On April 10, 2017 Geron Corporation (Nasdaq:GERN) reported that Janssen Research & Development, LLC has completed the second internal data reviews of IMerge and IMbark, the clinical trials of the telomerase inhibitor imetelstat in lower risk myelodysplastic syndromes (MDS) and relapsed or refractory myelofibrosis (MF), respectively (Press release, Geron, APR 10, 2017, View Source [SID1234518518]). For IMerge, the benefit/risk profile of imetelstat in the treated patients supports continued development in lower risk myelodysplastic syndromes. A data package and proposed trial design refinements are planned to be provided to the FDA. For IMbark, the current results suggest clinical benefit and a potential overall survival benefit associated with imetelstat treatment in relapsed or refractory myelofibrosis; the trial will continue unchanged to evaluate maturing efficacy and safety data, including an assessment of overall survival.

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IMerge

IMerge (NCT02598661) is a Phase 2/3 clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk 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 designed to be a Phase 3, randomized, controlled trial in approximately 170 patients. The primary efficacy endpoint is the rate of red blood cell transfusion independence lasting at least 8 weeks. Key secondary endpoints include the rates of red blood cell transfusion independence lasting at least 24 weeks and hematologic improvement. Part 1 of the trial is fully enrolled.

The second internal review of IMerge included data from the approximately 30 patients enrolled in Part 1. Based on this second internal review, the Collaboration’s Joint Steering Committee has determined the following:

The safety profile was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified.

The benefit/risk profile of imetelstat, including assessments of 8-week and 24-week transfusion independence and hematologic improvement by erythroid (HI-E) response, across multiple MDS sub-types, supports continued development in lower risk MDS.

Part 1 of the trial will continue unmodified, and patients remaining in the treatment phase may continue to receive imetelstat.

A data package, as well as proposed refinements to the trial design for Part 2 of IMerge, is planned to be provided to the FDA.

Data from Part 1 are expected to be submitted for consideration for presentation at a medical conference in the future.
Geron expects that FDA feedback and the totality of imetelstat program information, including an assessment of the evolving treatment landscape in MDS and the potential application of imetelstat in multiple hematologic malignancies, will inform Janssen’s decision to initiate Part 2 of IMerge. If Part 2 of IMerge is initiated, Geron expects this Phase 3 stage of IMerge to be opened for patient enrollment in the fourth quarter of 2017.

IMbark

IMbark (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 with Intermediate-2 or High risk 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 (≥35% reduction of spleen volume assessed by imaging) and symptom response rate (³50% reduction in Total Symptom Score) at 24 weeks.

The second internal review of IMbark included data from the approximately 100 patients who were enrolled in the trial, with each dosing arm analyzed separately. Based on this second internal review, the Collaboration’s Joint Steering Committee has determined the following:

The safety profile was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified.

The data support 9.4 mg/kg as an appropriate starting dose for the relapsed or refractory MF patient population.

In these relapsed or refractory MF patients treated in the 9.4 mg/kg dosing arm, the spleen volume response rate observed to date was less than that reported in front-line MF patients treated in trials with other drugs. However, activity within multiple outcome measures was observed with imetelstat treatment, which suggests clinical benefit in this relapsed or refractory MF patient population. These outcome measures included a range of spleen volume reductions, decreases in Total Symptoms Score, and improvements in hematologic parameters, such as anemia and peripheral blood counts. In addition, the data suggest a potential overall survival benefit associated with imetelstat treatment in these patients.

The trial will continue without any modifications, including conduct of all safety and efficacy assessments as planned in the protocol, including overall survival. Patients remaining in the treatment phase may continue to receive imetelstat.

Enrollment of new patients to the trial will remain suspended because the total number of patients enrolled to date is adequate to assess longer-term outcome measures when the data are fully matured.
During the next year, Geron expects Janssen to evaluate maturing efficacy and safety data from the trial, including an assessment of overall survival. Geron expects the longer-term data from the trial, potential health authority feedback, and the totality of imetelstat program information, including an assessment of the evolving treatment landscape in MF and the potential application of imetelstat in multiple hematologic malignancies, including MDS, will inform Janssen’s decision whether to continue development of imetelstat in relapsed or refractory MF.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Imetelstat has not been approved for marketing by any regulatory authority.

On April 10, 2017 FORMA Therapeutics announced today that it has successfully completed two additional objectives under its strategic collaboration agreement with Celgene Corporation, triggering two undisclosed payments from Celgene (Press release, Forma Therapeutics, APR 10, 2017, View Source [SID1234518517]). Previously, FORMA and Celgene entered a collaboration in the promising area of protein homeostasis to discover, develop and commercialize innovative drug candidates. This collaboration enables Celgene to evaluate select therapeutic candidates and programs in protein homeostasis during preclinical development.

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John Hohneker, M.D., Executive Vice President and Head of Research and Development at FORMA Therapeutics said, "FORMA’s integrated approach to drug discovery, bringing together distinctly novel and proprietary compound collections with clinically-meaningful biological assays across protein families, continues to deliver a promising pipeline. We have successfully identified several additional candidate compounds from our protein homeostasis programs, each with a compelling mechanism of action and potential to represent first in class therapeutic options for patients."

About Protein Homeostasis

Protein homeostasis, which is important in oncology, neurodegenerative and other disorders, involves a tightly regulated network of pathways controlling the biogenesis, folding, transport and degradation of proteins. Exploring the maintenance and regulation of such competing, yet integrated, biological pathways using a chemical biology approach, should directly contribute to the understanding of diseases associated with excessive protein misfolding, aggregation and degradation.

