Biotech Strategy Blog

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

Posts tagged ‘Cancer Drug Development’

One of the sessions that stood out for me at the recent European Society for Medical Oncology (ESMO) Congress in Madrid was a Special Symposium on “Advances in Precision Medicine of Metastatic Colorectal Cancer.”

Federica Di Nicolantonio ESMO 2014This blog post focuses on two presentations in the symposium:

  • “Emerging druggable targets in colorectal Cancer” by Federica Di Nicolantonio (Candiolo Cancer Institute, University of Torino, Italy).
  • “Signal Transduction Inhibitors and Pipeline Drugs” by Josep Tabernero MD PhD (Vall d’Hebron University Hospital, Barcelona)

Dr Nicolantonio, pictured right, is active on Twitter (@fdinicolantonio) and well worth a follow!

Since the advent of VEGF (Avastin) and EGFR (Erbitux) inhibitors way back in 2004, there haven’t been any new developments in this cancer type other than more of the same (Zaltrap and Vectibix, respectively), so I was particularly excited to see progress in colorectal cancer, and the promise of new drug targets on the horizon that may change the treatment landscape.

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The FDA approval earlier this week of ibrutinib (Imbruvica) for the treatment of mantle cell lymphoma (MCL), and the recent approval of GA101 / obinutuzumab (Gazyva), for previously untreated chronic lymphocytic leukemia (CLL) is good news for patients.

The forthcoming annual meeting of the American Society of Hematology (ASH) in New Orleans (Dec 7 – 10, 2013) is set to be an exciting event with the launch of new products to treat blood cancers.

Both ibrutinib in MCL and obinutuzumab were granted “breakthrough therapy” designation (BTD) from the FDA. Over the past several months I have been researching what a BTD may mean for cancer drug development.

The catchy “breakthrough” title has given companies and the FDA a noticeable bonanza of good PR, but there’s been a paucity of critical analysis by the media. I have yet to see a convincing argument that that there was a compelling need for a new approval pathway for cancer drugs, or that innovative and breakthrough cancer drugs such as imatinib (Glivec/Gleevec) and crizotinib (Xalkori) could have got to market any faster.

One of the key FDA decision makers is John K. Jenkins, MD, Director, Office of New Drugs in the Center for Drug Evaluation and Research (CDER); he’s Richard Pazdur’s boss. I had the privilege to conduct a phone interview with him over the summer.

In my first post from this interview, subscribers to Premium Content will obtain Dr Jenkins’ perspective on what constitutes a breakthrough? If you are an investor you want to try and predict what may be a “breakthrough” before it becomes one…

Scott Eliasof, Ph.D VP of Research at Cerulean presents at Molecular Targets press briefingBoston – at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference today we heard about CRLX101 (Cerulean Pharmaceuticals), a nanopharmaceutical in phase 2 development. The presentation highlighted the challenges and opportunities in cancer drug development.

This post is not intended to be a detailed review of the preclinical data presented, but offers a summary of the value proposition, the intended target and the insights we took away from a press briefing at the conference.

Cerulean Pharmaceuticals: Abstract B1, Synergistic activity of CRLX101, a nanopharmaceutical in phase II clinical trials, with antioangiogenic therapies mediated through Hypoxia-inducible factor (HIF) 1 alpha inhibition: A translational research program.

Scott Eliasof, Ph.D. VP of Research at Cerulean Pharmaceuticals presented preclinical data that showed CRLX101:

  • inhibits HIF-1α in multiple tumor types
  • inhibition of HIF-1α is maintained for more than one week after a single dose
  • inhibits HIF-1α and prevents the stimulation of HIF-1α by anti-angiogenic drugs
  • is synergistic with anti-angiogenic drugs
  • inhibits cancer stem cells

Combination trials are planned or starting soon in relapsed ovarian cancer with bevacizumab and in neoadjuvant tolorectal cancer in combination with radiation (CRT). In renal cell carcinoma (RCC) efficacy has been seen even in patients progressing through prior VEGFR therapy.

Challenges: HIF-1α is not has not yet been shown to be a validated cancer drug target.

