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Aptose Submits Formal Response to Clinical Hold for APTO-253

On September 12, 2016 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS), a clinical-stage company developing new therapeutics and molecular diagnostics that target the underlying mechanisms of cancer, reported that it has submitted a formal response to the U.S. Food and Drug Administration (FDA) regarding the previously announced clinical hold of Aptose’s Phase 1b clinical trial of APTO-253 in patients with hematologic cancers (Filing, 6-K, Aptose Biosciences, SEP 12, 2016, View Source [SID:SID1234515069]). Aptose provided responses to all of the questions cited in the clinical hold letter issued by the FDA.

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"This submission represents months of disciplined labor to resolve a manufacturing matter related to APTO-253 that arose during our Phase 1b Trial in patients with AML and high-risk MDS," commented Dr. William G. Rice, Chairman, President and Chief Executive Officer. "Although the FDA will make the ultimate decision whether our clinical trial may resume, all of their questions have been addressed."

During a Phase 1b clinical trial with APTO-253, a clinical site experienced stoppage of the infusion pump during an IV infusion caused by back pressure as a result of clogging of the in-line filter. The Company determined the root cause was a chemistry-based issue with the molecule, and the Company is now working with a drug product that does not cause filter clogging or pump stoppage during mock infusion studies performed to confirm the acceptability of the updated product through the clinical infusion procedures. Such improvements to the APTO-253 manufacturing process required to address the filter clogging event will be incorporated into a Chemistry, Manufacturing and Control (CMC) amendment to our Investigational New Drug application.

Sunesis Presents Dose Escalation Results from the Phase 1A Healthy Volunteer Study Evaluating Oral Non-Covalent BTK inhibitor SNS-062

On September 12, 2016 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported results from the Company’s Phase 1A study in healthy volunteers evaluating oral non-covalent BTK inhibitor SNS-062 (Press release, Sunesis, SEP 12, 2016, View Source [SID:SID1234515068]). The study demonstrated a favorable safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile for SNS-062 in healthy subjects. The results were presented on Saturday, September 10th at the European School of Haematology’s (ESH) 2nd International Conference on New Concepts in B-Cell Malignancies at the Estoril Congress Centre in Estoril, Portugal.

"Our first-in-human clinical results are encouraging and reinforce our belief that SNS-062 has the potential to become an important new treatment option for patients with B-cell malignancies," said Linda Neuman, M.D., Vice President, Clinical Development of Sunesis. "Notably, SNS-062 exposure, even at the lowest dose of 50 mg, exceeded those reported for both ibrutinib and acalabrutinib at their respective recommended dose levels, suggesting that SNS-062 has improved PK properties. Furthermore, as a non-covalent BTK inhibitor with a distinct binding profile, SNS-062 may overcome the acquired resistance to ibrutinib and other covalent clinical-stage inhibitors resulting from a point mutation (C481S) in the BTK active site."

"The safety profile and the extent and duration of BTK inhibition by SNS-062 support the timely advancement of this program into cancer-directed studies," said Daniel Swisher, President and Chief Executive Officer of Sunesis. "We look forward to moving SNS-062 into a planned Phase 1B/2 study of patients with advanced B-cell malignancies."

The reported data from this Phase 1A randomized, double-blind, placebo-controlled, single-dose study are from four sequential cohorts of 8 subjects each who were randomly assigned to receive progressively higher single oral administrations of SNS-062 at doses of 50, 100, 200, and 300 mg (n=6 per cohort) or placebo (n=2 per cohort). An evaluation of the effects of food and CYP3A4 inhibition on the PK of SNS-062 is ongoing.

For the primary endpoint of safety, investigators were blinded to treatment arm for assessment of relatedness. Overall, AEs were reported for 8 (33%) subjects who received SNS-062 and for 3 (38%) subjects who received placebo. Treatment-related AEs were reported in 6/24 (25%) subjects who received SNS-062 compared with 3/8 (38%) subjects who received placebo. For patients who received SNS-062, treatment-related AEs included headache, nausea, and supraventricular tachycardia. In the placebo group, treatment-related AEs included headache, nausea, and diarrhea. No obvious pattern of dose-dependent toxicity was observed. All AEs were transient and low grade. None of the AEs, laboratory abnormalities, or ECG or telemetry findings were considered clinically meaningful. No SAEs were reported.

