Saul Markman, Peeling The Onion (5 clicks)
Profile| Send Message|
Follow (12 followers)
AVEO Oncology: A New Platform To Create Oncology Drugs
Sep. 14, 2014 7:35 PM ET | 5 comments | About: AVEO Pharmaceuticals, Inc. (AVEO)
[Originally published 9/1/2014]
AVEO Oncology (NASDAQ:AVEO) is a Cambridge Mass. based company, founded 10 years ago and traded on NASDAQ. AVEO has created new and interesting oncology treatments, mostly antibodies. An interesting pipeline has been developed.
What is unique and interesting about this company, is that they have developed a platform on which to build an ever expanding pipeline. Their Human Response Platform (discussed below) is a new and patented methodology to identify potential targets for cancer treatments.
AVEO Oncology: Rating the Company
AVEO is very unique in its approach to developing oncologic products. They are not totally unique in the sense that many competitors are developing antibodies for targeted cancer therapy. The approach they are using can be used against many types of cancer rendering their market size enormous.
AVEO is still quite early in human trials for most of their pipeline.
AVEO Oncology: Human Response Platform
The Human Response Platform (HRP) is a new type of model intended to identify oncologic drug candidates. Models developed under the HRP should increase the success rate of developing anti tumor drugs.
The intention is to identify and test target genes that drive tumor growth, to develop drugs that block these targets and ultimately to identify patients most likely to respond to these drugs.
This is done through proprietary models, using new techniques discovered by AVEO’s scientists.
AVEO’s HRP: How it Works
AVEO was founded by two high ranking MDs from MD Anderson Cancer Center in Texas and a Harvard PhD. Better mouse models to drive the design and patient selection of clinical trials were, and are, at the core of AVEO’s work.
Here is a brief, simplified version of how the process works:
Incorporate into stem cells, human cancer lesions that have human oncogenes (cancer causing genes).
Put the stem cells into mice.
Develop a population of murine (mouse) tumors.
Gain insight about tumor characteristics and apply them to humans.
In essence you have designer tumors (because you’ve picked the oncogene) growing in mice. These are human tumors. Because the tumors are human in origin, they give better information about how to treat the particular tumor than you could get using mouse tumors. This is theoretically a better model than any test tube model.
The HRP platform allows insight into tumor biology and into the hows and whys of drug response and/ or resistance. Models such as these can be developed for virtually any tumor that has an oncogene that can be isolated.
AVEO’s Human in Mouse Model
The Human in Mouse Model (HIM) is another proprietary model developed at AVEO. Normal human breast tissue, usually taken from breast reduction surgery, is modified with oncogenes so that it will likely develop cancer. The modified tissue is injected into specially engineered mice. The injected cells become normal breast tissue and migrate to join the mouse’s breast tissue. The cells rapidly develop breast cancer in the mouse’s breast.
This allows the same kind of insights as the HRP platform.
AVEO’s Pipeline of Targeted Therapy
The importance of these models is to develop targeted therapy; that is, therapy designed for people who have tumors with the same oncogene as the tumors in the mouse. If you can prove that an anticancer treatment works on the human tumor in the mouse, then there’s a good chance it will work on a genetically identical tumor in patients.
AVEO currently has four drugs in the pipeline designed with that concept in mind. They have several others in development. The concept can be applied to many tumors. If you can find a target and if you can build an antibody to the target, then you can attack the tumor.
Below, I will discuss the various drugs in the pipeline.
AVEO’s AV-203
Recent evidence suggests that a molecule named Erb B3 is important in tumor formation and growth. When Erb B3 is activated it promotes new tumors, tumor growth and resistance to chemotherapy. For activation it binds to an Erb B3 receptor also known as Human Epidermal Growth Factor Receptor 3 (HER3), a receptor closely related to HER1 and HER2 which are targeted in certain breast cancer treatments. The Erb B3 receptor is expressed in many tumors.
AV-203 is an antibody against Erb-B3. It inhibits the ability of Erb B3 to send signals to the tumor to grow, or to form drug resistance. If the antibody works as planned, tumor growth is severely inhibited. AV-203 seems to work whether or not the Erb-B3 is attached to its receptor.
In pre-clinical studies AV-203 showed activity in models of many cancers including breast, head and neck, lung, pancreatic and ovarian. A Phase 1 study has delineated maximal acceptable dose for a good toxicity profile.
A biomarker has been developed and validated for patient selection. Patients whose tumors express this marker are more likely to respond to this therapy.
It has also been established that for any given cancer, an overexpression of Erb B3 confers a poor prognosis, much like HER1 and HER 2 in breast cancer.
AVEO’s Ficlatuzimab
Ficlatuzimab, which was developed as AV-299, is an antibody inhibitory to Hepatocyte Growth Factor (HGF). Ficlatuzimab binds with great affinity and great specificity to a small part (ligand) of the HGF molecule.
