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Preclinical Studies of CG200745, Novel Histone Deacetylase Inhibitor Discovered Using Structure-Based Drug Discovery Technologies

On April 29, 2009 Crystal Genomics reported Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes (Press release, CrystalGenomics, APR 29, 2009, View Source;id=596&page=10&num=27&nowpos=1252&type=&sermun=&qu=&tb_name=eng_news&rt_page=/en/news/news.php [SID1234539172]). Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the side chain of lysine of core nucleosomal histones. This posttranslational modification of core histone is involved in the regulation of the transcriptional activity of certain genes. It has been known that aberrant recruitment of HDAC activity is associated with the development of certain human cancers.

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In this study, we have discovered series of HDAC inhibitors by using the structure-based drug discovery technologies. The optimized compounds were evaluated by various enzyme inhibitory assays, anti-proliferation assays against cancer cell lines, FACS analysis and measurement of acetylated histone accumulation. We also carried out in vitro ADME studies including metabolic stability, CYP inhibition assays, and in vivo PK studies. The anti-tumor efficacy was also tested in the various xenograft tumor model. Many of them showed clear anti-tumor effects. Among them, CG200745 showed promising anti-tumor profiles. CG200745 inhibits histone deacetylase activity in low range nM of IC50 against class 1 and class II HDACs. The CG200745 exhibited a broad spectrum of anti-proliferative activity against various cancer cell lines at sub micromolar EC50. Mechanistically, the CG200745 induced dose -dependent increase in the accumulation of acetylated histone H4 and in apoptosis supported by annexin-V analysis in various tumor cell lines. CG200745 also showed potent antitumor effect in various xenograft tumor model.

In addition, the preclinical safety studies of CG200745 were performed in rodent and non-rodent systems for dose determination of first in human trial.

In conclusion, CG200745, novel HDAC inhibitors that are discovered through the structure based drug discovery, show potent anti-tumor activity in cell-based assays and animal studies. Currently, further PK/PD studies and preclinical safety studies of CG200745 are in progress

IRESSA (Gefitinib) Recommended for Approval for the Treatment of Non-Small Cell Lung Cancer in Europe

On April 23, 2009 AstraZeneca reported that the Committee for Medicinal Products for Human Use (CHMP), the scientific advisory committee of the European Medicines Agency (EMEA), has issued a positive opinion supporting approval of the targeted oral anti-cancer drug, IRESSA (gefitinib) (Press release, AstraZeneca, APR 23, 2009, View Source [SID1234571042]).

The CHMP has recommended the approval of IRESSA for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (epidermal growth factor receptor-tyrosine kinase), in all lines of therapy.

IRESSA acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus blocking the transmission of signals involved in the growth and spread of tumours. A mutation in the EGFR is a characteristic occurring in 10-15% of lung cancers in Europe, and studies have shown that these types of tumours are particularly sensitive to IRESSA. There are approximately 106,000 new cases of advanced lung cancer in Europe (top 5 countries) per year.

Anders Ekblom, Executive Vice President for Development at AstraZeneca, said: "Today’s positive CHMP opinion on IRESSA is an important step towards addressing the great unmet medical need of lung cancer patients in Europe, and supports AstraZeneca’s personalised healthcare strategy to develop the right medicine for the right patient. If IRESSA is approved, for the first time patients with these types of tumours will have a better alternative to chemotherapy as a first-line treatment."

The CHMP opinion is based on a submission package including two pivotal Phase III studies, IPASS and INTEREST.

The IPASS study exceeded its primary objective, demonstrating superior progression-free survival (PFS, the time a patient lives without their cancer progressing), greater objective response rate (ORR, tumour shrinkage), improved tolerability and significant quality of life benefits for IRESSA compared to carboplatin/paclitaxel doublet chemotherapy in clinically selected first-line patients in Asia. However, the treatment effect was not constant over time, with the probability of being progression-free in favour of carboplatin/paclitaxel in the first 6 months and in favour of IRESSA in the following 16 months. This was likely due to the different effect of IRESSA in subgroups defined by EGFR tumour mutation status. PFS was significantly longer for IRESSA than doublet chemotherapy in patients with EGFR mutation positive tumours, and significantly longer for doublet chemotherapy than IRESSA in patients with EGFR mutation negative tumours.

The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality of life benefits for IRESSA compared to standard chemotherapy (docetaxel) in the pre-treated setting. Pre-planned sub-group analyses showed a significant improvement in PFS and ORR for IRESSA over docetaxel in patients with EGFR mutation positive tumours.

AstraZeneca will be required to conduct a Follow-up Measure Study, to generate further data in a Caucasian NSCLC patient population. AstraZeneca is in discussion with the CHMP to finalise the study design and endpoints.

The CHMP positive opinion is now referred for final action to the European Commission, which grants marketing approval in the European Union.

