Drug Development

UPDATED: Cerulean crashes after lead nano drug flubs its second PhII cancer study

Cerulean Pharma’s lead nanotech cancer drug has run into another stone wall in the clinic. The Waltham, MA-based biotech $CERU says that CRLX101 combined with Avastin flubbed a Phase II study, failing to provide evidence of an improvement in progression-free survival when compared against standard of care therapies for renal cell carcinoma.

Cerulean’s shares were slammed on the news, plunging 62% and wiping out the lion’s share of its $75 million market cap.

The drug combo group actually performed worse than the control arm, with investigators reporting a 3.7 month median PFS for Cerulean’s drug compared with 3.9 months for standard of care. The objective response rate was even worse: 5% for the CRLX101 combination against 14% for standard of care.

This wasn’t the first failure for Cerulean. The drug, which combines tiny amounts of the anticancer toxin camptothecin with a polymer molecule in order to infiltrate leaky tumors, also failed a study for non-small cell lung cancer in 2014 that raised serious doubts about the technology.

The setback marks the end of a theory that CRLX101 could play a key role in cancer cell survival by inhibiting hypoxia-inducible factor-1α (HIF-1α). The focus now will shift entirely to inhibiting topoisomerase 1 (topo 1), which is involved in cellular replication. The biotech has several other ongoing studies.

“We are convinced that CRLX101 is an active drug,” CMO Adrian Senderowicz told analysts in a call Wednesday afternoon, zeroing in on early clinical evidence of monotherapy activity for pancreas and colorectal canncer.

The stock crunch comes at a bad time. The biotech reported that it had $47 million in its coffers at the end of Q2, giving it enough cash to make it through Q2 2017. CFO Gregg Beloff told analysts the company has options to extend the runway into Q3 of next year, while execs look to some interim catalysts with ongoing programs to fuel a new fundraising effort. Cerulean took out a loan from Hercules in early 2015, which won’t ease any concerns among the analysts about its cash position following a hard setback like this.

The biotech enlisted MIT’s prolific nanotech expert Bob Langer for its scientific advisory board. The IPO boom of the past few years took a few nanotech companies like Cerulean onto Nasdaq. But at least one – Bind Therapeutics, a Langer lab spinout – foundered and was recently bought out of a bankruptcy auction by Pfizer.

Michael Schmidt at Leerink is taking a more skeptical view of Cerulean’s future now. His comment:

“CRLX-101 is being also studied in platinum-resistant ovarian cancer; however with moderate single agent activity in this topo1-sensitive cancer, we think it’s difficult to interpret the early stage single-arm combination data. CRLX-101 generated 16% responses in 19 platinum resistant patients single agent, 17% ORR in combination w/ Avastin in 18 pts, and 5/9 (56%) in combination with weekly paclitaxel. Based on our prior MEDACorp KOL checks, we think more than 20-30% ORR would be required to be considered differentiated in this indication. Longer term we are more optimistic on the ongoing combination study with Lynparza given the stronger preclinical rationale, but we think it’s still too early to assign value to this opp’ty.”

Christopher D. T. Guiffre, Cerulean President & CEO

Christopher D. T. Guiffre, Cerulean President & CEO

“We are disappointed with this outcome and will undertake a thorough analysis of the data to understand why CRLX101 plus Avastin underperformed compared to the results we saw in an earlier investigator-sponsored trial,” said Christopher D. T. Guiffre, President and Chief Executive Officer of Cerulean, in a statement. “This outcome did not support our hypothesis that targeting hypoxia inducible factor (HIF) in combination with VEGF inhibitor in RCC, a HIF-overexpressing tumor type, would be beneficial, so we will not pursue HIF as a target going forward. We will continue to focus on the potent topoisomerase 1 inhibition of CRLX101’s payload, camptothecin, in topoisomerase 1-sensitive tumors. Our combinations with weekly paclitaxel and LYNPARZA (olaparib) are examples of ongoing trials that leverage CRLX101’s topoisomerase 1 inhibition in combination with chemotherapies and DNA damage repair agents.”

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