On December 9, 2013 Agios Pharmaceuticals reported that data from its lead programs were highlighted at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting this week in New Orleans (Press release Agios Pharmaceuticals, DEC 9, 2013, View Source;p=irol-newsArticle&ID=1883336&highlight= [SID:1234500778]).

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Two presentations featured in vivo efficacy data in acute myelogenous leukemia (AML) for the company’s lead cancer metabolism programs targeting IDH1 and IDH2 mutations. In AML and other cancers, IDH1 and IDH2 mutations initiate and drive cancer growth by blocking maturation of primitive cells. The data presented at ASH (Free ASH Whitepaper) demonstrate preclinical single agent and combination efficacy of Agios’ IDH mutant inhibitors in patient-derived primary models of AML. Agios also presented data on AG-348, its lead inborn errors of metabolism (IEM) program candidate focused on pyruvate kinase deficiency (PK deficiency), a rare, inherited hemolytic anemia with no approved therapeutic options.

"We are excited to present data highlighting our IDH and PKR programs, which focus on genetically identified patient populations with limited or no therapeutic options," said Scott Biller, Ph.D., chief scientific officer at Agios. "These results highlight the potential for all three programs to provide significant clinical benefit to patients in the future."

Agios Presentations

"AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model," an oral presentation, provides strong preclinical in vivo evidence of AG-221’s potential clinical benefit for patients with tumors that harbor an IDH2 mutation. AG-221 is a potent, selective, orally available IDH2 mutant inhibitor currently in clinical trials for patients with hematologic malignancies. In this study, Agios scientists evaluated the efficacy of AG-221 as a single agent in a primary human model of aggressive AML carrying an IDH2 mutation. AG-221 caused a potent reduction in 2HG, the oncometabolite produced by the mutant IDH2 protein, found in the bone marrow, plasma and urine of engrafted mice. Treatment also induced a dose-dependent, statistically significant survival benefit in which all mice in the high-dose treatment group survived to the end of the study.
"IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human IDH1 mutant AML xenograft model," a poster, evaluates the use of AGI-14100, a potent, selective, orally available IDH1 mutant inhibitor. Agios scientists treated a primary human mutant AML model with AGI-14100, either alone or in combination with low-dose chemotherapy (Ara-C). Researchers observed a significant decrease in tumor burden in peripheral blood in the model treated with AGI-14100 alone, and a more pronounced response, as measured by a simultaneous decrease in the bone marrow tumor burden, in the model that received combination therapy. The duration of response continued for three weeks after dosing of both drugs had been terminated. These data suggest that this combination therapeutic approach could be an important option for patients, to be explored in future clinical trials.
"Small Molecule Activation of Pyruvate Kinase Normalizes Metabolic Activity in Red Cells From Patients With Pyruvate Kinase Deficiency-associated Hemolytic Anemia," a poster, presents preclinical data supporting Agios’ lead IEM clinical candidate, AG-348, as a potentially effective approach to correcting the underlying pathology of PK deficiency. The results demonstrate that AG-348 potently activates a spectrum of PKR mutant proteins, the isoform of pyruvate kinase that is present in red blood cells, leading to a normalization of metabolic balance in patient-derived blood samples. These data support the hypothesis that drug intervention with AG-348 may restore glycolytic pathway activity and normalize red cell metabolism in vivo.

On December 5, 2013 CSL Limited reported an agreement with Janssen Biotech, Inc. that may one day lead to new treatments for haematological cancers and autoimmune diseases (Press release, CSL, DEC 5, 2013, View Source [SID:1234514853]).

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The agreement grants Janssen an exclusive worldwide license to develop and commercialise CSL362, a novel monoclonal antibody therapy. Currently, CSL362 is being studied in a Phase 1 clinical trial in acute myeloid leukaemia (AML) patients who achieved remission after treatment with chemotherapy and who are at high risk for relapse. AML is a fast growing cancer of the blood and bone marrow and is considered a significant unmet medical need with no new advances in the last few decades.

Laboratory studies have shown that CSL362 specifically targets AML cells and recruits and activates killer cells from the body’s innate immune system to attack the cancer cells. It is hoped that these natural killer or NK cells will eliminate residual AML cells, preventing relapse of the disease. The target to which CSL362 binds on AML cells (CD123) is also expressed on other haematological cancers and on rare blood cell populations thought to mediate autoimmune diseases such as lupus.

The agreement with Janssen was announced by CSL’s Chief Scientific Officer, Dr Andrew Cuthbertson, at the Company’s annual R&D briefing for investors.

"CSL362 is at a very exciting stage of development and required a partner with a proven capability in oncology and autoimmunity to maximise its potential. We are delighted to have attracted such a high quality partner in Janssen who share a deep commitment to developing this promising therapy for the benefit of very ill patients," said Dr Cuthbertson.

CSL362 was engineered by CSL scientists using, as a starting point, a unique antibody developed by Professor Angel Lopez at Adelaide’s Centre for Cancer Biology in the late 1990’s. The original antibody was able to recognise AML cells preferentially, but was not suitable for use in humans and it lacked the ability to recruit and activate the body’s NK cells. CSL scientists engineered the antibody to ensure that it is suitable for use in humans and to enhance its ability to recruit NK cells to kill the AML cells.

