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.
At the moment, there are two recently recruited patients who are receiving 112 mg/m2/week and so far there are still no toxicity issues, hence, there will likely be at least one more dose escalation to the 140 mg/m2 level. If we ignore the lowest dose, objective response rate was 22% (2 out of 9) and we should hopefully see even better response rates in the next doses. Still, it is quite clear that current results support either a single-agent phase II trial or combination trials with available multiple myeloma drugs such as Velcade or Revlimid. In a business update conference call, company’s management stated that several options are currently being evaluated, but no decision is to be made before final data from this phase I trial is available, probably by mid 2008.
During the call, Immunogen’s CEO expressed a great deal of optimism regarding the currently evaluated and future doses, stating that the company’s flagship product Herceptin-DM1 (T-DM1), proved to be highly effective among metastatic breast cancer patients at this dose range, although the two clinical programs differ greatly from one another. T-DM1 was dosed at around 130 mg/m2 per 3 weeks, so this is quite similar to the 60 mg/m2 dose of IMGN, since it is administered twice per 3 weeks. T-DM1 showed a response rate of 37%, while IMGN-901 showed a response rate of 22%. Bearing in mind that blood cancers in general and Multiple myeloma in particular are known to have a higher response rate than that of solid tumors, I would say that in general, IMGN-901’s success rate is ok but not as spectacular as T-DM1’s.
So what might be the factors that sabotage IMGN901’s potency? Initially, my prime suspect was the cleavable DM1 linker IMGN901 employs.This linker is “weaker”, as oppose to the more stable DM4 or DM1 thioether linkers that are utilized for IMGN242 and T-DM1, respectively. IMGN242 had originally been built with the cleavable-DM1 linker, but after major stability issues arose, the DM1 linker was replaced by the more stable cleavable DM4 linker. However, a quick response e-mail from the company revealed that other linkers had been tested with the 901 antibody but provided no benefit over its current configuration.
Another possible factor is the fact that the CD56 receptor, targeted by IMGN901, is also found on certain white blood cells (NK cells). Fortunately, CD56 is not expressed by the stem cells from which these cells are derived so there are no real toxicity issues. On the other hand, NK cells are constantly produced by the body’s immune system so there is actually constant “masking” since each IMGN901 molecule that binds an NK cell, is one less molecule that could bind a cancer cell. This phenomenon is quite common with other targets, but perhaps it is more significant in this specific case. Looking at the bright side, since the amount of NK cells in the blood is more or less stable, higher doses might lead to more drug molecules ending up in the target cells. It would therefore be very interesting to see pharmacokinetic data from higher doses of IMGN901 in addition to the clinical effect they’ll have.
Author is long IMGN