Hammer Stock Blog

Regardless of IMGN901’s specific case, the impression I am getting from all the scientific material I come across that deals with Immunogen’s (IMGN) technology, is that IMGN901 will probably be the last ADC (antibody-drug conjugate) powered by the cleavable DM1 linker. There are currently no ADC programs, except from IMGN901, that utilize this specific linker. As I mentioned in one of my SGEN’s (SGEN) pieces, Genentech seems to prefer a noncleavable linker for the majority of its ADCs. Another example may be, Centocor, who licensed Immunogen’s technology for arming a antibodies targeted against alpha integrin and evaluated both DM1 and DM4 cleavable linkers with the same antibody. Results from several animal experiments showed that the cleavable DM4 version was much more stable in the bloodstream and active in inhibiting tumor growth than the cleavable DM1 version.

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At ASH (American Society of Hematology), Immunogen (IMGN) and its partners presented data on several projects including IMGN901(formerly known as HuN901) for Multiple Myeloma and AVE9633 for AML (Acute Myelogenous Leukemia) .

The company presented updated results from its  phase I dose escalation study in Multiple Myeloma patients who have failed prior treatments. IMGN901 was administered weekly for 2 consecutive weeks in a 3-week cycle, and the company reported results from 12 patients in 4 cohorts of 3. The evaluated doses were 40 mg/m²/week, 60 mg/m²/week, 75 mg/m²/week, and 90 mg/m²/week. Immunogen had previously published results for the two lower doses, which included one partial response (PR) and 2 stable disease (SD) in the 60 mg/m²/week cohort. In its ASH presentation, the company revealed that among the 6 patients who received the 2 higher doses (75 and 90 mg/m²), there was also one partial response in a patient at the 90 mg/m²/week cohort, although this patient had to drop out of the trial due to unrelated issues. Of note, the patient who responded at 60 mg/m² is still on the study, after more than 10 months.

I must admit I expected results to be somewhat better, based on management’s remarks in several investor conferences. I wrongly concluded that if a company gets a partial response in 1 out of 3 patients who were dosed at 60 mg/m², and claims to be very excited about the 2 higher doses, there would be at least one partial response in each cohort to generate a response rate of 33%. Nevertheless, these results are quite positive for two reasons. First, all patients who participated in this trial were heavily pretreated patients, who had already received more than four prior therapies. Second, IMGN901 demonstrated excellent safety profile as no severe side effects were documented. This means that additional patients can be recruited and receive higher doses, that might be more effective.

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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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Chemotherapeutic Drugs in The Clinic – Competitors or Potential Partners?

Obviously, SGN-33 was not directly compared to any other agent, so insight gained from comparing SGN-33 to other agents from different clinical trials is far from being conclusive. In addition, a comparison of a naked antibody (that will likely be given in combination with other drugs), to other chemo and combination regimens is not a fair one. Nevertheless, these comparisons are the only means researchers and investors alike have when evaluating the prospects of SGN-33.

The efficacy/safety ratio of SGN-33 is very impressive when compared to available treatments as well as other treatments currently evaluated in clinical trials. The cornerstone treatment for older AML patients is low-dose araC which has less than 20% complete response rate as a single agent (compared with 29% for SGN-33 in the current trial). araC is typically administered with other agents and is currently evaluated in combination with some novel drug candidates. These combinations result in a much better response rate, in the range of 30-60% among a variety of patient populations.

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