It is not [a validated target] at this point. A lot of preclinical data suggest that HIF-1α plays an important role in a number of different pathways but since HIF-1α has really been undruggable up until now, the clinical data simply does not exist to really show that this is happening. There are also not good biomarkers yet for HIF-1α,” said Eliasof.

The challenge that CRLX101 faces is to better than the current standard of care in the indications it targets. A trial in non-small cell lung cancer was stopped earlier this year. As Eliasof noted, “we decided strategically at this point in time not to purse it since we couldn’t see something that was dramatically better.”

Opportunities: There is scientific rationale for targeting HIF-1 alpha in renal cell carcinoma (RCC). However, RCC is a crowded space, haunted by the ghost of AVEO.

“Not sure if we are actually going to pursue [RCC] in the long-term at this point in time but it seemed like a really good indication to pursue proof of concept for a HIF-1α inhibitor,” said Eliasof.

Whether combining CRLX101 with bevacizumab in ovarian cancer will lead to an increase in overall survival remains to be seen given the lack of success with this measure with VEGF inhibitors. It is hard to see how adding CRLX101 will shift the survival curve significantly to the right, especially in light of the AURELIA trial data for bevacizumab (Avastin) in ovarian cancer that was presented recently at ECCO 2013 in Amsterdam.

We were left with the impression that this was a “suck it and see” strategy without a clear rationale as to why resistance was occurring in ovarian cancer and whether this approach would logically help overcome it. The data presented today was not entirely convincing that this will be seen, but as Eliasof stated, “we will see” and it is of course possible that CRLX101 may lead to a survival advantage in combination with bevacizumab, but I would not bet money on it.

Today’s press briefing by Cerulean Pharmaceuticals highlights the need for companies to have a solid scientific rationale and development strategy when going after novel drug development targets that so far have proved undruggable. While RCC may have some potential, the market opportunity is small.

It remains to be seen whether there are opportunities for CRLX101 in combination with other drugs, but none of the data presented today was compelling. Instead we were left with the impression of a VC funded company throwing mud to the wall in the hope that something sticks. That’s not the way to approach cancer drug development.

Update: Oct 22, 2013 Is HIF-1α Ready for Prime Time?

If you are in Boston for the Molecular Targets meeting (#targets13) and have an interest in HIF-1α as a target then you may be interested in a symposium (looks like registration is free) taking place later today at Harvard Medical School. Here’s a link to the meeting program and registration.


The 2013 Molecular Targets and Cancer Therapeutics Conference (twitter #targets13) takes place in Boston from October 19-23 at the Hynes Convention Center. It’s a “must attend” meeting for anyone with an interest in cancer drug development and I’m really looking forward it. Boston is an exciting place for cancer research!

Molecular Targets Meeting AppJointly organized by the American Association for Cancer Research (AACR), European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute (NCI), it alternates each year between Europe the United States.

The molecular targets meeting program and abstracts are now available online. There’s also a meeting App that’s well worth downloading if you plan to be there.

As for what’s interesting at the meeting – the three media briefings give a flavor of what to expect:

Sunday, Oct. 20, 10 a.m. “Emerging Therapeutics,” including research on investigational drugs AZD9291 and PF-06463922, which have the potential to overcome drug resistance in some lung cancers.

Monday, Oct. 21, 9 a.m. “Overcoming Resistance and Hard-to-Treat Cancers,” including research on a new antibody-drug conjugate MLN0264 for pancreatic cancer and a new nanopharmaceutical CRLX101 for cancers resistant to antiangiogenic drugs.

Tuesday, October 22, 9 a.m. “Guiding Treatment for BRAF- and BRCA-related Cancers,” including updated data on the clinical benefit of the PARP inhibitor BMN 673 and a new diagnostic platform to rapidly identify BRAF mutations.

The AACR press team led by Jeremy Moore have done a good job of identifying some of the exciting new drugs in development.

Readers of blog premium content have already read about the potential of AZD9291 in T790M resistant lung cancer from ECCO 2013 in Amsterdam.  While it looks like the ECCO late-breaker did steal some of the thunder from the molecular targets meeting, there’s going to be more granularity on the compound at AACR, and hopefully some updated clinical data.

