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Karus Therapeutics Announces First Cancer Patients Dosed with KA2507, a Small Molecule HDAC6-Selective Inhibitor, in a Phase I Clinical Trial

On September 18,2017 Karus Therapeutics Ltd (‘Karus’), a leader in the design and development of innovative medicines with breakthrough potential in the treatment of cancer, reported that the first patients have been dosed with its histone deacetylase 6 (HDAC6) inhibitor, KA2507, in a Phase I clinical study (Press release, Karus Therapeutics, SEP 18, 2017, View Source [SID1234520560]). This is the Company’s second orally-active small molecule cancer therapeutic agent to enter clinical trials during the past 12 months.

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This Phase I study has been designed to assess the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of KA2507 in patients with PD-L1-expressing solid tumors. The trial is being conducted at the University of Texas MD Anderson Cancer Center in Houston, Texas, USA, and is part of a collaboration between the two organizations.

KA2507 is a highly-selective and potent inhibitor of the tubulin deacetylase, HDAC6. Selective inhibition of this enzyme confers a cancer immunotherapeutic response by regulating immune checkpoint markers within the tumor microenvironment. HDAC6 has also emerged as a potentially important therapeutic target due to its overexpression in solid tumors and its role in specific mutant-harboring cancers. Karus considers KA2507 to hold broad therapeutic potential for the treatment of solid tumors, as both a single agent and in combination with other drugs.

Stephen Shuttleworth – COO, CSO and founding scientist of Karus’s R&D programs – commented: "KA2507 is Karus’s second small molecule cancer therapeutic agent designed in our laboratories to enter Phase I trials within the last year, and the commencement of this clinical study represents another significant milestone for the Company. HDAC6 is an exciting new target in cancer, and KA2507 is the product of many years’ research and development. The drug has the potential to be a best-in-class agent, and represents another major step in our mission towards the development of new life-changing therapies for cancer patients."

Apostolia Tsimberidou MD, PhD, Professor in the Department of Investigational Cancer Therapeutics at the MDACC is the Principal Investigator for the clinical study.

Autolus Announces Initiation of the AMELIA and ALEXANDER Studies for AUTO3: Phase I/II Studies in paediatric ALL and DLBCL

On September 18, 2017 UCL Business spinout company, Autolus Limited, a clinical-stage biopharmaceutical company focused on the development and commercialisation of next-generation engineered T-cell therapies, reported initiation of both the AMELIA and ALEXANDER phase I/II studies of its novel, dual-targeting, AUTO3 Chimeric Antigen Receptor (CAR) T-cell therapy (Press release, UCLB, SEP 18, 2017, View Source [SID1234520559]).

AUTO3 is an autologous T-cell product, genetically modified to express two separate CARs which recognise CD19 and CD22; two antigens expressed by cancer cells in B-cell leukaemia and lymphoma. AUTO3 is designed to minimise the risk of relapse due to antigen loss, a key mechanism of resistance shown in single antigen targeting CAR-T therapies.

The AMELIA and ALEXANDER Studies are dose-escalation phase I/II studies in paediatric Acute Lymphocytic Leukaemia (ALL) and adult Diffuse Large B-Cell Lymphoma (DLBCL) in which cohorts of patients receive ascending doses of AUTO3 to determine the maximum tolerated dose and establish a recommended dose. The second part of the study is an expansion phase where patients receive AUTO3 to further evaluate the safety, tolerability and clinical activity at this recommended dose. In addition to the effects of AUTO3 alone, combination with short-duration use of a checkpoint inhibitor is also being evaluated in the ALEXANDER study.

Dr Martin Pule, Autolus’ Founder and Chief Scientific Officer said:

"Our approach at Autolus is to understand how tumours defend against T-cells and then design and programme CAR-T cell products which specifically address those defence and escape mechanisms. The AUTO3 programme seeks to overcome two limitations of current therapies by introducing dual targeting CARs and addressing checkpoint mediated inhibition."

Professor Persis Amrolia, Professor of Transplantation Immunology, Great Ormond Street Hospital, London commented:

"The advent of CD19 CAR-T cell based therapy is an exciting and revolutionary advancement in the treatment of children with relapsed ALL. However, in approximately a third of the patients the disease reoccurs by losing CD19 antigen. AUTO3, a dual targeting CAR, addresses this challenge by independently targeting CD19 and CD22 antigen, which has the promise of reducing antigen escape."

Dr Anas Younes, Chief, Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York commented:

"CD19-directed CAR-T cell therapies already offer the possibility of an important new treatment option for patients with relapsed and refractory DLBCL. AUTO3 is a novel approach which simultaneously targets a second clinically relevant antigen, CD22. The field is looking forward to seeing how patients respond to AUTO3 in clinical trials and whether dual antigen targeting CAR-T cell therapy offers the possibility of deeper initial and more sustained responses."