HGF is important in embryonic cell growth. Pathologically it plays a part in tumor genesis, rapid cell division and angiogenesis. Angiogenesis is an important mechanism to support tumor growth. It’s the development of new blood vessels to provide nutrition to rapidly growing tumors. HGF has to interact with its receptor (C-Met) to be effective. Ficlatuzimab inhibits the signalling function of the HGF/C-Met compound. Tumor growth is inhibited directly and by decreasing new vessel growth. Metastases are also inhibited.
Ficlatuzimab is being tested alone and in conjunction with an anti cancer drug called erlotinib. Erlotinib is one of a new class of anti cancer drugs that work by inhibiting tyrosine kinases. In particular it inhibits the Epidermal Growth Factor Receptor (EGFR). EGFR and HGF are often overexpressed in the same cancers , so the combination therapy is logical.
AVEO is also involved in an analysis of Veristocet which is a patented protein marker in the serum, believed to be predictive in the survival of patients with non small cell lung cancer treated with drugs such as erlotinib. It makes sense that if this marker predicts a poor outcome in patients treated with a tyrosine kinase inhibitor, that Ficlatuzimab be added to the regimen. An exploratory analysis is being done to predict benefits of adding Ficlatuzimab based on a Phase 2 study of first line treatment of non small cell lung cancer with tyrosine kinase inhibitors.
The HGF/C Met complex is overexpressed in colorectal, gastric, head and neck, breast, lung and prostate cancer amongst solid malignancies as well as hematologic malignancies.
AVEO’s Tivozanib
There are three Vascular Endothelial Growth Factor Receptors (VEGFRs). All 3 are blocked by Tivozanib (an anti VEGFR antibody). On the VEGF molecule there are five identified important ligands (ligands are small molecules that bind to larger molecules). These 5 ligands bind to the three VEGFRs with different but overlapping binding profiles. Block the 3 receptors and you neutralize all 5 ligands.
VEGFR 1 is crucial for new vessel growth in cancers and for the survival of the endothelial cells that line blood vessels. VEGFR 2 is not as well understood but appears to be important for the growth and appropriate migration of endothelial cells. VEGFR 3 is important in the formation of connecting networks of vessels.
Block all three VEGFRs as Tivozanib does and new vessels are not formed to promote tumor growth and nutrition. It’s analogous to choking off the root system of a growing plant.
AVEO was collaborating with Astellas to promote this product but as of August 2014, the rights revert to AVEO who will explore other partnerships.
AVEO’s AV-380
AV-380 is a first in class inhibitor of GDF-15. I will not go into the many functions of this member of the growth factor family.
Of importance to cancer patients is that it seems to mediate cachexia. Cachexia, sometimes called wasting syndrome, is a syndrome consisting of weight loss, muscle atrophy, loss of appetite, weakness and fatigue. Cachexia is present in over half of cancer patients. A myriad of other diseases including (but not limited to) AIDS, Congestive Heart Failure, Tuberculosis, Chronic Obstructive Lung Disease, Renal Failure and Multiple Sclerosis also have cachexia as a feature.
AVEO is attempting to rapidly show proof of clinical activity of AV-380 in cachexia with an eye towards human trials in about a year.
Other Molecules Developed by Human Response Platform
A limitless number of other targets can be identified by HRP. The next targets for antibodies have been identified in this manner.
Fibroblast Growth Factors and their receptors are an important signalling network in the regulation of cell growth, differentiation and survival. Often deregulated in cancer, they confer rapid growth and increased survival to tumour cells. They stimulate new vessel formation as well. There are 4 FGF receptors and AVEO is developing antibodies to FGFR 2 and FGFR 3.
Similarly the NOTCH signalling pathway is important in the genesis and growth of tumours. AVEO is developing antibodies against 2 of the 4 Notch receptors.
AVEO: Where are They Going?
I think AVEO is an exciting company. The HRP platform has been designed by an extremely strong scientific group. Its claims of being a better way to assess appropriate anti tumor targets appear to be valid.
Using the HRP platform they have developed a strong pipeline. The exciting part is that using the same technology they should be able to create a vast pipeline.
The market size is enormous as it encompasses many cancers. If AV-380 can really modulate cachexia, then we are talking about a market of unprecedented size, encompassing not only cancer patients but also patients with common diseases such as CHF, COPD, MS and renal failure.
A word of warning: Many antibodies are being produced and marketed, some very successfully. However 2014 has been marked by antibodies that looked great in pre-clinical studies, only to fail Phase 2 Trials. AVEO seems poised for success but as with any new product, success will hinge on Phase 2 clinicals.
Disclosure: The author has no positions in any of the stocks mentioned. The author wrote this article themselves and is not receiving compensation for it.
Zurück
Weiter
Werbung