There are three AZD9291 posters at the meeting, and I’ll be covering all of these while in Boston:

Sunday, Oct 20, 2013, 12:30 PM – 3:00 PM  A109: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM  B212: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM B94 Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor.

Another compound that I have been following with data at Molecular Targets is ABT-199/GDC-199.

You’ll find me in the poster halls every afternoon, so if you are going to be in Boston for Molecular Targets, I look forward to seeing you there!

As we herald in a New Year, it is time to reflect a little on the past year. 2012 was, to paraphrase Professor Bertrand Tombal’s quote about prostate cancer drug development, “a Grand Cru year” for the United States Food & Drug Administration (FDA) with 39 new molecular entitites (NMEs) approved. This is the highest approval number in the last 10 years, beating the previous high of 36 obtained in 2004. Reuters report it is a 16 year high.FDA 2012 New Molecular Entity NME Approvals Biotech Strategy Blog

Unfortunately, I don’t think can we can draw many conclusions about the state of drug development innovation from this 2012 high.

The FDA in their 2011 report on novel new drugs note that “the number of NMEs approved over time has not been substantially increasing.”

To me, the overall picture looks pretty flat. There’s bound to be variation between years as a result of timing differences with some regulatory submissions obtaining priority review, while others do not.  Some companies can take longer than others to close a clinical trial database and prepare a dossier.  We also have to factor in that some clinical trials may end earlier than expected, if the data is positive.

Regulatory approval is the result of innovation that started several years ago. It only represents the point at which you have a safe and efficaceous product that can be sold to the public. The number of approvals in any given year is not a surrogate benchmark for the state of current innovation.

Given it typically takes several years to bring a new product to market, what we are looking at today is the result of research done 5-10 years ago. It is, however, interesting to note that of the 39 NME approvals in 2012, one-third (13) were cancer related.FDA 2012 Cancer Related Approvals Biotech Strategy Blog

A key driver of innovation in this area is the increased knowledge we have of cancer biology.

In my view, investors will continue to support companies that develop new products with:

  • a clear scientific rationale as to why their mechanism of action may impact the disease
  • a focused clinical development plan that through use of biomarkers and diagnostics targets those most likely to respond
  • a market opportunity worth going after in what is increasingly a competitive landscape

2012 was a “grand cru year” for the FDA. I look forward to what 2013 may bring and to learning more about the new products in development that may make a difference to the lives of patients.

Happy New Year!


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.


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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Academic institutions are now bringing pharma/biotech companies together and facilitating rational combination trials that make solid scientific sense.

Combining at least two targeted drugs looks to be increasingly necessary in order to develop innovative new cancer treatments, where turning off one target may stimulate another, thus both need to be targeted for there to be an overall effect.

However, one company may not have all the pathways and drug targets covered by their portfolio.  The result is that companies may have to work together in combination trials with each providing one drug from their portfolio.

That was one of the key messages I took from Gordan Mills (UT MD Anderson Cancer Center) in his recent video interview with Sally Church from Pharma Strategy Blog:

Sally Church’s video interview with Professor Mills is well worth watching if you have not already done so.

Not only are universities and research institutions well placed to judge the scientific merits, but as Mills points out they can facilitate things as an independent third party and actively help bring partnerships together.  Given that combination therapies may be needed in order to turn off different parts of signaling pathways and cross-talk, I think we are likely to see more of this approach.

It’s going to be new territory for many companies – how to enter into a potential joint venture or alliance? However, if it results in a therapy that works, it is going to be win-win for all parties. It may also improve efficiency in drug development and lead to better use of patients in early stage development.

Some examples of where this is happening already in oncology include AstraZeneca and Merck with their MEK-AKT approach and GSK (MEK) with Novartis (PI3K), to name a couple.  This is a new trend we are likely to see more of in the future.

I can see universities hiring alliance managers who have industry experience to ensure these collaborations run smoothly.

The topic of the industry/academia interface in rational cancer drug development will also be discussed in a plenary session at the forthcoming American Association for Cancer Research (AACR) meeting on Molecular Targets and Cancer Therapeutics (November 12-16, 2011) in San Francisco.

How academia can better help the pharma/biotech industry bring innovative, rational drug combinations to market is a topic that I think we will be reading more about in coming months.

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