Discovery at 12:05 a.m. Eastern Time Oct. 12. Their paper on cytokine release syndrome was published online in the journal Blood Sept. 18.

The researchers anticipate that their work could be the basis for an algorithm that doctors could follow to reduce the risk of the severe side effects and occasional deaths, which have been seen in clinical trials of various CAR T-cell products. They said that their findings will need to be tested and improved upon by further study, and noted that their results arise from a clinical trial of a particular CAR T-cell product, which is made by and at Fred Hutch.

“It’s essential that we understand the potential side effects of CAR T therapies” said Fred Hutch’s Dr. Cameron Turtle, who led the research. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

The first CAR T-cell product was recently approved by the U.S. Food and Drug Administration to treat certain leukemias. That product, like the one studied by the Fred Hutch team, reprograms patients’ immune cells to kill blood cancer cells bearing a protein called CD19.

The 133 participants in the Fred Hutch clinical trial – believed to be the largest sample size in any published study of CAR T-cell therapy side effects – had advanced leukemias or lymphomas that had proven resistant to standard therapies. Over the last two years, Fred Hutch papers reported results from different groups of patients treated with the optimal regimen of chemotherapy and CAR T cells: 93 percent of participants with B-cell acute lymphoblastic leukemia went into complete remission; 64 percent with non-Hodgkin lymphoma experienced complete remission; and 86 percent of a subset of patients with high-risk chronic lymphocytic leukemia cleared disease from their bone marrow.

“These patients had highly resistant, refractory disease,” Turtle said. “For many of them, it was their last option.”

The two latest papers provide detailed descriptions of the clinical courses of cytokine release syndrome and of neurotoxicity in study participants, including the types of symptoms present, the timing of their occurrence and the course they ran to resolution. The neurotoxicity paper also includes detailed data from imaging and pathological studies.

As previously reported, complications of cytokine release syndrome, neurotoxicity or both were fatal for some participants. The new findings show that in the vast majority of patients (about 95 percent of participants) harms were either reversible or did not occur.

One of the studies’ novel findings is that severe cases of both types of toxicities were associated with signs that the endothelial cells, or the linings of patients’ blood vessels, were ramping up activity in response to injury. For example, the team found that the normally tight barrier between the blood and the brain had broken down in some patients with severe neurotoxicity, and cytokines and CAR T cells from the blood had entered the fluid bathing the brain. The researchers say that biomarkers for endothelial activation could help identify which patients are at greatest risk of CRS and neurotoxicity.

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but in terms of what triggers a person with cytokine release syndrome to get neurotoxicity — that’s something we need to investigate further,” said Dr. Kevin Hay, a research fellow at Fred Hutch and a lead author of both papers.

As the research progressed, the study investigators adjusted their CAR T-cell dosing strategy. This change appears to correspond with a reduction in the frequency of the most serious forms of these toxic effects, though more research is needed to confirm this.

In treating clinical trial participants at Seattle Cancer Care Alliance, Fred Hutch’s clinical partner, the researchers developed methods for monitoring and treating toxicities, as reported in these two papers, that allow study participants to receive the preparatory chemotherapy and subsequent CAR T-cell infusion as outpatients. Patients are admitted into the hospital if they spike a high fever in the days following the infusion.

“We have come a long way in understanding what these toxicity events are,” Hay said. “That’s really what these two papers demonstrate.”

Cytokine release syndrome

The symptoms of cytokine release syndrome include high fevers and low blood pressure. Cytokine release syndrome developed in 93 of 133 of patients on the trial. In most of these patients, it resolved on its own with no treatment. But 10 patients, most of who were treated early in the trial, developed the most serious symptoms of cytokine release syndrome (grade 4 or 5).

The researchers identified five independent factors relating to participants’ baseline health status upon trial enrollment and variation within the experimental treatment itself, such as cell dose, which predicted patients’ risk of developing any grade of cytokine release syndrome.

The researchers developed a simple two-part method to identify the patients who would go on to develop severe cytokine release syndrome. Within the first day and a half after T-cell infusion, the red flags were a fever of at least 102 degrees Fahrenheit and high levels of one particular immune-signaling chemical, a cytokine known as MCP-1. The algorithm was relevant to all three cancer types included in the trial.

While an effective therapy for cytokine release syndrome is FDA-approved — a cytokine-modulating drug and/or a steroid — it’s unclear what the best protocol is for early intervention in the development of side effects. The data from their study could inform the design of a clinical trial to test the best strategy for blunting the development of the most serious cases, the researchers say.

Neurotoxicity

A wide range of neurologic side effects are included under the umbrella of neurotoxicity, which occurred in 53 of the 133 trial participants after CAR T-cell infusion. The most common type of neurologic side effect was delirium with maintained alertness (35 patients), the team reported. Other manifestations of neurotoxicity included headache, problems speaking, a decrease in consciousness and, rarely, seizures (four patients) or coma (six patients). A total of seven patients experienced life-threatening neurotoxicity.

The researchers identified several preexisting factors that were associated with a higher risk of developing any level of neurotoxicity, such as patient age and cancer type. Only CAR T-cell dose was associated with later risk of developing the most serious neurotoxicity.

The team found that fever of at least 102 degrees Fahrenheit and high levels of two cytokines (IL-6 and MCP-1) in the first 36 hours after CAR T-cell infusion could identify, with high accuracy, those patients who would go on to develop life-threatening neurotoxicity.

There are no data that point toward the best treatment for neurologic toxicities of CAR T-cell therapy, and there are not yet any validated laboratory models to use for research to clearly elucidate their causes. The researchers hope that their comprehensive data provide a springboard for research teams to delve into its causes and best treatments.

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This research was funded by the National Institutes of Health; Juno Therapeutics Inc., the Life Science Discovery Fund; the Bezos family; and institutional funds from Bloodworks Northwest. Fred Hutch, where Turtle, Hay and several other co-authors are employed, has a financial interest in Juno and receives licensing and other payments from the company. The Hutch has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno. For additional disclosure information about the authors, please see the papers.

The Cancer Discovery paper on neurotoxicity was led by Turtle (senior author) and co-first authors Dr. Juliane Gust of the University of Washington, Hay and Dr. Laïla-Aïcha Hanafi of Fred Hutch. Other authors are from Fred Hutch, UW, BloodWorks Northwest, Juno and the University of British Columbia.

The Blood paper on cytokine release syndrome was led by Turtle (senior author) and Hay (first author). Other authors are from Fred Hutch, the University of Washington, Juno, Seattle Children’s Hospital and Bloodworks Northwest.

At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch’s pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation’s first cancer prevention research program, as well as the clinical coordinating center of the Women’s Health Initiative and the international headquarters of the HIV Vaccine Trials Network.

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