On February 20, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for TIBSOVO (ivosidenib) for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase 1 (IDH1) mutation who are not eligible for standard therapy (Press release, Agios Pharmaceuticals, FEB 20, 2019, View Source [SID1234533529]).

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The sNDA was granted Priority Review and has been given a Prescription Drug User Fee Act (PDUFA) action date of June 21, 2019. The FDA’s Priority Review status accelerates the review time from 10 months to a goal of six months from the day of filing acceptance and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. In addition, the FDA accepted the TIBSOVO sNDA under its Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency.

"In less than seven months since TIBSOVO’s approval in relapsed or refractory AML, we are pleased to be working with the FDA to expand its labeled indication into the frontline setting," said Chris Bowden, M.D., chief medical officer of Agios. "Patients with newly diagnosed AML who are not eligible for standard treatments, such as intensive and non-intensive chemotherapy, are currently offered only palliative care. There is tremendous need for new treatment options, and we believe AML patients with IDH1 mutations have the potential to benefit from this targeted therapy."

TIBSOVO is a first-in-class, oral, targeted inhibitor of mutant IDH1. The sNDA submission is based on results from the untreated AML patients from the Phase 1 dose-escalation and expansion study of ivosidenib in patients with newly diagnosed AML ineligible for standard treatment. Data from the untreated AML portion of this study were presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

About TIBSOVO (ivosidenib)

TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

On February 20, 2019 Torque, a clinical-stage immuno-oncology company developing first-in-class Deep Primed T Cell Therapeutics to direct immune power deep within the tumor microenvironment, reported that it has entered into a clinical trial collaboration agreement with Merck (known as MSD outside of the U.S. and Canada) (Press release, Torque Therapeutics, FEB 20, 2019, View Source [SID1234553880]). The collaboration will evaluate Torque’s Deep IL-15 Primed T Cells (TRQ-1501) both as a single agent and in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in a Phase 1/2 study in multiple solid tumor indications.

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"We are very excited about this clinical collaboration with Merck to evaluate the combination of KEYTRUDA with our Deep IL-15 Primed T cells," said Bart Henderson, Chief Executive Officer of Torque. "Torque’s new class of cellular immunotherapy is designed to harness the full biology of natural T cells for treating multiple solid tumors, and we believe the combination with anti-PD-1 therapy will further enhance the function of these cells by protecting them against immunosuppression in the tumor microenvironment. This combination has the potential to improve treatment outcomes for patients with solid tumors that are relapsed or refractory to currently available treatments and broaden the applications of cellular immunotherapy."

The Phase 1/2 trial will evaluate the safety, tolerability, immune biomarkers, and overall response rates achieved with TRQ-1501 in combination with KEYTRUDA in two groups of patients:

Patients with melanoma, non-small cell lung cancer, bladder cancer, renal cell carcinoma, and head and neck cancer who are relapsed or refractory to checkpoint inhibitor therapy (anti PD-1/PD-L1 inhibitor treatment)
Patients with advanced or metastatic ovarian cancer or sarcoma who are relapsed or refractory to standard-of-care treatments
Torque will conduct the trial at multiple clinical sites in the U.S. and expects to commence the combination arm of the study with KEYTRUDA later this year.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.

About TRQ-1501
Torque is developing a new class of Deep-Primed cellular immunotherapy designed to overcome the key challenges limiting broad use of cellular therapy in oncology, including the capability to target tumors that express multiple heterogeneous antigens, the ability to overcome the immunosuppressive microenvironment that shuts down T cell function, and the need for outpatient treatment with a high margin of safety. Torque uses its Deep-Priming technology to develop multi-targeted, antigen-primed T cells that carry surface-anchored immune-stimulatory drugs to drive a full immune response within the tumor microenvironment against tumors with heterogenous antigens. TRQ-1501 is an investigational immune cell therapy produced from a patient’s own T cells, which are primed to be active against multiple tumor-associated antigens and loaded with Deep IL-15 (a multimer of IL-15 cytokine) anchored to the T cells’ surface.

About Torque’s Deep-Primed Immune Cell Therapy Platform
Torque’s Deep-Priming platform uses advanced cell process engineering to:

prime and activate T cells to target multiple tumor antigens and
tether immune-stimulatory drugs to the surface of these multi-target T cells to direct immune activation in the tumor microenvironment
using a proprietary technology platform, without genetic engineering, for a high margin of safety.
Deep-Primed T cells both target multiple tumor antigens and pharmacologically activate an immune response with anchored cytokines. This process does not require genetic engineering of the T cells and so preserves the natural T cell receptor for delivering a regulated immune response, with the potential for a high margin of safety. In addition to antigen priming, immunomodulators are tethered to the surface of Deep-Primed T cells—initially IL-15 and IL-12 cytokines, and TLR agonists—that activate both innate and adaptive immunity. Administering these immunomodulators systemically to a patient can cause lethal toxicity by activating immune cells throughout the body. By loading precise doses of cytokines onto the surface of T cells, Deep Priming focuses the immune response to target the tumor, without systemic exposure.

In hematologic cancers, this new class of immune cell therapeutics has the potential to improve on the initial success of single-target CAR T therapeutics with expanded efficacy and also move cell therapy treatment out of the hospital with a high margin of safety. For solid tumors, Deep-Primed T cells have the potential to enable efficacy against tumors with heterogeneous antigens protected by hostile microenvironments, which are not readily addressable with the first generation of immune cell therapies.