"The development of CSL362 to date is another fine example of the power of collaboration and speaks to the outstanding quality of science in Australia’s medical research institutions. With the addition of Janssen we have the modern model of drug development which uses the distinctive strengths of all parties to bring new therapies to patients sooner," said Dr Cuthbertson.

The clinical trial for CSL362 is being conducted in Australia and the USA. The Australian study is being led by Professor Andrew Roberts, who is a clinical haematologist at the Royal Melbourne Hospital, Head of Clinical Translation at the Walter and Eliza Hall Institute and Metcalf Chair of Leukaemia Research at the University of Melbourne.

"Acute myeloid leukaemia is a very aggressive type of cancer and has very poor survival rates. Although we can induce remission with chemotherapies there is a high likelihood of relapse, at which point the outcome is often very poor," said Professor Roberts.

"CSL’s investigational antibody therapy offers a novel treatment approach because it is designed to recruit the body’s immune system to help keep the leukaemia in remission. We are hopeful that what has been seen in the laboratory to date can be replicated in the clinic. If it is, then we will have taken the first key step towards improving survival rates for those with AML" added Professor Roberts.

Under the terms of the agreement with Janssen, CSL will receive a license fee and be entitled to development, regulatory and sales based milestone payments, as well as royalties on sales. CSL will be responsible for the completion of the Phase 1 clinical trial in AML and Janssen will be responsible for all further development and commercialisation in AML and other indications. The parties will continue to work collaboratively on research programs primarily to support the use of CSL362 in other indications.

On December 4, 2013 3-V Biosciences reported the recent initiation of a Phase 1 clinical study of TVB-2640 in patients with advanced solid tumors (Press release 3-V Biosciences, DEC 4, 2013, View Source [SID:1234500430]). TVB-2640 is an oral, proprietary fatty acid synthase (FASN) inhibitor being evaluated for the treatment of solid tumors. FASN is an enzyme responsible for the synthesis of palmitic acid and has a key role in tumor metabolism, lipid signaling and tumor cell survival.
The Phase 1 open-label, dose-escalation trial will enroll patients with advanced solid tumors whose cancer has become refractory to standard therapy, and for whom no useful treatment exists. Patients will receive TVB-2640 once daily for 21 days. The primary endpoint for the Phase 1 study is the identification of any dose-limiting toxicities and the establishment of a maximum- tolerated dose (MTD) for oral TVB-2640. Secondary and exploratory endpoints include safety, pharmacokinetics, and initial signs of efficacy and evidence of FASN biomarker activity.
FASN over-expression is associated with aggressive disease and poor prognosis in a number of cancers. In a series of preclinical studies, 3-V’s FASN inhibitors demonstrated potent activity against multiple tumor types, including breast, lung, pancreatic, ovarian and colon cancers. FASN inhibition reduced cell proliferation and induced apoptosis (cell death) in a dose-dependent manner and single-agent FASN inhibition both blocked tumor growth and resulted in significant tumor regression in patient-derived xenografts. In addition, 3-V has demonstrated potential synergy of its FASN inhibitors with cytotoxic agents.

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(Press release, Flag Therapeutics, DEC 4, 2013, View Source [SID:1234503449])

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On December 3, 2014 Kancera reported the discovery of a new class of compounds that inhibits the epigenetic enzyme histone deacetylase 6 (HDAC6) and thereby controls the activity of the cancer cell genes (Press release Kancera, DEC 3, 2013, View Source;releaseID=835081 [SID:1234500120]). Severe side effects, due to poor selectivity, have limited the clinical use of HDAC inhibitors in the treatment of cancer, despite their promising treatment efficacy. For this reason, the pharmaceutical industry is now looking for HDAC inhibitors displaying a higher level of selectivity within this family of enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution to how physicians could take advantage of HDAC inhibitors in the treatment of cancer without causing the patient severe side effects.

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There are currently two HDAC inhibitors on the market for the treatment of various forms of T-cell lymphoma. These inhibitors are active against several members of the HDAC family of enzymes leading to side effects including severe nausea and potentially an increased cardiovascular risk. Selective inhibition of HDAC6 is expected to reduce these side effects, while activity against cancer cells is maintained.

Kancera´s unexpected discovery of such selective HDAC6 inhibitors is the result of an incidental finding made following an EU-funded project against epigenetic targets for the treatment of parasitic diseases. Laboratory tests have shown that Kancera’s inhibitors display a higher level of selectivity against the HDAC6 enzyme as compared to a competing inhibitor, ACY-1215. Kancera´s HDAC6 inhibitors have furthermore been shown to be able to kill cancer cells in vitro.

ACY-1215, developed by the Boston-based company Acetylon Pharmaceuticals, is currently in early clinical trials ( Phase 1b) for the treatment of multiple myeloma. In July 2013 it was announced that Celgene for a $100 million upfront cash payment received an option to acquire Acetylon Pharmaceuticals with ACY -1215 as their main asset.

Kancera now intends to file patent applications for these inhibitors and to further evaluate the potential of them in the treatment of cancer, including multiple myeloma.