U.S. FDA Approves New Indication for Ipsen’s Somatuline® Depot (lanreotide) Injection for the Treatment of Carcinoid Syndrome

On September 18, 2017 Ipsen (Euronext: IPN; ADR: IPSEY) (Ipsen), reported that the U.S. Food and Drug Administration (FDA) has approved a supplemental indication for Somatuline Depot (lanreotide) Injection 120 mg for the treatment of carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analogue rescue therapy (Press release, Ipsen, SEP 18, 2017, View Source [SID1234520558]).

Somatuline Depot is also approved for the improvement of progression-free survival (PFS) in patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).[1]

Alexandre Lebeaut, MD, Executive Vice-President, R&D, Chief Scientific Officer, Ipsen, said: "The new indication for Somatuline Depot offers patients in the U.S. a valuable treatment option for debilitating carcinoid syndrome associated with neuroendocrine tumors. It also reaffirms Ipsen’s global commitment to helping to improve lives of patients with cancer."

"This new indication for Somatuline Depot gives doctors the only somatostatin analog approved by the FDA in adults for both improving progression-free survival in patients with unresectable, well- or moderately- differentiated, locally advanced or metastatic GEP-NETs and for the treatment of carcinoid syndrome," said Cynthia Schwalm, Executive Vice-President, and President, North American Commercial Operations, Ipsen. "The additional approval also confirms Ipsen’s commitment to developing research-driven treatments intended to help provide patients battling cancer with new therapy options."

The additional Somatuline Depot approval for carcinoid syndrome was based on "Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial," published in Endocrine Practice.1,2

IMPORTANT SAFETY INFORMATION

Contraindications

Somatuline Depot is contraindicated in patients with hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide.
Warnings and Precautions

Cholelithiasis and Gallbladder Sludge
Somatuline Depot may reduce gallbladder motility and lead to gallstone formation.
Periodic monitoring may be needed.
Hypoglycemia or Hyperglycemia
Pharmacological studies show that Somatuline Depot, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Patients treated with Somatuline Depot may experience hypoglycemia or hyperglycemia.
Blood glucose levels should be monitored when Somatuline Depot treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
Cardiovascular Abnormalities
Somatuline Depot may decrease heart rate.
In patients in the GEP-NET pivotal trial, 23% of Somatuline Depot-treated patients had a heart rate of less than 60 bpm compared to 16% of placebo-treated patients. The incidence of bradycardia was similar in the treatment groups. Initiate appropriate medical management in patients with symptomatic bradycardia.
In patients without underlying cardiac disease, Somatuline Depot may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to treatment, sinus bradycardia may occur. Care should be taken when initiating treatment in patients with bradycardia.
Most Common Adverse Reactions

GEP-NETs: Adverse reactions occurring in greater than 10% of patients who received Somatuline Depot in the GEP-NET trial were abdominal pain (34%), musculoskeletal pain (19%), vomiting (19%), headache (16%), injection site reaction (15%), hyperglycemia (14%), hypertension (14%), and cholelithiasis (14%).
Carcinoid Syndrome: Adverse reactions occurring in the carcinoid syndrome trial were generally similar to those in the GEP-NET trial. Adverse reactions occurring in greater than 5% of patients who received Somatuline Depot in the carcinoid syndrome trial and occurring at least 5% greater than placebo were headache (12%), dizziness (7%) and muscle spasm (5%).
Drug Interactions: Somatuline Depot may decrease the absorption of cyclosporine (dosage adjustment may be needed); increase the absorption of bromocriptine; and require dosage adjustment for bradycardia-inducing drugs (e.g., beta-blockers).

Special Populations

Lactation: Advise women not to breastfeed during treatment and for 6 months after the last dose.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at +1-855-463-5127 or FDA at +1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here for the full Prescribing Information including Patient Information.

Oncolytics Biotech® Announces Successful End-of-Phase 2 Meeting with FDA for REOLYSIN® in Metastatic Breast Cancer

On September 18, 2017 Oncolytics Biotech Inc. (TSX: ONC) (OTCQX: ONCYF) (Oncolytics or the Company), a biotech company developing REOLYSIN (pelareorep) a first-in-class, intravenously delivered immuno-oncolytic virus that activates the innate and adaptive immune systems, reported a successful End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for REOLYSIN in combination with paclitaxel, for the treatment of hormone receptor positive, HER2 receptor negative (HR+/HER2-) metastatic breast cancer (mBC) patients (Press release, Oncolytics Biotech, SEP 18, 2017, View Source [SID1234520555]). The purpose of the meeting was to discuss the preclinical and clinical programs, including the design of the phase 3 registration study to support a future Biologics License Application (BLA) submission in the U.S.