On February 20, 2019 Sapreme Technologies, a privately-held biotech company developing a technology platform to enable the cytosolic delivery of macromolecule therapeutics, reported that it has been awarded a 6.8 M€ grant together with a multidisciplinary consortium including 11 other academic and industrial parties (Press release, Sapreme Technologies, FEB 20, 2019, View Source com/201902201890/sapremetechnologies-in-a-6-8-m-eu-alliance-to-develop-an oligonucleotide-delivery-platform-based-on-its-proprietary-endosomal-escape-enhancers.html [SID1234538878]). The grant was provided by the European Union (EU) through Horizon 2020 to develop a non-viral based gene therapy using Sapreme’s proprietary endosomal escape enhancers.

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Ruben Postel, CSO of Sapreme Technologies, "We are pleased to see that the EU has recognized the great potential of the ENDOSCAPE project and the expert multi-disciplinary consortium developing a novel oligonucleotide delivery technology for treatment of cancer and haemophilia patients"

Ernst Geutjes, acting Managing Director, "The fact that the EU awarded the proposal with the maximum score demonstrates the potential of Sapreme’s proprietary endosomal escape enhancement technology as well as the exceptional quality of the proposal and the consortium spearheaded by Sapreme and Charité – Universitätsmedizin Berlin"

On February 20, 2019 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer, autoimmune diseases, asthma and allergic diseases, reported that the U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on its Phase 1 study of XmAb14045, a CD123 x CD3 bispecific antibody molecule being evaluated in patients with relapsed or refractory acute myeloid leukemia and other CD123-expressing hematologic malignancies (Press release, Xencor, FEB 20, 2019, View Source [SID1234533491]). Patients currently on treatment and benefiting from treatment may continue treatment on the study. No new patients will be allowed to enroll in the study until the partial clinical hold is lifted by the FDA.

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The partial clinical hold was initiated following recent safety reports Xencor submitted to the FDA on two patient deaths that were considered at least possibly related to XmAb14045. One patient experienced cytokine release syndrome (CRS) after their first dose, the treatment of which was complicated by the patient’s decision to withdraw care. One patient developed acute pulmonary edema following several doses of XmAb14045. The FDA has placed the trial on partial clinical hold pending review of additional details regarding these events, safety and efficacy information across the study, and satisfactory review of amendments to the study protocol and related documents. Xencor will be working closely with the FDA to review these events and resolve the partial clinical hold.

"Patient safety is Xencor’s highest concern," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "We are working with the investigators and the FDA and will provide an update when more information about resuming enrollment can be shared. Our ongoing Phase 1 studies evaluating our other CD3 bispecific antibodies, XmAb13676 and XmAb18087, are not affected."

About XmAb14045

XmAb14045 is a tumor-targeted antibody that contains both a CD123 binding domain and a cytotoxic T-cell binding domain (CD3) in a Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and other CD123-expressing hematologic malignancies. An XmAb Bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb14045. CD123 is highly expressed on AML cells and leukemic stem cells, and it is associated with poorer prognosis in AML patients. Engagement of CD3 by XmAb14045 activates T cells for highly potent and targeted killing of CD123-expressing tumor cells.

On February 20, 2019 The Melanoma Research Alliance (MRA), the largest non-profit funder of melanoma research worldwide, reported the U.S. Food & Drug Administration (FDA) approval of Merck’s pembrolizumab (Keytruda) in the adjuvant setting for melanoma patients with lymph node involvement following complete lymph node resection (Press release, Melanoma Research Alliance, FEB 20, 2019, View Source [SID1234533510]).

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Melanoma, the deadliest skin cancer, is the fifth most common cancer in the U.S. An estimated 9% of new cases have spread to lymph nodes or nearby sites around the tumor— referred to as Stage III disease—with correspondingly high risk of recurrence and death. Reducing the risk of recurrence after surgery represents a major opportunity to eliminate melanoma suffering and death.

"Over the last year we have seen a flurry of drug approvals that help reduce the risk of recurrence for high-risk Stage III melanoma following surgery while reducing treatment-related side effects," said Chief Science Officer Marc Hurlbert, Ph.D. "This is important because it makes more treatment options available to patients and assists in making the decision to start adjuvant therapy that much easier for patients and their doctors."

Pembrolizumab, an anti-PD-1 antibody, works by stimulating the patient’s immune system to attack melanoma by promoting the tumor-killing effectiveness of T cells. It was first approved for the treatment of unresectable or metastatic melanoma in 2014 and has since gained FDA approval to treat multiple cancers, including certain cancers of the lung, bladder and blood.

"Giving patients access to more, better tolerated, treatments to choose from at an earlier stage of disease is critical to achieving our mission of ending suffering and death due to melanoma," said MRA President & CEO Michael Kaplan.

Without adjuvant therapy, about 60% of Stage III melanoma patients will relapse within three years of surgical resection. While adjuvant therapy works to reduce this risk, it does have its own range of side effects. Doctors and patients must work together to weigh the relative benefits of adjuvant therapy.

FDA approval of pembrolizumab in the adjuvant setting is based on results from the KEYNOTE-054 trial. In this phase-three study, pembrolizumab significantly reduced melanoma recurrence/death (26%) compared with patients receiving placebo (43%). The safety of pembrolizumab has been evaluated in 4,948 patients with various cancers and the most commonly reported adverse reactions were fatigue, rash, and nausea.