IRESSA is already an established therapy for pre-treated NSCLC in the Asia-Pacific region, where AstraZeneca is in consultation with regulatory authorities to discuss the potential use of IRESSA in first-line therapy.

NOTES TO EDITORS:

In 2005, AstraZeneca withdrew its EU marketing authorisation application for IRESSA following data from the Phase III international ISEL study in pre-treated patients not eligible for further chemotherapy. ISEL did not meet its primary objective of a statistically significant improvement in OS for IRESSA compared to placebo, but did confirm a number of important clinical benefits for IRESSA including tumour shrinkage and a significant improvement in time to treatment failure. The refractory* nature of the ISEL population is the most likely explanation for the magnitude of the survival improvement with IRESSA compared to placebo not reaching statistical significance.

* Patients whose tumours had grown during or soon after receiving prior chemotherapy

Following delivery of the INTEREST data, AstraZeneca submitted a new regulatory package to the EMEA in May 2008; the IPASS data were added to the submission package when they became available in Q3 2008.

There is a rolling programme of approvals and licence updates for IRESSA around the world in a broad second-line population based on data from the INTEREST study.

Potential new drug blocks pathway of deadliest cancers

On April 19, 2009 Cancer Research Technology Ltd (CRT) reported that its scientists will present exciting new findings showing that a potent and selective inhibitor of protein kinase D called CRT0066101, inhibits the growth of pancreatic tumours (Press release, Cancer Research Technology, APR 19, 2009, View Source [SID1234523357]).

The research – to be presented by CRT’s Dr Christopher Ireson at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference today (Sunday) – was a collaborative effort between scientists at CRT’s discovery laboratories and the University of Texas MD Anderson Cancer Center. These results show for the first time that an inhibitor of PKD can slow the growth of tumours in pancreatic cancer models. In addition, experiments carried out by CRT have shown that CRT0066101 is also effective at inhibiting the growth of tumours in a lung cancer model. The scientists believe that the drug has the potential to treat other cancers too.

PKD is a relatively newly identified family of serine/threonine kinases comprising PKD1, PKD2 and PKD3. The potential of PKD as a new drug target was discovered by Enrique Rozengurt, Doreen Cantrell and Peter Parker and funded by Cancer Research UK. Following this discovery, an intensive drug discovery effort led by CRT’s Head of Medicinal Chemistry, Dr Tony Raynham, culminated in the identification of CRT0066101 as a lead candidate for pre-clinical studies. Since then, PKD has been identified as playing a central role in the development of a number of cancers. In addition to its role in the growth of tumour cells, PKD has also been shown to play a pivotal role in cell survival and angiogenesis – a process by which tumours form new blood vessels – which is central to tumour growth and spread.

CRT’s discovery laboratories director Dr Hamish Ryder said: "We focused on pancreatic and lung cancer tumours because they represent cancers with a significant unmet medical need. The CRT model of combining promising basic science with the capability of the industrially-focused discovery laboratories gives us a unique opportunity to rapidly develop potential new molecules to novel targets, and through partnering with industry, explore the potential to see if one day it might help treat cancer patients in the future".

Dr Sushovan Guha who leads the laboratory at MD Anderson Cancer Center, said: "We are very optimistic about CRT0066101’s pharmacological potential. We believe this is the first orally administered small-molecule inhibitor of PKD with significant biological efficacy in pre-clinical animal models of pancreatic cancer. My conviction is that we will show the drug can also prevent the proliferation of cancer cells by blocking their supply of blood – through neo-angiogenesis. This would mean it offers a double action treatment but this needs to be proved through further work."

Sanofi-aventis to Acquire BiPar Sciences, a US Biopharmaceutical Company

On April 15, 2009 Sanofi-aventis (EURONEXT:SAN) (NYSE:SNY) reported that it has signed a binding agreement for the acquisition of BiPar Sciences, Inc. ("BiPar"), a privately held US biopharmaceutical company, developing novel tumor-selective approaches for the treatment of different types of cancers (Press release, BiPar Sciences, APR 15, 2009, View Source [SID1234523619]).

BiPar is the leading company in the emerging field of DNA (DeoxyriboNucleic Acid) repair using PARP (Poly ADP-Ribose Polymerase) inhibitors. PARP inhibitors represent a new, targeted approach to treating many types of cancers. By preventing cancer cells from repairing their own DNA, PARP inhibitors ultimately cause cancer cell death.

BiPar’s lead product candidate is BSI-201, a potential first-in-class PARP inhibitor currently being studied in Phase 2 clinical trials in metastatic triple negative breast cancer (TNBC), ovarian cancer and other malignancies.

"We are extremely pleased to join with one of the most successful and innovative global pharmaceutical companies," said Hoyoung Huh, M.D., Ph.D., president and Chief Executive Officer of BiPar Sciences. "This agreement validates BiPar’s novel scientific approach and will maximize patient access to this new class of breakthrough cancer therapy."

