Seattle Genetics (SGEN) recently published clinical data from a phase I which evaluated SGN-33 for the treatment of elderly AML (Acute Myelogenous Leukemia) patients. AML is a common type of blood cancer, with around 13,000 new cases and 9000 deaths expected to occur during 2007 in the US alone. Prognosis of the disease is very poor, especially among elderly patients (over 60 years old), who have a long term survival rate of 5%, compared to 20% in the case of patients who are under 60. The dismal prognosis elderly AML patients have can be attributed to their inability to tolerate aggressive chemotherapy or stem cell transplant. Moreover, AML among elderly patients is inherently more resistant to standard chemotherapy due to several factors. Therefore, there is a unique challenge in developing better treatments for elderly AML patients, because these treatments must be very safe in addition to being effective. Antibodies, as well as other targeted therapies are regarded as excellent candidates, as they have an excellent safety profile and can be usually co-administered with other treatments. The market opportunity for such treatments is substantial, due to the high incidence of AML among elderly patients, so naturally there are multiple treatments currently being evaluated. The majority of these treatments are chemo agents but there are several targeted therapies, the most promising of which is SGN-33.
SGN-33 is a naked antibody that specifically binds the CD33 receptor, which is highly expressed in the vast majority of AML cases. Fortunately, stem cells in the bone marrow don’t express CD33, making the targeting of CD33 very attractive. In addition, CD33 has already been validated as a target for antibody-based therapy by Wyeth’s (WYE) Mylotarg, an anti-CD33 Antibody-drug conjugate [ADC]. SGN-33 is a very interesting antibody since it has a dual mechanism of action [MOA]. The first MOA is the recruitment of components of the immune system that attack and destroy cells bound by the antibody. This MOA is very common among cancer antibodies such as Herceptin and Rituxan. The second MOA, is the activation of the CD33 receptor which leads to a change in gene expression that results in “weakening” of the cancer cells.
According to the results presented in ASH 2007, SGN-33 is highly effective among elderly AML patients. Among the 17 evaluable AML patients, 5 (29%) achieved complete response and two patients (11%) achieved partial response. The average age of the 5 patients who achieved CR was 78 years, very impressive considering the inverse relation between age and response rate in AML. Since this was a dose escalation study, 4 doses were evaluated, and interestingly, there was no typical dose dependent response, as there was at least one CR in every cohort.
SGN-33 seems to have an excellent safety profile, as no MTD was reached, even at the highest dose (8 mg/kg), which is considered fairly high compared to other antibody regimens. As discussed above, the safety issue in older AML patients is crucial, since these patients are intolerant to aggressive therapies. Of note, the dosing in this trial was quite intense, with 5 consecutive weekly doses followed by additional 5 bi-weekly administrations of SGN-33.The only substantial side effect was seen in 2 patients, however, this specific side effect is more likely to be attributed to the disease rather than to the drug itself. Althogh SGN-33 is not the only candidate that is in clinical trials, on the next post, I’ll try to explain why it is the safest bet among all other candidates. It doesn’t mean SGN-33 is a sure bet, but it does mean it has high chances of becoming a standard component in the majority of AML regimens, with potential in additional conditions such as MDS (Myelodysplastic Syndrome).
Author is long SGEN