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Commencement of First-in-Human Clinical Trial for New Molecular Targeting Drug, Co-Developed with The University of Tokyo and National Cancer Center, to Treat Malignant Lymphoma (Including Adult T-cell Leukemia-Lymphoma)

On March 22, 2016 The National Cancer Center, The University of Tokyo, and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported a collaboration to develop a histone methylation enzyme EZH1/2 dual inhibitor (DS-3201), as a new molecular targeting agent for hematologic malignancy, and the commencement of Phase 1*1 clinical trial in patients with malignant lymphoma and adult T-cell leukemia-lymphoma (ATL) (Press release, Daiichi Sankyo, MAR 22, 2016, View Source [SID:1234511231]).

One contributing factor to the poor prognosis for malignant lymphoma is the existence of Cancer Stem Cells*2 capable of regenerating cancer cells and thought to persist after treatment, making the eradication of Cancer Stem Cells essential to the cure of hematologic malignancy. National Cancer Center Research Institute, Division of Hematological Malignancy research group led by Issay Kitabayashi discovered that EZH1/2 are essential enzymes in the maintenance of Cancer Stem Cells, and produced research results suggesting that inhibiting both enzymes may eradicate Cancer Stem Cells to overcome drug-resistance and suppress recurrence. To date, several preclinical studies suggest that this may be an effective treatment for acute myeloid leukemia (AML) and malignant lymphoma.

Searching for an effective ATL treatment, a research group chiefly led by Professor Toshiki Watanabe and Project Research Assistant, Makoto Yamagishi, of The University of Tokyo, Graduate School of Frontier Sciences, discovered an abnormal accumulation of epigenetic changes*3 due to inappropriate activation of EZH1/2 in ATL cells. Also, as ATL cells are more strongly dependent on epigenetic changes caused by EZH1/2 compared to normal cells, the research developed a new compound that simultaneously inhibits the function of both EZH1 and EZH2. This dual inhibitor reversed inappropriate methylation of histones in ATL cells and also selectively eliminated ATL cells and HTLV-1-infected immortalized cells in the peripheral blood.

Malignant lymphoma
Malignant lymphoma is the most prevalent hematologic malignancy. Malignant lymphoma is classified into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Recent advances in the management have led to the improvement in therapeutic outcomes of patients with malignant lymphoma, especially Hodgkin lymphoma and B-cell non-Hodgkin lymphoma. However, relapsed or refractory patients with both diseases and T-cell lymphoma patients are still of unfavorable prognosis. Among various subtypes of T-cell lymphoma, ATL is the disease caused by human T-cell leukemia virus type I (HTLV-1) with the poorest prognosis. About 1,000 patients suffer from ATL every year in Japan, where approximately 1.2 million individuals are infected by HTLV-1. The number of HTLV-1-infected individuals (carriers) is estimated to be about 10 to 20 million in the world. About 5 percent of carriers develop ATL during their lifetimes. However, no onset prevention methods or effective treatments of ATL have been established. The prognosis of ATL is very poor mainly because of the high frequency of drug resistance. As the only HTLV-1 endemic country among developed nations, the world expects Japan to lead global efforts to develop new treatments towards onset prevention and effective treatments of ATL.

Clinical trial
This Phase I is the multicenter, study conducted by the National Cancer Center Hospital (Chuo-ku, Tokyo), and other facilities in Japan.

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8-K – Current report

On March 22, 2016 IntelGenx Corp. (TSX-V: IGX) (OTCQX: IGXT) (the "Company" or "IntelGenx") reported financial results for the three and twelve-month periods ended December 31, 2015. All amounts are in U.S. Dollars unless otherwise stated (Filing, Q4/Annual, IntelGenx, 2015, MAR 22, 2016, View Source [SID:1234509840]).

2015 Fourth Quarter Financial Highlights:

• Revenues reached $1.5 million, an increase of 82% over the same period last year

• Net comprehensive income was $233 thousand, compared to a net comprehensive loss of ($339 thousand) over the same period last year

• Adjusted EBITDA was $429 thousand, compared to a negative ($225 thousand) over the same period last year

• Cash and cash equivalents totaled $2.87 million as at December 31, 2015

2015 Twelve-Month Financial Highlights:

• Revenue was $5.1 million, an increase of 207% over the same period last year

• Net comprehensive income was $800 thousand, compared to a net comprehensive loss of ($2.2 million) over the same period last year

• Adjusted EBITDA was $1.7 million, compared to a negative ($1.6 million) over the same period last year

Recent Operational Highlights:

• Net sales of Forfivo XL continued to improve significantly in the fourth quarter of 2015 by 24% to $3 million ($5.4 million gross) compared to the third quarter of 2015

• For the past twelve months, net sales of Forfivo XL totaled $9.3 million ($17.4 million gross), an increase of 102% compared to the twelve-month period in 2014

• Received the remaining $2 million milestone payment from Edgemont Pharmaceuticals

• Construction completed of IntelGenx’ new state-of-the-art manufacturing and laboratory facilities which are expected to be fully operational by 2017

"We are most pleased with the record results and progress we have made as an organization in 2015," said Dr. Horst G. Zerbe, President and CEO of IntelGenx. "Our continued sales growth of Forfivo has enabled us to achieve two consecutive quarters of profitability. We have invested these profits back into transforming IntelGenx by building a stronger management team with the clear goal of accelerating the execution of our business plan coupled with the completion of the construction of our state-of-the-art manufacturing facilities. Both these strategic initiatives will enable us to become a global leader in pharmaceutical oral film development and manufacturing."

