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. The 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.
The market of monoclonal antibodies for cancer is one of the fastest growing segments in the pharmaceutical industry, with several blockbuster drugs such as Rituxan and Herceptin. Although over a year has passed since the FDA last approved an antibody for the treatment of cancer, the extensive activity in the field will surely lead to a substantial addition of antibodies in the coming years. Continue reading
This Antibody-drug conjugate was created by ImmunoGen and licensed to Sanofi-Aventis. AVE9633 consists of the huMy9-6 antibody, which binds specifically to the CD33 antigen found on acute myeloid leukemia cells, and Immunogen’s DM4 cell-killing agent. There expected to be more than 13,000 new cases of AML this year in the US alone, and around 9,000 americans are expected to die as a result of the disease. Although during the last decade, an increase in survival rates was achieved due to the introduction of new treatments, most patients will die less than 5 years after diagnosis. The high likelihood of disease relapse is especially unsatisfactory, despite the relatively high portion of complete responses achieved by chemotherapy and Wyeth’s (WYE) Mylotarg®, the sole approved antibody-drug conjugate to date. CD33 antigen is present in approximately 90% of AML patients, which makes it a very attractive target. More importantly, the concept of targeting CD33 has been validated by the impressive activity of Mylotarg in AML. On he other hand, AVE9633 will have to be show at least the same activity and safety profile in order to be approved. This a relatively high bar, and according to preliminary results, chances are pretty low.
AVE9633 entered phase I in 2005, where the compound was dosed once per three weeks at doses up to 260 mg/m2, without encountering dose-limiting toxicities. Since there was no substantial clinical activity, Sanofi-Aventis decided to launch 2 additional phase I trials where AVE9633 is dosed more frequently. Although data is yet to be reported from this trial, the company defines results “encouraging”. Clinical findings from this trial are expected to be presented in ASH 2007 as well. The comparison to Mylotarg is inevitable, since both compounds are ADCs that target CD33. In pre-clinical trials, AVE9633 was found to be more active than Mylotarg, however, a quick glance at the dosing profile of the two agents reveals a staggering difference. Mylotarg is dosed twice at 9 mg/m2, with 14 days between the first and the second dose, and achieves impressive clinical response, including 20-30% complete responses. AVE9633 could not achieve an objective response at a single dose of 260 mg/m2. What is even more discouraging is the fact that according to several trials, Mylotarg reaches complete saturation of CD33 sites present in the bloodstream and 42% to 90% saturation in the bone marrow at a dose of 9 mg/m2. In other words, there is no use to administer additional amount of drug since it has no target to bind. Therefore, unless there is something we are totally missing here, something went very wrong with AVE9633.
Author is long IMGN