SGN-35, which is Seattle Genetics’ lead ADC, is comprised of SGN-30 and Seattle Genetics’ highly toxic chemo drug – MMAE. SGN-35 is, in fact, the company’s flagship ADC candidate, since it was its first wholly owned ADC to utilize the company’s new ADC technology, including its peptide-based linker and auristatin-based drug. Having both a naked antibody and an ADC based on the same antibody simultaneously in the clinic is quite unusual, but more than anything, this situation is fascinating because it can clearly exhibit the advantages ADCs have over naked antibodies. In that sense, SGN-35 is similar to Genentech’s Herceptin-DM1, which is currently being developed with Immunogen (IMGN). Herceptin-DM1 served as a validation for Immunogen’s ADC technology since it showed very encouraging results among breast cancer patients, who do not respond to naked Herceptin. Hence, if Seattle Genetics can show that SGN-35 succeeds where SGN-30 fails (hint- Hodgkin’s Lymphoma), without causing substantial side-effects, it should be a very strong proof-of-concept.
The company launched a phase I clinical trial in November 2006 in patients with relapsed or refractory CD30-positive hematologic malignancies, mainly HL. Phase I trials are typically dose-escalating studies, where the first set of patients receives a very low dose of the drug and if there are no severe side-effects, the next set receives a higher dose and so on, until a maximum tolerated dose [MTD] is reached. This study evaluated SGN-35 as a single agent, administered every three weeks, in 23 evaluable patients, 21 of which had HL. Of note, these patients had received a median of 4 prior therapies, including bone marrow transplant, but their disease eventually relapsed, making them a very challenging patient population
The company sounded very upbeat about preliminary results and intended to present data from this trial this month at the 2007 American Society of Hematology [ASH] meeting, but for some reason, the company’s abstract was rejected by the organizing committee. The company therefore decided to present the data last month in a conference focused on HL in Germany, and indeed, results were very encouraging. First, no maximum tolerated dose [MTD] was reached, or in other words, the company can increase the dose administered to newly accrued patients until MTD is reached. Overall, there were 4 partial responses, 3 of which among HL patients, which leads to an objective response rate of 14% among HL patients. This number will hopefully improve going forward, as higher doses are evaluated.
When analyzing small dose escalating trials, the first thing to look for is a correlation between dose and clinical response. Although the number of patients in each cohort is generally too small to be regarded as conclusive evidence, higher doses resulting in better clinical response is always a great sign. In the case of SGN-35, there was a fluctuated yet obvious dose dependent response, as 12 out of the 13 patients who received the 4 higher doses (0.6, 0.8, 1.2, 1.8 mg/kg), saw their tumor shrink (either stable disease or partial reponse). This is in contrast to 4 out of 10 patients in the 3 lower doses (0.1, 0.2, 0.4 mg/kg).
The comparison to SGN-30 (the naked antibody) is very impressive. SGN-30 was evaluated in 38 HL patients, 15 of whom received a weekly dose of 6 mg/kg for six consecutive weeks and 23 patients received a dose of 12 mg/kg. The recent SGN-35 trial included administration every 3 weeks, so just in order to compare the two, we’ll define the SGN-30 doses as 18mg/kg or 36mg/kg per 3 weeks. These doses are substantially higher than the 0.6-1.8 mg/kg per 3 weeks of SGN-35. Of the evaluable 35 patients who received the naked antibody [SGN-30], 9 had stable disease, whereas of the 13 patients who received the 4 higher doses of the ADC [SGN-35], 12 had stable disease or better. Although the two drugs were not directly compared in the same trial, the similar patient population combined with the striking dose differences leads to the inevitable conclusion that arming SGN-30 did result in a substantial enhancement of the therapeutic effect. All that is left to do now is to wait for an update from the ongoing SGN-35 trial. Judging by the high linker stability of SGN-35, and the limited expression of CD30 on normal tissues, substantially higher doses may be reached before hitting MTD.
Author is long SGEN