SNS-062 was rapidly absorbed and had mean plasma half-life values across all dose cohorts of 7.4 to 17 hours. SNS-062 concentrations declined in a multiphasic manner. Total exposure (AUC and Cmax) increased proportionally with dose. SNS-062 demonstrated rapid, profound (~100%), and prolonged inhibition of BTK at all dose levels supporting a future twice-daily dosing regimen.

The poster, titled "A Phase 1A Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the Noncovalent Bruton Tyrosine Kinase (BTK) Inhibitor SNS-062 in Healthy Subjects: Preliminary Results" is available on the Sunesis website at www.sunesis.com.

About SNS-062
SNS-062 is a novel, second-generation BTK inhibitor, a class of kinase inhibitors that selectively inhibits the enzyme Bruton’s tyrosine kinase (BTK). This target mediates signaling through the B-cell receptor, which is critical for adhesion, migration, proliferation and survival of normal and malignant B-lineage lymphoid cells. SNS-062’s favorable safety, pharmacokinetics, potency, kinase selectivity and non-covalent binding profile support the advancement to a Phase 1B/2 study in patients with B-cell malignancies. This study will include patients with an acquired resistance from a C481S mutation at the point in the enzyme’s binding site required for covalent binding of ibrutinib and other covalent inhibitors.

TESARO Receives FDA Fast Track Designation for Niraparib and Initiates Rolling NDA Submission

On September 12, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to niraparib for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer (Press release, TESARO, SEP 12, 2016, View Source [SID:SID1234515067]). TESARO has initiated a rolling submission of a New Drug Application (NDA) for niraparib to the FDA, and intends to complete this submission during the fourth quarter. The Marketing Authorization Application (MAA) for niraparib is planned for submission to the European Medicines Agency (EMA) in the fourth quarter.

The FDA Fast Track designation is designed to facilitate the development and expedite the review of medicines that are intended to treat serious conditions and address unmet medical needs. As part of the Fast Track program, the FDA allows for the submission of completed portions of an NDA on an ongoing or rolling basis.

"The initiation of this rolling NDA submission is a significant milestone for TESARO, and we are committed to working collaboratively with the FDA to advance the review of the niraparib application," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We look forward to presentation of data from the Phase 3 NOVA trial of niraparib in a Presidential Symposium session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) congress on October 8."

NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled more than 500 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy.

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in four ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with platinum-sensitive, recurrent ovarian cancer (the NOVA trial); a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial); a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); and a Phase 3 trial for the treatment of patients with BRCA-positive breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and bevacizumab.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA or any other regulatory agencies.

Geron Provides Update on Imetelstat Trials Being Conducted by Janssen

On September 12, 2016 Geron Corporation (Nasdaq:GERN) reported updates on the clinical trials being conducted by Janssen Research & Development, LLC, of the telomerase inhibitor imetelstat (Press release, Geron, SEP 12, 2016, View Source [SID:SID1234515066]). Planned internal reviews of initial data from both trials have been completed by Janssen, and both trials are continuing in order to evaluate additional and more mature data.

IMbarkTM

IMbarkTM (NCT02426086) was originally designed as a Phase 2 clinical trial to evaluate two dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered every three weeks) in approximately 200 patients (approximately 100 patients per dosing arm) with Intermediate-2 or High risk myelofibrosis (MF) who have relapsed after or are refractory to prior treatment with a JAK inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate and symptom response rate at 24 weeks. To date, over 90 patients have been enrolled in the trial across both dosing arms.