"The FDA’s feedback and positive End-of-Phase 2 meeting outcome support our proposed target patient population of HR positive/HER2 negative metastatic breast cancer patients for our registration study," said Dr. Matt Coffey, President and CEO of Oncolytics Biotech. "With statistically significant and clinically compelling overall survival data, Fast Track designation and now clear guidance from the FDA, we are focused on finalizing the adaptive study design that will include approximately four hundred patients with a pre-determined interim analysis. Importantly, the FDA provided guidance that if the study achieves its primary endpoint, then it will be the only study required for BLA approval. The design of the study and this FDA guidance will also continue to drive our partnering process."

Oncolytics’ proposed target population for its phase 3 study of pelareorep is patients with HR+/HER2- mBC, which represents approximately 73 percent of metastatic breast cancer cases that have limited treatment options that offer survival benefit. Details of the pivotal phase 3 registration study will be made available following evaluation and completion of discussions with clinical advisors, European regulators and potentially partners.

About Metastatic Breast Cancer
Metastatic breast cancer, also known as advanced or Stage 4 breast cancer, has spread to other parts of the body. Most commonly the lungs, liver, bones or brain. The disease affects over 154,000 women in the United States and according to the American Cancer Society, has a five-year survival rate of just 22 percent. Significantly lower than stage 3, with a five-year relative survival rate of 72 percent and stage 2, with a five-year survival rate over 90 percent.

About REOLYSIN
REOLYSIN is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers.

Can-Fite Files Patent Application to Treat Cytokine Release Syndrome, a Potentially Life-Threatening Complication of CAR-T Cell Therapy

On September 18, 2017 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE:CFBI), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address cancer, liver and inflammatory diseases, reported it has filed a patent application to protect the use of its drugs and other ligands which target the A3 adenosine receptor (A3AR) to treat cytokine release syndrome (CRS) (Press release, Can-Fite BioPharma, SEP 18, 2017, View Source [SID1234520553]).

"CAR-T and other cancer immunotherapies are a very promising category of drugs and may shape the treatment of cancer in the future. When they work, they can save lives, however, a concern that needs to be addressed with this class of treatment is the relatively high incidence of CRS, a side effect which can kill patients. We believe our drugs, which bind to A3AR, have the potential to treat CRS, which could make CAR-T and other immuno-oncology drugs safer for patients," stated Dr. Pnina Fishman, Can-Fite’s CEO. "A safe and effective treatment for CRS that does not inhibit the efficacy of CAR-T and other immuno-oncology therapies meets a growing unmet medical need in the treatment of cancer."

CAR-T cell therapies are designed to treat certain cancers by modifying an individual patient’s own immune cells to specifically target their cancer cells. CRS, which is caused by an overactive immune response to the treatment, has been identified as a potentially severe and life-threatening side effect of CAR-T cell therapies.

While most people with CRS experience mild or moderate flu-like symptoms which are easily managed, some patients experience more severe symptoms that may lead to potentially life-threatening complications such as cardiac dysfunction, acute respiratory distress syndrome or multi-organ failure. One recently approved CAR-T therapy shows 79% of patients receiving the treatment got CRS and 49% got severe CRS, according to the drug’s prescribing information.*

Can Fite’s platform technology selectively targets A3AR, which plays a central role in mediating the mechanism of inflammation by reducing elevated levels of pro-inflammatory cytokines such as IL-6, IL-1β, NF-Kβ, TNF-α, and more. As such, the Company believes that A3AR targeting may serve as an important treatment option for patients in reducing the risk of CRS without limiting the utility of the underlying cancer immunotherapy.

Current treatment for CRS includes aggressive immunosuppression through the use of high doses of corticosteroids to reverse the syndrome. However, while corticosteroids may control some of these toxicities, their potential to block T-cell activation and negate the clinical benefit of CART-T is a concern (Maude SL, et al, Cancer J, 2014). ACTERMA (tocilizumab), in August 2017 became the first FDA approved treatment for severe CRS induced by CAR-T, however it can mediate the immunosuppressive effect which could limit the efficacy of the immunotherapy (Lee et al, Blood, 2014).

In addition to CAR-T, CRS is also associated with therapeutic monoclonal antibody (mAb) infusions, most notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), anti-CD20 (rituximab), and the CD28 super-agonist, TGN1412.

* The recently approved CAR-T cell immunotherapy, KYMRIAH (tisagenlecleucel), reveals in its prescribing information notes that in its registration study, 79% (54/68) of patients receiving the drug developed CRS, with the median time to onset of 3 days (range: 1-22 days). The incidence of severe CRS, Grade 3 or Grade 4, was 49% (33/68).