Biotech Strategy Blog

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

Posts tagged ‘LCL161’

As often happens in cancer research, a new class of compounds emerges every so often, fades out with various tricky clinical challenges then roars back again anew with target variations on a similar theme, as new data become available.

Most cancer signalling pathways veer towards the complex rather than simple, so can we learn from the past and try again by aiming at different compartments and cells?

Some recent translational data relating to IO and cancer immunotherapy can offer us fresh hope for potential novel combinations, especially with immunotherapies rather than chemotherapies.

The molecule designs have also moved on too thus offering additional opportunities and possibilities, which may not have the same difficulties with the therapeutic window limitations seen a decade ago.

There’s always something new to be hopeful about, so let’s take a look at what new ideas are emerging from the doldrums…

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This year at the American Society of Hematology (ASH) there are over 800 abstracts on multiple myeloma alone. Obviously, one can’t possible do them all justice, but there are a number of important ones that are well worth highlighting, especially given the raft of new products in development, as well as some solid data from existing approved products.

Myeloma has long been dominated by proteasome inhibitors and immunomodulatory (IMiD) agents in combination with prednisone, dexamethasone, melphalan or as a triplet such as RVd, VMP etc. In Europe, melphalan still dominates as part of the base therapy, while in the US, dexamethasone (dex or simply d) is preferred partner since the tolerability is much improved along with a lower risk for secondary primary malignancies (SPMs).

In this detailed preview, the following companies and products are covered:

Companies: Millennium, Celgene, J&J, Amgen, Novartis, GSK, Array, Actelion, Biotest, KaloBio, Curis, Verastem, Karyopharm, Aeterna Zentaris.
Products: Ixazomib, lenalidomide, pomalidomide, carfilzomib, panobinostat, daratumumab, ibrutinib, CC-292, afuresertib, GSK2857916, ARRY-520, ACY-1215, indatuximab ravtansine, CUDC-907, VS-5584, selinexor, LCL161, BYL917, perifosine.

I also discuss some controversial topics such as lack of overall survival in the Revlimid trials and the risk of cardiovascular adverse events with Kyprolis. There are also an exciting raft of new compounds with new targets in various stages of development.

Obviously there will be more to come at the meeting, but for now, there’s plenty to discuss and review ahead of time.

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The forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC is a must attend for anyone interested in cancer research and new cancer drugs in development.

 

Many readers will know that one of the hallmarks of cancer is the evasion of apoptosis or cell death.  Drugs in development that act as an inhibitor of apoptosis proteins (IAP) are starting to show promise against this target.

Novartis IAP Inhibitor LCL161

At the 2012 San Antonio Breast Cancer Symposium (SABCS), a phase 1 trial with LCL161, a novel-IAP antagonist from Novartis, showed promising responses in triple negative breast cancer when given in combination with paclitaxel chemotherapy. The SABCS data showed that in the 52 patients treated with LCL161, a complete response was observed in 1 patient, and a partial response was seen in 15 patients.

Caution must obviously be expressed at extrapolating from early-stage data in a non-randomized trial.

Several other companies have IAP antagonists in early development, including Curis (CUDC-427).

  • Curis announced in November they had licensed GDC-0917 from Genentech. I am hopeful there will be new data on CUDC-427 at the AACR annual meeting.  At the recent Citi Global Healthcare Conference on Feb 25, 2013, Curis stated they could start phase 2 development of CUDC-427 by mid-2013 and were looking at it in combination with capecitabine (Xeloda) in breast cancer as well as monotherapy.
  • Ascenta Therapeutics licensed their IAP inhibitor AT-406 to Debiopharm in August 2011.

Nature Reviews Drug Discovery has a review article on “Targeting IAP proteins for therapeutic intervention in cancer” for those interested in learning more about some of the compounds in preclinical and clinical development, and the scientific rationale behind this target.

IAP inhibitors are an interesting class of compounds to watch as they move forward in clinical development.

IAP Inhibitors may promote Bone Metastasis

Research published in the February 2013 issue of the AACR journal Cancer Discovery shows that in mouse experiments a side-effect of IAP inhibitors is promotion of osteoclast activity.  Whether these preclinical results in animal models translate to man remains to be seen, but the research by Chang Yang and colleagues from the Washington University School of Medicine in St Louis, MO is worth noting.

 

In simple terms, osteoclasts are the cells that remove bone as part of a dynamic equilibrium with osteoblasts, the cells that produce and lay down new bone.

An increase in osteoclasts caused by IAP antagonists activating alternative NF-κB signalling through NF-κB-inducing kinase (NIK) results in the disruption of normal bone metabolism.  In mouse experiments, this led to over-degradation of bone and osteoporosis (pathological bone loss), as well as providing a microenvironment that favors tumor expansion and metastasis.

Osteoclasts embedded in the bone matrix also release tumor growth factors, so if there are more osteoclasts then more growth factors are produced resulting in the creation of a more favourable microenvironment for bone metastasis.

In addition to showing the effects of IAP antagonists on the bone microenvironment, Chang Yang and colleagues demonstrated that drugs that prevent bone resorption such as zoledronic acid were able to decrease the incidence and severity of bone metastasis.

Many breast, cancer, prostate and lung cancer patients end up with bone metastases, which is why bone targeted agents have an important role to play in the treatment of the disease.

They conclude in their Cancer Discovery research paper that “future clinical trials of IAP antagonist-based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents.”  

The potential implications of this research is that bisphosphonates such as zoledronic acid and RANKL-targeted compounds, such as denosumab, may need to be used in conjunction with IAP antagonist treatment.

This is an important finding. If the animal results translate to humans, then concomitant administration of a bone target agent may be necessary.  Future clinical trials of IAP antagonists could end up with more complex and expensive study designs if bone side effects needs to be monitored and addressed.

I look forward to learning more about IAP antagonists at the AACR meeting in April, and to following progress in this novel class of new drugs that seek to address one of the hallmarks of cancer.

ResearchBlogging.orgYang, C., Davis, J., Zeng, R., Vora, P., Su, X., Collins, L., Vangveravong, S., Mach, R., Piwnica-Worms, D., Weilbaecher, K., Faccio, R., & Veis Novack, D. (2012). Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation Cancer Discovery, 3 (2), 212-223 DOI: 10.1158/2159-8290.CD-12-0271

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