Biotech Strategy Blog

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

Posts tagged ‘AACR Molecular Targets Boston’

Every year at AACR meetings there seems to be a new update on how researchers are doing with their work on overcoming resistance in metastatic melanoma. We’ve seen some stunning photos where targeting the BRAF V600E mutation with a specific kinase inhibitor such as vemurafenib (Zelboraf) or dabrafenib (Tafinlar) results in dramatic reduction, and sometimes even complete disappearance of the lesions, only for resistance to set in and the melanoma sadly comes back with a vengeance. Adding a MEK inhibitor such as trametinib (Mekinist) was originally thought to be a rather promising strategy, until it became clear that this only gave a few extra months with exactly the same result.

Over on Pharma Strategy Blog, I’ve written a lot about the fascinating research on various mechanisms of resistance in this disease. They range from specific mutations emerging to activation of COT or MEK and others in response to therapy. There are a number of questions we can ask that need to be addressed:

  • Do we need a better/more potent BRAF inhibitor?
  • Do we need a better/more potent MEK inhibitor?
  • What other combinations and targets can be explored?
  • Is timing and dosing important? (e.g. continuous vs. intermittent dosing)
  • And many others…

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchAt the recent AACR Molecular Targets meeting in Boston I chatted with Dr Bill Sellers, who is the Global Head of Oncology Research at the Novartis Institutes for Biomedical Research (NIBR) and oversees the drug discovery efforts in this space for Novartis.

Yesterday we highlighted NIBR’s work with CDK4/6 inhibition in breast cancer, but this compound may have surprising utility in metastatic melanoma.

Novartis also have several other melanoma agents in their pipeline in the clinic, including a BRAF inhibitor (LGX818), a MEK inhibitor (MEK162) and more recently, an Mdm2 inhibitor (CGM097) in preclinical development.

To read more about the new developments in advanced melanoma, you can sign in or sign up below.

Boston – at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference today, preclinical data was presented on a first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase c (GCC) expression in pancreatic cancer.

Petter Veiby Ph.D presenting at Molecular Targets press briefing Petter Veiby, Ph.D, Global Head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, MA took the assembled press corps through data that showed MLN0264 demonstrated antitumor activity in GCC-pancreatic cancer xenograft models.

In drug development, as in life, timing is everything. The recent FDA approval of Celgene’s nab-paclitaxel (Abraxane) has changed the standard of care in pancreatic cancer.

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.

2 Comments

Susan Galbraith MD PhD at Molecular Targets Press BriefingBoston – At the AACR-EORTC-NCI Molecular Targets and Cancer Therapeutics conference, Susan Galbraith, M.D, Ph.D. Head of the Oncology Innovative Medicines Unit at AstraZeneca discussed the development of AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and wild type T790M mutations in non-small cell lung cancer (NSCLC).

Dr Galbraith reviewed the three abstracts presented at Molecular Targets and answered questions on the AZD9291 clinical data presented at ECCO 2013 in Amsterdam.

4 Comments

Boston – Preclinical data for PF-06463922 (Pfizer), a next generation ALK inhibitor, with potency for all known Crizotinib ALK resistant mutants and ability to cross the blood brain barrier was presented today at the 2013 International Conference on Molecular Targets and Cancer Therapeutics co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC).

In addition to being a competitor to other next-generation ALK inhibitors in development such as AP26113 (Ariad), LDK378 (Novartis) and alectinib (Roche/Chugai), PF-06463922 shows activity in both crizotinib-naive and crizotinib-resistant cells, so could end up being a replacement for crizotinib (Xalkori) front-line if clinical results confirm preclinical efficacy.

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!

error: Content is protected !!