Biotech Strategy Blog

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

Posts tagged ‘Molecular Targets Boston’

Immuno-oncology is fast becoming one of the hottest topics in cancer research following the approval of the anti-CTLA4 checkpoint antibody, ipilimumab, in advanced melanoma, as well as emerging solid data from anti-PD-1 and PD-L1 antibodies in melanoma, lung and renal cancer at ASCO in June.

The big question on many people’s minds though, is what other checkpoint inhibitors are out there and can they safely be used either as single agents or in combination with the above agents, or even with existing standard of care combinations (chemotherapy and targeted therapies)?

I have long argued that what will really make a difference in this space is combinations and the ability of sponsors to successfully evaluate novel-novel agents in clinical trials. After all, BMS have a huge advantage with ipilimumab and the ability to combine it with their PD-1 or other immunotherapeutics, since their rivals will be greatly hampered by the $120K per person price tag for the commercial drug required as part of clinical trial costs.

This means most companies in this space are looking at other options in the search for better outcomes.

At the AACR-NCI-EORTC Molecular Targets conference in Boston this week, the last day was devoted to two sessions in immune-oncology and one of the plenary sessions included Dr Susan Topalian discussing an update on nivolumab and anti-PD-1/L1 therapies post ASCO. There was also ample opportunity to discuss immunotherapy with the many attendees in the busy poster sessions.

The first immunotherapy session on Weds morning particularly caught my attention and it seems a good opportunity to summarize some of the key observations emerging in this field. Here are my detailed notes from the session, which raise a lot of fascinating questions from the presenters about this field and – more importantly – where it’s going:

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.


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.

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