CR011-vcMMAE is an ADC currently being developed by Curagen (CRGN), based on Seattle Genetics’ ADC technology. The ADC comprises of an antibody against GPNMB, a protein on the surface of melanoma cells linked to a drug payload. Both the drug and the linker in this case are identical to those used by Seattle Genetics in SGN-35. The story behind this agent demonstrates the need of ADC technology and the high value it has in today’s drug development market. It also demonstrates that going after one of the most challenging indication with a relatively new platform, may not be the best way to validate it.
Curagen discovered GPNMB, after thoroughly scanning and analyzing multiple melanoma samples. Despite the large amount of known cancer related targets, it is very hard to discover such targets, let alone specific targets that are expressed exclusively on cancer cells. The company then generated an antibody [CR011] against GPNMB, which did a great job binding a broad range of melanoma cells in a very specific manner, but it had one flaw: It didn’t have any anti-tumor effect. This frustrating situation is the perfect opportunity for ADCs, since arming antibodies can theoretically transform any antibody into a very potent agent, regardless of the activity the antibody has by itself.
Curagen decided to arm its antibody with Seattle Genetics’ technology, which turned the “worthless” antibody into a very strong and specific drug against melanoma cells. After encouraging pre-clinical data, Curagen initiated a phase I dose-escalating trial in June of 2006, exactly two years after the official partnership with Seattle Genetics had been announced.
CR011-vcMMAE was evaluated in advanced stage metastatic melanoma patients who failed no more than 1 chemotherapy treatment. Preliminary results were published in October. Of the 23 evaluable patients, none had a partial response (30% reduction in tumor size) but six had stable disease, with four of the six demonstrating tumor shrinkage of up to 20%. In addition, there was a clear dose-dependent response, as all 5 patients who received the 2 highest doses, achieved stable disease. This is in contrast to one stable disease among the remaining 18 patients. Curagen is still enrolling patients for the dose escalation trial and expects to initiate a phase II trial immediately upon reaching MTD.
CR011-vcMMAE is the only candidate in Seattle Genetics’ clinical pipeline that targets a solid cancer, as all the other 4 candidates target blood-borne cancers. We believe that one of the greatest advantages of ADC technologies, such as that of Seattle Genetics, is their enabling of the development of effective treatments for solid tumors such as breast, lung and prostate cancers. This kind of cancer is responsible for the vast majority of cancer-related deaths, but is still poorly addressed by approved antibodies such as Herceptin and Erbitux. Nevertheless, metastatic melanoma specifically might not be the ideal place to start the evaluation of any ADC platform. While early stage melanoma can be cured by resection, advanced stage melanoma is considered one of the deadliest and most chemo-resistant cancers, with median survival of less than a year. This is due to the small number of available treatments for advanced stage melanoma, the best of which have a short-lived 10-20% response rate. In addition, no significant advances in the treatment of metastatic melanoma have occurred over the past 30 years.
While assessing its new ADC platform, Seattle Genetics must pick its fights carefully. On the one hand, in order to validate the new platform, it should fill a true unmet medical need and succeed where other drugs fail. On the other hand, with all the uncertainty involved in drug development, the bar mustn’t be set too high. In general, we believe that while most antibody companies spend too much time and money on blood cancers just to play it safe, going after a tough condition such as melanoma is admirable. However, in this case, we believe Curagen picked the wrong fight for Seattle Genetics’ novel ADC technology. It’s not like CR011-vc-MMAE is doomed to fail, especially in light of the clear clinical activity, it is simply facing a very challenging task.
Looking at the bright side, although no objective response was achieved, MTD hasn’t been reached, which implies that there is still a chance to see a partial response in patients who receive higher doses. Even if CR011-vcMMAE does not show an objective response in metastatic melanoma, the minor responses seen in the trial are a great indication for the technology’s prospects in more manageable solid cancers. In addition, the ADC might be evaluated with other treatments, such as dacarbazine, which is the standard of choice for metastatic melanoma, or perhaps even with other experimental drugs such as Medarex’s (MEDX) immunostimulatory antibody, MDX-010, which is currently in phase III trial for the treatment of melanoma.
Curagen decided to license Seattle Genetics’s ADC technology for an additional antibody, CR014, which is currently in preclinical development. CR014-vcMMAE targets TIM-1, a protein expressed on the surface of ovarian and renal cancer cells.
Author is long SGEN