On April 10, 2017 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that Alecensa as an initial (first-line) treatment showed that patients lived significantly longer without disease worsening (progression-free survival, PFS) compared to crizotinib in the ALEX Study, a global phase III study targeting ALK fusion gene positive non-small cell lung cancer (NSCLC), conducted by F. Hoffmann-La Roche Ltd (Press release, Chugai, APR 10, 2017, View Source [SID1234518514]). The safety profile of Alecensa was consistent with that observed in previous studies, with no new or unexpected adverse events.

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"Following the Japanese phase III J-ALEX study, the ALEX study, the head to head trial with crizotinib, Alecensa demonstrated a significant prolongation of PFS compared to crizotinib. This finding greatly encourages the patients suffering from ALK fusion gene positive NSCLC," said Dr. Yasushi Ito, Senior Vice President, Head of Project & Lifecycle Management Unit. "We believe that Alecensa will also contribute to improving the outcomes for overseas patients from first line therapy in the future."

The ALEX study was an open-label, randomized global phase III study that compares the efficacy and safety between both monotherapy of Alecensa and crizotinib. The ALEX study enrolled treatment-naïve 303 patients with ALK fusion gene positive NSCLC. The subjects were allocated to either the Alecensa arm or the crizotinib arm in a one to one ratio. The primary endpoint of the ALEX study was PFS as assessed by the investigator. The secondary endpoints included Independent Review Committee-assessed PFS, overall survival, objective response rate, duration of response, safety, and other endpoints. The full data of the ALEX study will be presented at a future medical meeting and submitted to global health authorities, including the United States Food and Drug Administration.

Alecensa is a highly selective oral ALK inhibitor created by Chugai. It has been reported that approximately five percent of patients with NSCLC express a chromosomal rearrangement which leads to fusion of the ALK gene with another gene.1) ALK kinase signalling is constantly active in cells with such fusion genes, resulting in uncontrolled growth of tumour cells and transforming the cells into tumour cells.2, 3) Alecensa exerts its anti-tumour effect by selectively inhibiting ALK kinase activity to inhibit tumour cell proliferation and induce cell death.4) In addition, Alecensa is not recognized by the active efflux system in the blood brain barrier which actively pumps molecules out of the brain. Thus, Alecensa is able to remain active in the central nervous system and has proven activity against brain metastases.

Alecensa is currently approved in the United States, Kuwait, Israel, Hong Kong, Canada, South Korea, Switzerland, India, the EU, Australia and Taiwan for the treatment of adult patients with ALK-positive, metastatic (advanced) NSCLC who have progressed on or those intolerant to crizotinib." In Japan, "Alecensa capsule 150mg" is available to patients with "ALK fusion gene positive unresectable, recurrent/advanced NSCLC" and is marketed by Chugai.

1) Biomarker committee of The Japan Lung Cancer Society, Guidelines for ALK gene tests in lung cancer patients
2) Soda et al., Nature. 448: 561-566 (2007)
3) Takeuchi et al., Clin Cancer Res. 15: 3143-3149 (2009)
4) Sakamoto et al., Cancer Cell. 19: 679-690 (2011)

Note: The description of Japanese package insert
– Dosage and administration for Japanese patients: "the usual adult dosage is 300mg alectinib administered orally twice daily."
– In the current Japanese package insert, it is described that "2. efficacy and safety of ALECENSA in chemotherapy-naïve patients have not been established.

On April 9, 2017 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported that an abstract regarding a mouse model study that examined the potential clinical efficacy of MN-166 for glioblastoma (GBM) has been accepted for presentation at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held June 2-6, 2017 in Chicago, Illinois (Press release, MediciNova, APR 9, 2017, View Source [SID1234518515]).

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The presentation entitled "Treating glioblastoma with a cytokine inhibitor, ibudilast in combination with temozolomide extends survival in a patient derived xenograft model," will be presented by Associate Professor Kerrie McDonald, Head of the Cure Brain Cancer Foundation Biomarkers and Translational Research Group at the Lowy Cancer Research Centre, University of New South Wales. In this presentation, Dr. McDonald will present detailed information about the effectiveness of MN-166 and temozolomide combination treatment in the GBM model.

Presentation details are as follows:

Session Date and Time: Monday, June 5, 2017

Session: Central Nervous System Tumors

Location: McCormick Place, 2301 S. Lake Shore Drive, Chicago, Illinois

MediciNova is currently preparing to initiate a Phase 2 clinical trial for the treatment of recurrent Grade IV glioblastoma.

About Glioblastoma

Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than melanoma. According to the American Association of Neurological Surgeons, glioblastoma (GBM) is an aggressive, extremely lethal form of brain malignancy that develops from glial cells (astrocytes and oligodendrocytes) and rapidly grows and commonly spreads into nearby brain tissue. GBM is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that GBM represents 15% of all brain tumors and 55% of all gliomas and has the highest number of cases of all malignant tumors, with an estimated 12,390 new cases predicted for 2017. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy, and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with GBM. Median survival is 14.6 months and only approximately 5% of GBM patients survive longer than 36 months.

About MN-166 (ibudilast)

MN-166 (ibudilast) has been marketed in Japan and Korea since 1989 to treat post-stroke complications and bronchial asthma. MediciNova is developing MN-166 for progressive MS and other neurological conditions such as ALS and drug use disorders. MN-166 (ibudilast) is a first-in-class, orally bioavailable, small molecule phosphodiesterase (PDE) -4 and -10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses pro-inflammatory cytokines and promotes neurotrophic factors. It attenuates activated glia cells, which play a major role in certain neurological conditions. Ibudilast’s anti-neuroinflammatory and neuroprotective actions have been demonstrated in preclinical and clinical study results and provide the rationale for its therapeutic utility in neurodegenerative diseases (e.g., progressive MS and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, substance abuse/addiction and chronic neuropathic pain.