On November 1, 2013 Nimbus Discovery reported that it will present preclinical data at The Liver Meeting, the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), that show the company has optimized a unique series of Acetyl Co-A Carboxylase (ACC) allosteric inhibitors that bind to the BC domain of ACC and demonstrate excellent potency, drug-like properties and preclinical efficacy (Press release Nimbus Discovery, NOV 1, 2013, View Source [SID:1234501248]). The novel, internally-developed small molecules, ND-654 and ND-630, demonstrated desirable in vitro and in vivo efficacy in experimental models of metabolic disease, diabetes and hepatic steatosis. In an iterative design fashion over 16 months, the potency of this family of compounds were improved >1000x utilizing the company’s proprietary small molecule computational drug discovery technology, and drug-like properties were optimized to efficiently deliver development candidate quality molecules.

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Simultaneous inhibition of both isoforms of ACC decreases fatty acid synthesis and stimulates fatty acid oxidation and has the potential to favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver diseases including non-alcoholic steatohepatitis (NASH). Nimbus’ ACC inhibitors, including ND-654 and ND-630, are believed to be the first drug-like allosteric inhibitors to bind the biotin carboxylase (BC) domain of ACC with high potency and selectivity.

Key findings of the Nimbus compounds presented at the conference include:

ND-654
Liver specific ND-654 has favorable drug-like properties with a 2700:1 liver to muscle exposure
Proof-of-mechanism: ND-654 acutely inhibits ACC, with virtually no effect on muscle, resulting in focused pharmacological effects on the liver
Proof-of-concept: ND-654 demonstrated target engagement in the liver and dose dependently decreased fatty acid production in the liver
NC-630
Liver selective ND-630 has favorable drug-like properties with a 100:1 liver to muscle exposure
Proof-of-mechanism: ND-630 acutely inhibits ACC, demonstrating efficacy in both liver and muscle by preventing malonyl Co-A production
Proof-of-concept: ND-630 demonstrated target engagement in the liver and muscle
Dosing of ND-630 in high sucrose fed diet-induced obesity (DIO) rats showed improvement in insulin sensitivity, improvement in hepatic cholesterol and normalization of hepatic triglycerides, dose dependent decrease of plasma triglycerides and FFAs, and decrease in plasma cholesterol

"Within 16 months, Nimbus has become the first company to identify and optimize a broad portfolio of liver directed, small molecule inhibitors of ACC — a previously intractable disease target," said Rosana Kapeller, M.D., Ph.D., Chief Scientific Officer of Nimbus. "We are now preparing for ND-630 to enter the clinic in 2015 for the treatment of NASH and diabetes, while we continue to progress ND-654 in preclinical models of hepatocellular carcinoma."

On October 31, 2013 THE Cancer Research Technology Pioneer Fund (CPF) reported a collaboration with Chroma Therapeutics Ltd to develop cancer drugs targeting macrophages – white blood cells – associated with tumours (Press release, Cancer Research Technology, 31 31, 2013, View Source [SID1234523249]).

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This investment by the CPF will accelerate the development of a promising ‘lead’ molecule – taking it from the laboratory into clinical trials for patients.

Chroma has licensed to CPF the rights to further develop and commercialise molecules to target a key mitogen activated protein kinase (p38). Inhibiting p38 activity alters the behaviour of tumour-associated macrophages (TAMs) so that instead of driving tumour growth, the TAMS switch to destroying tumours.

Richard Bungay, chief executive of Chroma, said: "Immuno-modulation is an exciting new field of cancer research and we are delighted to be working with CPF in order to accelerate the evaluation of the unique ability of our ESM technology to target key immune system cells as a new therapeutic approach."

The molecules have been modified to accumulate inside myeloid cells (blood cells) using Chroma’s own Esterase Sensitive Motif (ESM) technology. This technology attaches specific chemical motifs onto drugs, which are freely transported into cells. Once inside the cell, enzymes called esterases remove the motifs to create a compound that cannot easily exit the cell. Over time, the drug accumulates in TAMS, and reprogrammes them to attack tumours.

