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There are currently two ongoing and one planned clinical trials for the evaluation of Seattle Genetics' (NASDAQ:SGEN) 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.

First, it would show whether SGN-33 can be combined with chemotherapy without leading to substantial side effects. Judging by the safety profile SGN-33 demonstrated in the phase I trial and the fact naked antibodies are often combined with much more aggressive treatments than araC, chances are that the combination would be safe.

The second issue is characterized by a higher degree of uncertainty. In contrast to the phase I trial, which evaluated SGN-33’s short-term clinical effect (e.g. complete response, partial response), the primary endpoint of this phase II trial is improvement in survival. It is crucial to understand that increasing patients’ survival is much more challenging than showing “just” a clinical effect. Even if we examine drugs that showed impressive clinical effect, not all of them resulted in a real benefit in terms of survival. One can hope that the possibility to administer consecutive high doses of SGN-33 better positions it to show an effect on the survival front as well, but this issue is clearly uncharted territory. The company hopes to show that SGN-33 increases overall survival by at least 2 months, a result which, according to management, will lay the foundations for a larger phase III pivotal trial.

The third trial will evaluate SGN-33 in combination with Revlimid for the treatment of intermediate and high risk myelodysplastic syndrome [MDS]. Since SGN-33 managed to show only minimal clinical effect on MDS patients (stable disease in 6 out of 10 MDS patients), it was only natural to combine it with chemotherapy. In addition, Revlimid is postulated to have a synergistic effect on antibodies’ activity, making this specific combination very attractive.

The company has stated that although its initial registration strategy will focus on older AML patients, it intends to evaluate SGN-33 among younger AML patients as well. Younger AML patients have better options in terms of chemotherapy as well as stem cell transplant, but many of them eventually relapse. Seattle Genetics intends to evaluate SGN-33 as a means to reduce relapse rate among these patients, either as mono-therapy after stem cell transplant or in combination with chemo treatments. In these settings, Mylotarg might be a tougher opponent, as it is generally better tolerated by younger AML patients. Mylotarg is currently being evaluated in younger AML patients in combination with chemotherapy or following stem cell transplant, with some encouraging results and decreased toxicity, so it might already be approved for some of these indications by the time SGN-33 starts addressing this market.

The company does not hide its enthusiasm about SGN-33, designating it to be the “Rituxan of AML”. What this title actually means is an antibody which is potent by itself but will also be combined with other therapies and will become the cornerstone of AML treatment among all patient populations and stages of the disease. The company hopes SGN-33 will be as common in AML as Rituxan is in NHL (Non-Hodgkin’s Lymphoma). Although, the NHL market is much bigger than the AML market, it will also become very competitive in the coming years, with a wave of new antibodies, including SGN-40 expected to hit the market. The number of antibodies in the clinic for the treatment of AML is substantially smaller, which should enable SGN-33 to get a substantial share, especially among older AML patients. Nevertheless, there is no guarantee SGN-33 will demonstrate efficacy among all subtypes of AML patients, and even if it does, the registration and evaluation processes will take quite a while.

Although I still believe the long term potential of Seattle Genetics lies in its ADC technology, I have to admit it is currently developing 2 very impressive naked antibodies (SGN-33, SGN-40) that seem to work very well without any effector molecule attached to them. Monoclonal antibodies such as SGN-33 are considered to be relatively safe and to operate in a totally different way of chemo drugs. As a result, the research and development activity in the AML market (and most other kinds of cancer) can be separated into two distinct routes. The first route involves the evaluation of non-targeted therapies such as chemo drugs, while the second involves the development of targeted therapies such as antibodies. Typically, the effective chemo drugs will be combined with the effective antibodies in regimens that would hopefully lead to an additive or even synergistic effect. Based on the preliminary results we have seen thus far, the most effective antibody in development for older AML patients is SGN-33 due to its impressive safety/activity ratio. As a result, companies that develop chemo drugs for the treatment of AML in older patients, such as Vion and Genzyme would naturally like to combine their investigational and approved chemo drugs with the safest and most effective monoclonal antibody out there. Regardless of which chemo drugs are eventually approved or proven superior, all roads lead to Seattle.

Disclosure: Author is long SGEN

Source: Seattle Genetics at ASH 2007 (Part III)