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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘AMG-386’

Read and writing about malignant brain cancers, gliomas or glioblastoma multiforme (GBM) always makes me sad as life span from diagnosis is often only a year. Over the last decade we have seen many advances in surgery, radiation, chemotherapy and targeted therapies in many cancers, yet this one remains largely immune to significant progress.

Background

Angiogenesis inhibitors targeting the VEGF signaling pathway have been shown to be effective both in preclinical cancer models and in clinical trials. This has led to the approval of several agents targeting VEGF in cancer, including bevacizumab (Avastin), sorafenib (Nexavar) and sunitinib (Sutent). To date, bevacizumab, has been approved for the treatment of relapsed glioblastomas in the US, at a dose of 10 mg/kg IV every 2 weeks. The approval in GBM was based on objective response rate, not survival.

There have been concerns in the past about the use of anti-angiogenic therapy (see references below) with malignant gliomas, principally malignant progression of the tumours with increased local invasion and distant metastasis. In other words, the cancer become more aggressive, which is not a good thing.  Still, the concerns and risk involved must be balanced with the severity of the disease and relatively poor prognosis. Development of resistance is also an ongoing problem.

This morning though, I was a little more cheered about the topic after someone kindly sent me a new clinical paper on angiogenesis and GBM.  

Angiogenesis 

Brunkhorst et al., (2010) looked more closely at the mechanisms underlying tumour angiogenesis, principally angiopoeitins, and found some interesting relationships:

"We establish that Ang-4 is upregulated in human GBM tissues and cells. We show that, like endothelial cells, human GBM cells express Tie-2 RTK."

In simple terms, angiopoietins (Ang-1, Ang-2, and Ang-4) are the ligands of the Tie-2 receptor tyrosine kinase (RTK). More details can be found in an excellent review of angiopoietins and Tie2 in a review by Huang et al., (2010).  While the roles of Ang-1 and Ang-2 are reasonably well known, little is understood about the role of Ang-4, so Brunkhorst et al., set out to research this in more detail.

What they found was really interesting:

"Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells.

Together, our results suggest that the Ang-4–Tie-2 functional axis is an attractive therapeutic target for GBM."

The pipeline

There aren't too many inhibitors of Tie-2 in development, as this is a relatively new area of research.  That said, I did find a couple in my database:

  • ARRY-614 (Array): inhibits p38, Abl, Tie2 and VEGFR2, research in MDS
  • XL-184 (Exelixis): inhibits VEGFR-2, MET, c-KIT, FLT-3, and Tie2
  • ABT-869/linifarnib (Abbott): Inhibits VEGF, FLT3, Tie2, c-FMS, PDGF, c-kit
  • AP-24534/ponatinib (Ariad): inhibits BCR-ABL, FLT3, VEGFR, FGFR, Tie2 
  • AMG-386 (Amgen): inhibits angiopoeitin 1 and 2, thus Tie2 is indirectly inhibited.

Insights

Regarding the relationship between angiopoetin and Tie2, Herbst et al., summarised it succinctly:

"AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2."

Mita et al., (2010) have generated some initial research looking at this compound in a catch-all phase I trial in advanced solid tumours with the standard combinations and dose finding approach. It's too early to say whether the agent will pan out, but some evidence of anti-tumour activity was seen.

In the original article on GBM and angiopoeitins, Brunckhorst et al., (2010) demonstrated that Ang-4 promotes GBM progression by promoting tumour angiogenesis. What was also clear from their data is that Ang-4 seems to display a more potent proangiogenic activity than Ang-1.  

More importantly, they found that GBM cells express Tie-2 and thus there may be a novel role for Ang-4 in promoting Erk1/2 kinase activation in GBM cells and in enhancing GBM cell viability.

Clearly, we still have a long way to go in figuring out the precise details around the broader angiogenesis process involved in tumour growth and development, but expanding the potential targets beyond VEGF into angiopoeitins, Tie2 and even platelet derived growth factor (PDGF), fibroblast growth factor (FGFR) and others will hopefully yield some productive bench to bedside success in the near future. 

 

References

ResearchBlogging.org Brunckhorst, M., Wang, H., Lu, R., & Yu, Q. (2010). Angiopoietin-4 Promotes Glioblastoma Progression by Enhancing Tumor Cell Viability and Angiogenesis Cancer Research, 70 (18), 7283-7293 DOI: 10.1158/0008-5472.CAN-09-4125

Verhoeff, J., van Tellingen, O., Claes, A., Stalpers, L., van Linde, M., Richel, D., Leenders, W., & van Furth, W. (2009). Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme BMC Cancer, 9 (1) DOI: 10.1186/1471-2407-9-444

Pàez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027

Herbst, R., Hong, D., Chap, L., Kurzrock, R., Jackson, E., Silverman, J., Rasmussen, E., Sun, Y., Zhong, D., Hwang, Y., Evelhoch, J., Oliner, J., Le, N., & Rosen, L. (2009). Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors Journal of Clinical Oncology, 27 (21), 3557-3565 DOI: 10.1200/JCO.2008.19.6683

Mita, A., Takimoto, C., Mita, M., Tolcher, A., Sankhala, K., Sarantopoulos, J., Valdivieso, M., Wood, L., Rasmussen, E., Sun, Y., Zhong, Z., Bass, M., Le, N., & LoRusso, P. (2010). Phase 1 Study of AMG 386, a Selective Angiopoietin 1/2-Neutralizing Peptibody, in Combination with Chemotherapy in Adults with Advanced Solid Tumors Clinical Cancer Research, 16 (11), 3044-3056 DOI: 10.1158/1078-0432.CCR-09-3368