"The acquisition of BiPar, one of the pioneer for novel tumor-selective therapies, is a further step in our company’s goal to focus on new approaches to strengthen our oncology R&D portfolio," said Christopher A. Viehbacher, Chief Executive Officer of sanofi-aventis. "This acquisition illustrates our strong commitment to oncology to provide patients, physicians and public health stakeholders with breakthrough medicines addressing unmet medical needs."

Under the agreement, the purchase price will depend on the achievement of milestone payments related to the development of BSI-201, which could achieve a maximum of $500 million.

The closing of the transaction is expected to occur in the 2nd quarter of 2009, subject to the receipt of the FTC clearance.

About Triple Negative Breast Cancer (TNBC)

When patients are diagnosed with breast cancer, their tumors are routinely tested for and classified based on the presence of estrogen, progesterone, and HER2 receptors. Commonly used breast cancer therapies target these receptors. However, up to 20 percent of all breast cancers are negative for all three receptors, thus giving rise to the term "triple negative breast cancer (TNBC)."

TNBC is a difficult-to-treat cancer subtype that does not have an approved standard-of-care and does not respond to current hormone-based and targeted therapies. TNBC is a very aggressive cancer, with higher rates of metastases and poorer survival rates than other breast cancer subtypes. The prevalence of the TNBC subtype is higher in younger and African-American women.

Breast cancer is the most prevalent cancer in the world today and the most common cause of cancer-related deaths among women. It is estimated that 182,000 new cases of invasive breast cancer were diagnosed in women in the U.S. during 2008.

About BSI-201

Among other PARP inhibitors in the industry, BSI-201 is the furthest along in clinical development in TNBC. With first-in-class and best-in-class potential, BSI-201 is highly potent against tumors and inhibits PARP activity for prolonged periods of time. BSI-201 enhances the effect of chemotherapy-induced DNA damage. The development of BSI-201 is supported by a strong safety profile based on studies of more than 200 patients.

Recently, BiPar announced positive interim safety data from an ongoing Phase 2 clinical trial of the company’s PARP inhibitor, BSI-201, in combination with chemotherapy in patients with metastatic triple negative breast cancer (TNBC). The company also presented gene expression data that confirmed significant upregulation of PARP in the tumors of the first 50 patients enrolled in the Phase 2 trial. Results were presented at the recent annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) in December 2008.

New deal boosts development of targeting peptides in nanotechnology

On March 2, 2009 Cancer Research Technology Limited (CRT), the oncology-focused development and commercialisation company, and the newly established oncology therapeutics company Aura Biosciences reported that they have agreed to take a promising new set of peptides into development for use in targeting cancer (Press release, Cancer Research Technology, MAR 2, 2009, View Source [SID1234523358]). The move marks significant extra investment in a potential treatment which will use these peptides to target cancer cells with RNAi or drug-loaded nanoparticles.

This deal will further the development of scientific work carried out by Cancer Research UK and DebRA – a charity which works on behalf of people in the UK with the genetic skin blistering condition Epidermolysis Bullosa (EB). Researchers developed short peptides that bind strongly to the protein called integrin avb6*, a cell-surface protein that is over expressed in a wide range of cancers but is not present at high levels in normal healthy tissue. The strong presence of integrin avb6 has been shown to be an indicator of a more aggressive tumours and poorer prognosis for cancer patients in breast cancer and in other tumours.

Dr John Marshall from Queen Mary, University of London – who will lead the study on these peptides said: "We are delighted to be joining forces with Aura Biosciences to develop this technology. We believe it has great potential to target and deliver a therapy to many tumours which over-expresses integrin avb6. This is supported by a wide body of literature showing that integrin avb6 is expressed at high levels in many different cancer types, including some of the cancers which currently have limited treatment options available for them such as pancreatic and head and neck cancer."

The terms of this deal will allow for the scientists at Queen Mary to continue to develop the peptides through a new research evaluation programme, sponsored by and run in collaboration with Aura Biosciences.

Under the terms of the agreement, Aura Biosciences will make payments to CRT in exchange for an option to take an exclusive worldwide licence on the peptides for certain applications – on pre-agreed financial terms which include an upfront fee, development milestones and royalties on future sales. Aura Biosciences will fund and oversee the next stage of the evaluation work. CRT will retain rights to the peptides in all other fields of use.

Dr Elisabet de los Pinos, chief executive officer of Aura Biosciences said: "We are very pleased to be progressing this research as we believe the peptides have exciting potential in combination with our proprietary nanoparticle technology already developed. We hope this collaboration will help us provide a unique way to target our nanoparticles to tumour sites more specifically."

Dr Phil L’Huillier, CRT’s director of business management said:"This deal will enable the development of technology which we hope will one day allow doctors to use these peptides to deliver drug-loaded particles directly to the tumour, reducing the side effects often associated with standard therapies and improving how well they work."