Super Results for Genentech/Immunogen's "Super-Herceptin" Collaboration

Let me just start by saying, “wow!” As I mentioned in my last update a few weeks before the annyal ASCO meeting, I have been waiting to hear from Genentech (DNA) on the progress of their collaboration with Immunogen (IMGN) on a “supercharged” Herceptin, known as Herceptin-DM1. What follows is a short summary of several “wow!” moments from me as I reviewed this data and compared it to previous Herceptin data. Before I get to that, one quick “wow” quote from a recent largely unnoticed, but well-written Luke Timmerman piece
that should summarize why I am excited about Immunogen’s potential for serious valuation appreciation:

"This is the most exciting thing to me that we are doing,'' said Pamela Klein, Genentech's vice president of clinical hematology and oncology, in an interview yesterday. “

Wow. “THE most exciting thing” Genentech is doing, according to their VP of hematology and oncology? THAT is exciting stuff to read and the FIRST real validation of Immunogen’s technology in human clinical trials. Yes, Immunogen has advanced previous internal candidates (years ago) to Phase III trials and has another internal candidate in a Phase I/II trial now, but that is nothing compared to validation like this from Genentech, the people who KNOW cancer and great technology for fighting it.

So why is Dr. Klein so excited about Immunogen’s technology and the Herceptin-DM1 supercharged drug? Here’s a quick summary of the Phase II trial Genentech reported on in January of 2004, wherein they tested Herceptin as a standalone agent administered on a once every three week schedule. I chose this trial for comparison because it lines up nicely on the dosing schedule. Genentech is also now testing Herceptin-DM1 in a weekly dosing format, which I expect to be even a little more efficacious, but we’ll have to wait and see on that data. For now, here’s what we have.

From the January 2004 summary of trial data:

This open-label, multicenter single arm study evaluated the efficacy and safety of a three weekly regimen of Herceptin monotherapy in women with metastatic breast cancer with over-expressed or amplified HER2. Herceptin was administered as a loading dose of 8 mg/kg IV, followed by 6 mg/kg every three weeks.

Test product, dose and mode of administration or test procedure:

Herceptin 8mg iv loading dose, followed by 6mg iv every 3 weeks.

Herceptin (8 mg/kg starting dose, 6 mg/kg thereafter) administered once every three weeks at three times the standard weekly dose to patients with HER2-positive metastatic breast cancer had similar anti-tumor efficacy to the standard weekly regimen: 2% of patients had a complete and 17% of patients had a partial tumor response. The overall response rate in the per protocol subset (patients with measurable and centrally confirmed HER2 positive disease) was 23%.

So to takeaway, here are the key points that I see: dosing after load was 6 mg/kg once every three weeks, overall response rate in the ‘per protocol’ subset was 23%, largely partial responses. There was definite indication in this trial of the cardiotoxicity that has troubled Genentech, so it was well-documented in this trial, as in others, as a key adverse event.

Now, let’s move to the data as reported by Genentech at this year’s ASCO convention. From Immunogen’s release:

To be eligible for enrollment in this trial, patients must have HER2-positive metastatic breast cancer that has progressed on treatment with Herceptin plus chemotherapy. Increasing doses of trastuzumab-DM1 - given once every three weeks - were administered to new patients until the maximum tolerated dose [MTD] of the compound was established, and then nine additional patients were dosed at the MTD.

Eighteen patients had been enrolled in this ongoing study, with an average (median) age of 50. In addition to prior treatment with Herceptin, these patients had received multiple prior chemotherapy regimens (median of 7.5).

Ok, so eighteen patients were enrolled, ten of whom received either 2.4 or 3.6 mg/kg of Herceptin-DM1. This is a much smaller sample size than the Phase II trial I profiled above, so it’s not quite apples to apples, but it’s the closest we have at this point. Note that Genentech also announced at ASCO that they will move this product into Phase II testing next, so we got a “GO” far earlier in 2007 than I had expected (wow), but it’s easy to understand why when you examine the data they’re seeing.

Four of the ten patients who received 2.4 or 3.6 mg/kg of trastuzumab-DM1 had an objective response and, in fact, Genentech noted that a fifth patient appeared to experience a partial response as well but was not able to be verified as such by RECIST criteria due to the location of the patient’s spinal lesion. So either way, we’re looking at 40% or 50% of patients receiving one of the two highest doses showing an objective response. That is stunningly good biological activity for a Phase I trial. (Wow)

For further consideration of how good this response rate is, consider that as opposed to the Phase II patients listed above; the patients in this Herceptin-DM1 trial had to have already failed (i.e. shown disease progression) on Herceptin combined with chemotherapy treatments. To repeat from the release above:

“In addition to prior treatment with Herceptin, these patients had received multiple prior chemotherapy regimens (median of 7.5).”

So patients in this study had had multiple prior chemo regimens plus Herceptin and had continued to progress and see their disease worsen. It is these patients in whom Herceptin-DM1 achieved either a 40% or 50% objective response rate in the groups receiving one of the two highest doses (i.e. the dose that will be used in the coming Phase II trial.) Further, the highest dose given was 3.6 mg/kg as compared to the Phase II trial which, after loading, used 6 mg/kg. In part, I suspect, as a result of this lower dose being so effective, this key finding was observed (bold is mine):

“No cardiac toxicity was observed.”

No cardiac toxicity for a treatment known to have predilection for cardiac toxicity is a stunningly good result. If this result bears out in Phase II/III trials, Genentech will have a MONSTER drug on their hands, both in frontline use for Her2 positive breast cancer patients as well as for patients that have previously failed Herceptin and/or chemo regimens. THAT is why these findings are so exciting and why, I believe, Dr. Klein of Genentech said:

"This is the most exciting thing to me that we are doing…''

In Timmerman’s Bloomberg article, Klein went on to say that these patients in the study were difficult to treat and she did not expect to see such a tumor response. She also cautioned that of course the company needs to do further studies in larger patient populations and ‘has much work to do’ but clearly her quote above is a great top-line summary and takeaway of Genentech’s thoughts.

Wow. It will now be interesting to see whether the dosing schedule for the Phase II trial uses weekly or the once every three week dose and also how long it takes Genentech to begin testing this in first-line patients, not just the ones who have failed previous Herceptin regimens. Also, it will be crucial to watch and see if Genentech brings another Immunogen-created conjugate into the clinic this year. They have previously shown slides with a number of their blockbuster antibodies conjugated to one of Immunogen’s toxins (and they have also tested a number of toxin combos from Seattle Genetics, but as yet, the only conjugate Genentech has taken into the clinic is Herceptin-DM1 with Immunogen).

I’m currently watching and waiting to get details of what Immunogen has disclosed as a soon-to-be begun trial in their own huC242-DM4 conjugate against gastric cancer (a notoriously difficult to treat cancer with few patient options) as well as more details on Immunogen’s plans for its internal huN901-DM1 conjugate that it appears they may advance in trials against Multiple Myeloma. When I have more details on these two internal products (and any updates from either Genentech or Sanofi or Biogen Idec, etc. among Immunogen’s other partners), I will put together more valuation analysis. For now, I expect Immunogen to flirt with $7 (they have a ridiculously low forty some million shares outstanding) giving them a valuation just under $300 million, something I view as exceedingly inexpensive given the validation Genentech just delivered.

"This is the most exciting thing to me that we are doing…''

One final “Wow”. Keep your eyes on this one. I’ll do the same.

Disclosure: Author has a long position in IMGN