Back in 2013, a Phase III failure in glioblastoma patients prompted Merck Serono to add cilengitide to its growing pile of discarded assets. That wasn’t the end of the story, though. The following year, researchers writing in The Lancet Oncology asked “does cilengitide deserve another chance?” Now a startup has set out to answer that question--and has enlisted the support of the Serono R&D chief who axed the drug.
The startup, Iceni Pharmaceuticals, was set up on the strength of preclinical evidence to suggest that cilengitide can boost the effectiveness of proteasome inhibitors such as Amgen’s ($AMGN) Kyprolis and Takeda’s Velcade. In myeloma mouse models, a mix of cilengitide and Velcade has suppressed tumor volumes to a greater extent than either drug in isolation, a result Iceni thinks could be caused by one of several mechanisms. One possibility is that cilengitide is binding to myeloma cells, causing them to detach from the bone marrow surface and making them more susceptible to Velcade.
“There's several different mechanisms, all of which work in vitro,” Iceni CEO John March told FierceBiotech. Iceni is now working toward the generation of clinical data to show whether it can translate these findings into humans. A Phase II trial is scheduled to get underway next year. The clinical trial will primarily look at safety--while both cilengitide and the proteasome inhibitors have been tested extensively in humans, they have never been given in combination--but will also assess some surrogate markers of protection to get an early glimpse at potential efficacy.
Before Iceni can start the trial, it needs to persuade someone to bankroll it. March sees two options: “One is that we are looking to potentially partner the trial with a pharmaceutical company. The other thing that we're looking to do is actually raise additional investment to pay for the trial.” March would prefer to raise capital, as that would allow Iceni to retain control of the design of the trial, notably the choice of which proteasome inhibitor to pair with cilengitide. Either way, Iceni will need to convince someone it can succeed with a drug that failed at Merck.
Merck canned cilengitide after the integrin inhibitor failed to significantly increase overall survival in a study of 500 people newly diagnosed with glioblastoma and methylated MGMT gene promoter status. The data sounded the death knell for cilengitide at Merck. But at least some people outside of the German life science company thought it could be a case of right drug, wrong indication. Researchers from the University of Bari, who had studied cilengitide in multiple myeloma, were among the most vocal, writing the aforementioned letter to The Lancet Oncology calling for a reevaluation of the drug.
March stumbled onto the work while running studies at Iceni’s predecessor, DNA vaccine player Big DNA. “We were actually looking at using integrin-binding peptides and proteasome inhibitors to basically improve the efficiency of DNA delivery into cells. Purely by chance, we discovered that this combination was actually very potent at killing the cells,” March said. “It was originally a result we didn't want because we were trying to get the DNA into the cells and get it expressed at high levels. What we were finding was that, rather than improving the process, it was killing all the cells.”
The finding led March to dive into the literature, pivot away from DNA vaccines and get in touch with people who originally developed--and later killed--cilengitide. Annalisa Jenkins, who headed up R&D at Serono when cilengitide was axed, is on Iceni’s scientific advisory board, as are the German firm’s former oncology SVP, Bruno Osterwalder, and the drug’s inventor, Horst Kessler. “[Kessler] is working with us on the more technical side of things,” March said. “Annalisa is much more at the commercial end. It really says quite something about what we’re doing that she’s willing to come back on board and look to develop a drug that she actually had to make the decision to stop working on.”
In the longer term, Iceni plans to consider other indications for cilengitide--which is off patent--and repurpose other drugs, including an as-yet-undisclosed second program that is already underway. March is a believer in the repurposing model, arguing that it can enable faster, shorter development timelines that will ultimately lead to cheaper drugs, a particularly important consideration in cancer and in Europe. March is far from the first person to argue this case, though. And, while the idea has been in vogue at times, it has arguably failed to live up to the claims of its advocates.
Some companies, such as Allergan ($AGN) and Astellas Pharma-partnered NuMedii, have tried to improve the odds of success in repurposing using tech. Iceni is pinning its hopes on hard work. “I think there's a lot of drugs out there which can be relatively simply repurposed if you approach it correctly with an open mind,” March said. “What we do is the boring donkey work. We read extensively round the literature to find out where you can actually potentially repurpose something based upon data that's already strongly indicated it's going to work.”
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