To inform an assessment of the appropriate dose and schedule for relapsed or refractory MF patients in IMbarkTM, Janssen conducted a planned internal interim review of safety, efficacy and pharmacokinetic data from 20 patients from each dosing arm who have been followed on the trial for at least 12 weeks. Based on this first internal review at the early 12-week time point, the following has been determined by Janssen:

The safety profile was consistent with previous imetelstat clinical trials in hematologic myeloid malignancies. No new safety signals were identified.

Activity in the 4.7 mg/kg dosing arm does not warrant further investigation of that dose and this arm will be closed to new patient enrollment. An amendment to the trial protocol is planned to allow eligible patients in this arm to increase their dose to 9.4 mg/kg per investigator discretion.

In the 9.4 mg/kg dosing arm, even though at the week 12 data assessment an insufficient number of patients met the protocol defined interim criteria, this arm warrants further investigation because encouraging trends in the efficacy data were observed. Patients already enrolled in this arm may continue to receive imetelstat. New enrollment in this arm will be suspended while the trial continues in order to obtain additional and more mature data that includes a longer follow-up of patients at 24 weeks, consistent with the co-primary efficacy endpoints. The number of patients enrolled to date is expected to be sufficient to inform potential future development of this dose.

Janssen plans to conduct an additional internal data review in the second quarter of 2017 to include a longer follow-up of patients at 24 weeks. Potential outcomes of the second internal review at the 24-week time point could include resuming enrollment in the 9.4 mg/kg dosing arm, with or without changes to the dosing regimen; adding a new dosing arm; or closing the trial.

Any protocol amendments will be subject to review by health authorities around the world.
IMergeTM

IMergeTM (NCT02598661) is a Phase 2/3 clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (MDS) who have relapsed after or are refractory to prior treatment with an erythropoiesis stimulating agent (ESA). The clinical trial is in two parts: Part 1 is a Phase 2, open-label, single-arm design in approximately 30 patients and Part 2 is a Phase 3, randomized, double-blind, placebo-controlled design in approximately 170 patients. The primary efficacy endpoint is the rate of red blood cell transfusion-independence lasting at least 8 weeks. Part 1 of the trial is fully enrolled.

Janssen has conducted an initial internal review of efficacy, safety and pharmacokinetic data from a subset of patients from Part 1 of IMergeTM and this review indicated that emerging safety and efficacy in IMergeTM is consistent with data reported from the pilot study conducted at Mayo Clinic in MDS patients. IMergeTM will continue unmodified at this time.

Further assessment of data from IMergeTM is expected to occur in the second quarter of 2017 to include longer follow-up of all patients enrolled in Part 1. A decision on whether to move forward to Part 2 of IMergeTM will be based on an assessment of the benefit/risk profile of imetelstat in these patients. If Janssen decides to move forward with Part 2, the Phase 3 clinical trial is expected to be open for patient enrollment in mid-2017.

Janssen expects to submit data from Part 1 of IMergeTM to be considered for presentation at a medical conference in the future.

Celyad completes the NKR-2 Phase I trial with successful safety follow-up of the fourth dose level

On September 9, 2016 Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of cell therapies, reported the successful completion of the 21-day safety follow-up of the last patient enrolled at the fourth dose level in its Phase I clinical trial evaluating the safety and feasibility of its NKR-2 T-cell therapy – in Acute Myeloid Leukemia and Multiple Myeloma patients (Press release, Celyad, SEP 9, 2016, View Source [SID1234516410]). No safety issues or toxicities were reported.

Dr. Christian Homsy, CEO of Celyad: "We are pleased that no adverse safety signal has been reported. Based on the successful completion of the fourth cohort, we are looking forward to starting the global Ph I/IIa multiple dose trial, in the US and EU, of our NKR-2 autologous therapy in the fourth quarter of this year."

Dr. Frédéric Lehmann, Head of Immuno-Oncology at Celyad: "The absence of any safety or toxicity signal up to this point continues to support our belief that this unique engineered T-cell construct can be safely administered and potentially lead to a therapeutic effect providing hope to the thousands of patients who need better treatments for both AML and MM."