Huang, H., Bhat, A., Woodnutt, G., & Lappe, R. (2010). Targeting the ANGPT–TIE2 pathway in malignancy Nature Reviews Cancer, 10 (8), 575-585 DOI: 10.1038/nrc2894

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A short while ago on this blog we began a series on Making a Difference about people in the cancer field who have a real passion and excitement for lasting and impactful change. The first one was an interview with Alain Moussy of AB Science in Paris.

image from news.ucsf.edu Today, I had the pleasure of chatting with the admirable Dr. Susan Desmond-Hellmann, formerly Head of R&D at Genentech and now Chancellor at UCSF. It’s a strange business sometimes as we were both working in industry at the same time on different targeted cancer drugs in liquid and solid tumours but our paths never crossed, although it seems we share similar views on cancer drug development, ie purer targeted agents and finding faster ways to market for effective therapies that impact the lives of people with cancer.

Which brings me to the main topic of today’s discussion

There are many challenges in cancer drug development, not least of which are regulatory hurdles, time consuming, risky and expensive clinical trials (we’ve seen a lot of phase III failures lately), basic research, biomarker development and many others. Traditionally, cancer trials take two main strategies to market:

  • Head to head comparison with standard care or a with and without approach if adding a new agent to the combination
  • As a single agent in the relapsed, refractory setting

Both of these approaches are typically tested in the advanced or metastatic setting when the disease burden is relatively high and the risk of a drug failing in phase III trials is also high. In solid tumour cancers, once a drug has been shown to be effective, studies tend to move into the earlier, adjuvant setting after surgery has taken place but these trials can take a very long time to reach fruition, typically 5-10 years in some cases.

For many of us, the challenges of how to think outside the box and speed up development while treating earlier stage of disease more effectively has occupied many thoughts. Sometimes the bureaucracy across so many functions is just mind boggling.

No more.

Dr Desmond-Hellmann was telling me about the Investigation of Serial Studies to Predict your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) project, which was launched in DC this morning and aims to change the way we think about cancer drug development.

“What’s really neat about the I-SPY trial is that Laura Esserman, the PI of the trial, is a breast cancer surgeon here at UCSF and has added so much value to the project because she sees patients early and has a unique opportunity to offer neoadjuvant therapy.

Patients are getting their primary therapy before they get surgery, so for imaging and biomarkers – either established or exploratory – it is a fantastic opportunity. The endpoint is pathological complete response, so you can see if the tumour has disappeared or not.”

Treatment with therapeutics prior to surgery is known as neoadjuvant therapy and has a much shorter time span (around a year) for collecting results than adjuvant trials.  Furthermore, Dr. Hellmann elaborated what is exciting about this new approach:

“It’s a fantastic rapid readout model so you can get answers much more quickly in a year, including pathological specimens, along with the answers from biomarkers and imaging, which are important.”

The FDA has allowed a master IND agreement for this study, so it will be possible to move agents in and out of the trial quickly. So if agent A looks promising it can be advanced quickly and more patients put on it, but if agent B looks toxic, it can be discarded quickly. It’s not just a clinical trial, but a experimental trial process that gives you a rapid readout of whether the agent works or not.

The hope is that you won’t be wasting time and money in phase III trials, but most importantly, patients experience on that molecule.  If the answer is yes on I-SPY, you then have a biomarker hypothesis for that agent and can then do a more traditional phase III trial having increased your chances of success.

In this way, we will also learn more about the biology of the cancer and effectiveness of the treatments earlier in the course of the disease, which may lead to better long term survival than if treatment is delayed to the later stage of disease, when the cancer has spread and metastasised.

You can find out more about the clinical trial process here and here.

The trial will look at the following protocol:

Picture 28
Source:
I-SPY2.org

For breast cancer, the standard of care is paclitaxel followed by four cycles of anthracycline therapy.  In this model, women with breast cancer can also receive other therapies, either marketed or investigational, to see if their outcome can be improved. For this I-SPY2 project, the five initial investigational agents are provided by Pfizer, Abbott and Amgen:

  1. ABT-888 (veliparib) from Abbott, is a PARP inhibitor
  2. AMG 655 (conatumumab) from Amgen is an APO/TRAIL protein that causes apoptosis
  3. AMG 386 from Amgen is a VEGF angiogenesis inhibitor similar to Genentech’s Avastin
  4. CP-751,871 (figitumumab) from Pfizer is an IGF-1R inhibitor that targets the insulin receptor
  5. HKI-272 (neratinib) from Pfizer is a Pan ErbB inhibitor similar to Herceptin

None of the I-SPY-2 breast cancer project would have been possible without the passion, energy and enthusiasm of women such as Drs Sue Desmond-Hellmann, Laura Esserman or Janet Woodcock of the FDA, who has been pressing for more creative solutions to fast track better cancer drugs for some time.  This consortium is particularly fascinating to watch because it brings together the major players – academia, industry and the FDA, in a way that has never been done before.  We should salute their originality and endeavour to think, and more importantly, do things differently.

If the basic concept proves successful, such a revolutionary clinical trial process may well become the new model for early and more effective drug testing, not only in cancer, but also for other diseases such as alzheimers, diabetes and other chronic diseases. In the long run, this approach may also lead to lower healthcare costs by improving efficiencies.

While Dr Hellmann was excitedly describing the process, I was thinking how much intuitive sense it makes and wished that the bureaucratic hurdles to more collaborative academia-industry-FDA clinical trials had fallen long ago.

The important thing though, is that it’s actually happening right here, right now and for people with cancer, that is good news indeed.

The future of Oncology… is in neoadjuvant therapy and biomarker led trials.

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