This is the third investment made by the CPF. It builds on initial research funded by Cancer Research UK and CRT led by Dr Thorsten Hagemann, at Queen Mary University of London, Barts Cancer Institute. This early research proved that the lead molecule, which was designed and synthesised by Chroma, can effectively switch macrophage behaviour to attack a range of cancer types, including lymphoma and pancreatic tumours in laboratory and animal studies.

Cancer Research Technology (CRT), Cancer Research UK’s commercial arm, and the European Investment Fund (EIF) launched the £50m CPF to bridge the UK funding gap between cancer drug discovery and early treatment development and appointed Sixth Element Capital to manage the fund.

Dr Robert James, managing partner of Sixth Element Capital, said: "We’re delighted to announce this collaboration between the CPF and Chroma to progress an innovative new approach to develop cancer drugs. CPF was set up to invest in the most exciting science behind new potential techniques to treat cancer, such as this."

Dr Keith Blundy, chief executive of Cancer Research Technology, said: "We’re extremely pleased to announce this innovative partnership, which will take forward the work done by Cancer Research UK-funded scientists and Chroma from the laboratory into clinical trials. Ultimately we hope this collaboration will produce potential new cancer drugs to improve survival for cancer patients."

On October 30, 2013 Merrimack reported results of a global, Phase 2, open-label, randomized study of MM-121 in combination with paclitaxel versus paclitaxel alone in patients with platinum-resistant or platinum-refractory advanced ovarian cancers (Press release Merrimack, OCT 30, 2013, View Source [SID:1234500597]).

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This study did not meet the primary endpoint of progression free survival in the overall population. The hazard ratio (HR) for progression free survival (PFS) was 1.0 [95% CI 0.74 – 1.4].

Ongoing analysis of a pre-specified set of biomarkers mechanistically linked to ErbB3 signaling identified a potential subpopulation of patients benefiting from MM-121 treatment in combination with paclitaxel. When using a combination of two biomarkers, the hazard ratio for PFS was 0.37 [95% CI 0.2 – 0.8] in the 34% of patients who were biomarker positive. The hazard ratio for PFS in the biomarker negative population was 1.54 [95% CI 1.0 – 2.4].

An overall increase in all grades of gastrointestinal toxicities, including diarrhea (73.6% vs. 42.5%), vomiting (31.4% vs. 18.8%) and other mucosal toxicities such as rhinitis (7.1% vs. 1.3%), epistaxis (23.6% vs. 17.5%), stomatitis (22.1% vs. 10.0%) and mucosal inflammation (22.1% vs. 1.3%), were observed in the combination as compared to paclitaxel alone, the majority of which were mild to moderate in severity. An increase in the pulmonary embolism rate was observed with the combination of MM-121 and paclitaxel (5.0% vs. 1.2%). No enhancement of paclitaxel-related peripheral neuropathy was reported with the combination.

"This unique study design lays the groundwork for future translational studies in ovarian cancer. The rapid enrollment into this study was a testament to the commitment of patients and physicians to advance our knowledge and improve upon available therapies in advanced ovarian cancers," said Dr. Akos Czibere, Clinical Director of the MM-121 program at Merrimack. "These data are a step forward for women with ovarian cancer."

"Research at Merrimack and elsewhere has shown that ligand-driven signaling through ErbB3 is one way in which cancer cells become resistant to therapy," said Gavin MacBeath, Ph.D., Co-Founder and Vice President of Translational Research at Merrimack. "MM-121 was designed to block this pathway. We are particularly encouraged by the biomarker findings in this trial, which are consistent with our preclinical hypotheses. This gives us increased confidence in our network biology platform and in our translational program at Merrimack."

This study was designed to evaluate whether MM-121 in combination with paclitaxel is more effective than paclitaxel alone, based on progression free survival. Patients were randomized at a 2:1 ratio for MM-121 in combination with paclitaxel versus paclitaxel alone. The study was conducted in the United Stated and Europe, and 223 patients were randomized. Patients enrolled in this study had locally advanced/metastatic or recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, had received at least one prior platinum-based chemotherapy regimen, and were platinum-resistant or refractory. The full data from the study will be presented at a future conference.

(Filing, 10-Q, Neurocrine Biosciences, OCT 29, 2013, View Source [SID:1234506073])

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(Press release, Shanghai Fosun Pharma, OCT 28, 2013, View Source [SID:1234505733])

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