Financial Results:

Total revenues for the three-month period ended December 31, 2015 amounted to $1.5 million, representing an increase of $677 thousand or 82% compared to $825 thousand for the three-month period ended December 31, 2014. Total revenues for the twelve-month period ended December 31, 2015 amounted to $5.1 million representing an increase of $3.4 million or 207% compared to $1.7 million for the twelve-month period ended December 31, 2014. The increases for the three-month and twelve-month periods ended December 31, 2015 compared to the last year’s corresponding periods are mainly attributable to the attainment of milestones, totaling $2.7 million from IntelGenx’ licensing partner Edgemont. The milestone was triggered by Edgemont reaching in July 2015, $7 million of cumulative net trade sales of Forfivo XL over the preceding 12 months. From the $2.7 million milestones, $1 million was received in the third quarter. From the remaining balance, $1 million was received in the fourth quarter and $1 million was received in the first quarter of 2016, with revenue to be recognized in the first quarter of 2016 of $333 thousand. Nevertheless, 3/6 of the $2 million was recognized as revenue in the fourth quarter and 5/6 of the $2 million was recognized as revenue in the twelve-month period ended December 31, 2015.

Operating costs and expenses were $3.71 million for the twelve-month period of 2015, versus $3.44 million for the corresponding period of 2014.

For the twelve-month period of 2015, the Company generated operating income of $1.4 million compared to an operating loss of ($1.8 million) for the comparable period of 2014.

Net comprehensive income was $800 thousand or $0.01 on a basic and diluted per share basis for the twelve-month period of 2015 compared to a net comprehensive loss of ($2.2 million) or ($0.03) on a basic and diluted per share basis for the comparable period of 2014.

"We are focused on a strong financial discipline in managing our expenses and ensuring high standards of financial controls be implemented throughout the organization," said Mr. Andre Godin, Executive Vice-President and CFO of IntelGenx. "We are committed to working at building the visibility of the corporation in the marketplace."

Cash on hand as at December 31, 2015 was $2.87 million, representing a decrease of ($1.53 million) compared with the balance of $4.4 million as at December 31, 2014. The decrease in cash relates primarily to the investments made into our state-of-the-art manufacturing and laboratory facilities.

Verastem Announces Oral Presentation of Data Supporting the Preferential Targeting of Ovarian Cancer Stem Cells at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer

On March 22, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of scientific data at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer being held March 19-22, 2016 in San Diego, CA (Press release, Verastem, MAR 22, 2016, View Source;p=RssLanding&cat=news&id=2150260 [SID:1234509826]).

"The data presented today at SGO 2016 are important because they provide further scientific evidence that chemotherapy can lead to an increase in ovarian cancer stem cells (CSCs), making the tumor more aggressive and resistant to further treatment," said Dr. Jonathan Pachter, Verastem Head of Research. "At Verastem, we believe that our compounds in development may be especially beneficial as therapeutics when used in combination with other agents, including current and emerging standard of care treatments and immunotherapies, and have the potential to create a more durable clinical response. We look forward to the initiation of a Phase 1/1b clinical trial of the combination of VS-6063 and avelumab, in collaboration with Pfizer and Merck KGaA, for patients with ovarian cancer in the second half of this year."

Verastem, and its collaborators, are presenting these scientific data in support of Verastem’s development programs which utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. The Company’s most advanced clinical product candidates are the Focal Adhesion Kinase inhibitors, VS-6063 and VS-4718, and the dual PI3K/mTOR inhibitor, VS-5584. Research on the FAK and PI3K/mTOR signaling pathways has revealed critical roles for each in cancer stem cell survival and disease progression.

Details for the SGO presentation are as follows:

Oral Presentation

Title: Standard chemotherapy for ovarian cancer increases expression of cancer stem cell biomarkers which is predictive of survival

Session: Scientific Plenary IX: Ovary

Date and time: Tuesday, March 22, 2016 at 8:30 – 10:05 AM

Location: Hall A

Summary: In ovarian cancer, certain molecular mediators are thought to possess CSC characteristics and the presence of these mediators, which is linked to earlier recurrence and shorter survival, is possibly brought about by chemotherapy. The aim of this study was to explore the effect of chemotherapy on ovarian cancer stem-like mediators and to determine if there was a relationship to survival. Researchers obtained matched pre- and post-chemotherapy tumor specimens from stage IIIC/IV ovarian cancer patients (n=22) who all underwent neoadjuvant chemotherapy with interval debulking surgery. Samples were then analyzed for expression of 27 CSC markers. CSC markers were then validated in tumorsphere model and in vivo tumor initiating studies.

All 27 CSC markers demonstrated a mean increase in gene expression after exposure to chemotherapy. A 3-fold or greater increase in gene expression after exposure to chemotherapy was seen in 8 of 27 (30%) markers: ABCG2, ALDH1A1, CTGF, DPP4, MYC, CD133, SOX2, and POSTN. Three markers demonstrated a significant fold increase that correlated with platinum resistance: POSTN (4.1-fold), ALDH1A1 (5-fold), and SOX2 (14.5-fold). When implanted into immunocompromised mice, SOX2(hi) cells exhibited significantly higher levels of tumorsphere forming potential than SOX2(lo) cells and were more tumorigenic. High gene expression in these 3 markers demonstrated shorter progression free survival, compared to low expression. These results support the further investigation of directed agents to inhibit these CSC markers to potentially extend survival for patients with ovarian cancer.

A copy of the oral presentation will be available at http://bit.ly/R3M6wc

Pharmacokinetics and safety of subcutaneous pasireotide and intramuscular pasireotide long-acting release in Chinese male healthy volunteers: a phase I, single-center, open-label, randomized study.

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).
In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.
Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.
The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
Copyright© Ferrata Storti Foundation.