Immunogen’s lead candidate – Herceptin-DM1 (T-DM1)

There is no doubt that Immunogen’s most high-profiled candidate is Herceptin-DM1. Its development started back in 2000, as it looked like the perfect candidate for ADC development. Herceptin is an approved block-buster antibody for the treatment of breast cancer. It recognizes and binds the Her2/ErbB2 receptor, which has been strongly validated as a specific and efficient for the targeting of breast cancer cells. In addition, the superiority of Herceptin-DM1 can be easily demonstrated by administering it to patients who do not respond to Herceptin. If Herceptin-DM1 demonstrates a clinical effect among these “Herceptin resistant” patients, it may be the ultimate proof of concept for Immunogen’s platform.

Herceptin-DM1 has recently entered a phase II clinical trial, following a phase I trial which was launched in April 2006. The study was designed to evaluate Herceptin-DM1 among patients who had initially responded to Herceptin but then relapsed. In other words, in the beginning, these patient benefited from Herceptin but for some reason, their tumors eventually became resistant to Herceptin. It is important to note that the tumors which became resistant to Herceptin were still recognized by the antibody despite being unaffected by its binding. This leads us to one of the major advantages immunoconjugates have over “naked” antibodies.

One of the biggest problems with developing antibodies for cancer is that most of them have no therapeutic effect by themselves, even if they target and bind cancer cells specifically. As a result, for every Herceptin out there, there are dozens, if not hundreds of antibodies who can bind and recognize specific antigens on cancer cells, but have no therapeutic use. Attaching drugs to those antibodies may turn many of them into very potent agents, regardless of their inactivity as naked antibodies. All of the sudden, those “useless” antibodies turn into an infinite pool of potential drugs, so there is no need to develop new antibodies. That is why, in our opinion, technologies such as Immunogen’s do not only advance the field of cancer antibodies toward safer and more effective treatments, but actually represent a true revolution, as it shortens time-to-market of potential drugs. Since there are so many well studied antibodies that have already been developed and characterized, the resources and time required for bringing such immunoconjugates to the clinic become dramatically lower.

Back to our Herceptin-DM1, Genentech started the phase I in April 2006 and disclosed initial results in December 2006, followed by more updates in 2007. The goal of phase I trials is primarily to evaluate whether the drug is safe, by examining side effects and several doses. When dealing with a potent agent such as DM1, there is always a chance for something to go wrong, but luckily, Herceptin-DM1 did not have any special side effects, even in relatively high doses. In this specific phase I trial, the maximum tolerated dose (MTD) was set at 3.6 mg/kg every three weeks. At that dose level, 5 out of 15 patients who received Herceptin-DM1 had a partial response (tumor load went down at least 50% and stayed in remission for at least 6 weeks). Actually, another patient who received a lower dose of 2.4 mg/kg also had a partial response, so if we include her as well, the objective response rate for the two doses is 37.5%.

Since the patients had stopped responding to naked Herceptin, we can safely assume that the broad clinical effect was a result of the potent DM1 infiltrating into the cancer cells following the binding of the Herceptin moiety. Based on historical figures, the overall amount of DM1 that was used in this trial could not have led to this clinical response on its own, so we know the DM1 was targeted to tumors specifically.

In addition, Herceptin-DM1 had a favorable safety profile, since a clinical effect was achieved with relatively minor side effects. This implies the linker which glue the antibody to the drug is fairly stable in the blood stream.

Finally, the patients who participated in this trial had undergone numerous chemotherapy treatments and saw their cancer relapse prior to receiving Herceptin-DM1. Thus, their disease was in a very advanced and aggressive mode. It is likely that the drug would be more effective in earlier disease stages and less pretreated patient population. Although we view these results as very positive, we must admit we had expected a more potent activity by this promising candidate.

The reason for our extremely high expectations was the high potency of DM1 and promising pre-clinical results of Herceptin-DM1. When Herceptin-DM1 and Herceptin were evaluated for the treatment of mice bearing Herceptin-resistant tumors, Herceptin alone had no effect on tumor growth, while Herceptin-DM1 caused >90% tumor reduction in all mice examined. In addition, earlier pre-clinical studies showed that DM1 conjugates were +1000-fold more potent than naked Herceptin against breast cancer cell lines. Herceptin is dosed at 2 mg/kg per week, while in the phase I trial, T-DM1 was injected every 3 weeks at a dose of 3.6 mg/kg. This puts Herceptin-DM1’s clinical activity in a somewhat unflattering light.

Make no mistake, Herceptin-DM1 still has very promising prospects as it managed to show a significant effect where all other alternatives failed. Obviously, small phase I trials’ results are not reliable for deciding whether a drug candidate is effective or not. Still, the fact that the candidate had an effect among 37.5% of Herceptin-resistant patients is an extremely important indication. Although not as bright as we had expected, Herceptin-DM1 is still the jewel in the crown of the cancer antibodies field.

4 thoughts on “Immunogen’s lead candidate – Herceptin-DM1 (T-DM1)

  1. Hey Ohad

    I know there are many folks out there waiting to hear your opinion on the ASCO data for T-DM1. The stock responded quite well today.

    thank you,
    Rupert

    Like

  2. Hey Rupert

    Hope all is well. Aren’t you supposed to be on vacation or something???

    Hopefully, I will have something ready next week.

    To make a long story short, I believe the best is yet to come, as Genentech might unveil more data from the weekly trial during the conference.

    Best,
    Ohad

    Like

  3. Ohad,

    I think if you look at the data shown in the Abstract last week, in an escalating dose trial it’s possible that after dismissing the two lowest doses, all others may produce Partial Responses for all. Not saying they will, but with only 7 patients, 4, presumedly the 4 receiving the higher doses all had PR’s. We’ll know a lot more in two weeks when several more patients should be added and at least the four should now be confirmed PR’s or better. They were not confirmed before because the trial hadn’t run long enough to confirm them.

    Gary

    Like

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