Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Agios’

If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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Acute Myeloid Leukemia (AML) is usually a disease of the elderly and an area of high unmet medical need, especially in those who unfortunately relapse post stem cell transplantation (SCT) or are considered ineligible for a transplant. In some ways, it has languished in the graveyard of R&D with very few new therapies approved by the FDA or EMA over the last decade. In fact, it has been quite the opposite with Pfizer’s gemtuzumab ozogamicin (Mylotarg), an anti-CD33 antibody drug conjugate (ADC) approved and subsequently withdrawn from the US marketplace following lack of confirmatory phase III data.

The list of agents, targeted and and cytotoxics, that have been evaluated and found wanting in the elderly AML setting is very long. These patients are usually considered ineligible for transplant and rather challenging to treat given the concomittant co-morbidities and often frail performance status often exclude them from drug clinical trials also. A number of phase II trials have also generated promising efficacy data, only to fall short in larger randomised studies.

There are now a new raft of compounds in development, quite a few with data at ASCO or EHA, making it a suitable time for an update of the AML landscape.

Companies mentioned: Karyopharm, Astellas, Ambit, Arog, Sunesis, Celgene, Novartis, Genentech, Agios

Compounds mentioned: selinexor, ASP2215, crenolanib, quizartinib, trebananib, vosaroxin, Vidaza, midostaurin, ABT-199, GDC-0199, AG–221, TIM3.

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One of the challenges of the next decade in cancer research will be targeting cancer metabolism; imaging is likely to play a key role in drug development.

NMR-image-of-brain-gliomaThe cover of the January 11 online issue of Science Translational Medicine (STM) shows a brain tumor (glioma) in red, detected using non-invasive nuclear magnetic resonance imaging that highlights cancer metabolism.

In a paper published in STM, Andronesi and colleagues from Harvard & other Cambridge, MA institutions (including Agios Pharmaceuticals – more on them later), showed that excess production of the metabolite 2-hydroxyglutarate (2HG) could be used as a biomarker for a subset of glioma.

The subset this metabolic biomarker identified, were those patients with mutations of the isocitrate dehyrogenase gene (IDH1), present in 86% of the grade II & III gliomas and secondary glioblastomas.

Agios Pharmaceuticals founded by eminent cancer researchers, Lewis Cantley, Tak Mak and Craig Thompson is targeting the IDH1 and IDH2 metabolic pathways.

They have shown that mutations of the metabolic gene IDH1 are consistent with that of a cancer-causing oncogene.  Interestingly, Agios notes on their website that IDH1 and IDH2 mutations have also been seen in acute myeloid leukemia (AML).

What makes 2HG a functional biomarker for glioma is its correlation with survival.  2HG accumulates in the brains of patients with IDH1 mutations. These patients have a greater survival than those with wild-type IDH1 gliomas.

Developing a drug that targets cancer metabolism in the brain is not easy. NMR imaging of the 2HG in the brain will help researchers non-invasively follow the effects of inhibitors of mutated IDH1. This is particularly important given that, according to Andronesi et al,  “no report exists about increased D-2HG in the blood, cerebrospinal fluid, or urine of glioma patients with IDH1 mutations.”

The January 11 online issue of STM, also contains another paper on the detection of 2HG using NMR. Elkhaled and colleagues from UCSF report a technique of proton high-resolution magic angle spinning spectroscopy.  Their data confirms the potential of 2HG as a surrogate marker of patient survival.

Cancer metabolism as a drug development target is an area I expect we will see more of in the next ten years.  Key to success will be the ability to identify biomarkers with which to assess and monitor the success of drug candidates.

The identification of 2HG as a biomarker for IDH1 in glioma patients shows that cancer metabolism is an area of potential for drug development.

One cloud on the horizon for Agios Pharmaceuticals is, however, the filing of a lawsuit late last year by the Abramson Cancer Institute of the University of Pennsylvania. This alleges that Craig Thompson concealed the start-up of Agios while working for Penn, and in essence took the intellectual property of the University to the company. The merits of this claim have yet to be decided.

References

ResearchBlogging.orgAndronesi, O., Kim, G., Gerstner, E., Batchelor, T., Tzika, A., Fantin, V., Vander Heiden, M., & Sorensen, A. (2012). Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy Science Translational Medicine, 4 (116), 116-116 DOI: 10.1126/scitranslmed.3002693

Elkhaled, A., Jalbert, L., Phillips, J., Yoshihara, H., Parvataneni, R., Srinivasan, R., Bourne, G., Berger, M., Chang, S., Cha, S., & Nelson, S. (2012). Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas Science Translational Medicine, 4 (116), 116-116 DOI: 10.1126/scitranslmed.3002796

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