Hammer Stock Blog

There are currently 2 ongoing and one planned clinical trials for the evaluation of SGN-33.

The first clinical trial is the extension of the phase I trial, but this time all patients are to receive the highest dose tested in the original phase I (8mg/kg). The company expects to have data from this trial by the beginning of 2009. Typically, these types of trials should result in better performance than the first dose escalation trial, since the highest dose is expected to achieve better results than lower doses. In this case, since clinical activity in the highest dose and in the lower doses was similar, I wouldn’t expect to see a substantial improvement in the rate of CR in the ongoing trial. This can be explained by the fact that even lower doses ( 4 and 2.5 mg/kg) lead to the saturation of the vast majority of CD33 in the bone marrow, so any additional antibodies that enter the bone marrow has no targets left to bind. This is also why the dose was not escalated beyond 8 mg/kg even though there were no dose limiting toxicities.  

The second trial (and the more important one) is a randomized double-blind trial where SGN-33 is combined with low-dose araC, the standard therapy for older AML patients. Half of the patients are to receive araC+ placebo with the other half  receiving araC+ SGN33. This trial will hopefully shed some light on two crucial issues.

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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.

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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