For ImmunoGen, a Lot Depends on Antibody–Cytotoxic Drug Conjugate T-DM1

[Hopeful]

Eight compounds currently in the clinic rely on ImmunoGen's technology for creating antibody-cytotoxin linked cancer drugs, with another two to four expected to reach that stage in 2010.
Only one really matters, though. The most advanced, and the most important to the biopharma's future, is T-DM1, the Herceptin-based hybrid in development by Genentech.
"T-DM1 has a significant impact in changing the perceptions of ImmunoGen, the [antibody-cytotoxic agent conjugate] field in general, the potential value of our partnerships, plus its impact on our path to sustained growth," ImmunoGen CEO Daniel Junius said during the company's R&D day Feb. 27.
ImmunoGen is counting on the Genentech compound's continued success as it heads into Phase III studies to further validate its technology and bring in new and richer partnering deals.
T-DM1 is an antibody-cytotoxic agent conjugate that uses trastuzumab's HER2 targeting ability to carry ImmunoGen's anti-microtubule agent DM1 into breast cancer cells, where the cytotoxic DM1 activates and kills the targeted cells.
ImmunoGen provides both the hyphen and the cytotoxin to T-DM1, Junius explained in an effort to dispel the perception, "real or not," that the value in the compound is supplied by Herceptin.
"We chafe at that a little bit because these are patients who are refractory to existing trastuzumab therapy, so clearly it's got to be the change associated with the conjugate that's having the impact," he stressed.
Genentech reported at an R&D day March 2 that it has a "fast and broad" Phase II development plan evaluating T-DM1 in first-, second- and third-line settings, with plans to approach FDA about accelerated approval if third-line results are compelling. Enrollment closed on that monotherapy trial during this quarter - ahead of schedule - and results from those 100 patients are anticipated in first-quarter 2010.
At its R&D day, Genentech updated data from a Phase II proof of concept study of T-DM1 in Herceptin refractory HER2+ metastatic breast cancer patients first reported at the San Antonio Breast Cancer Symposium in December.
As of Jan. 20, 36 of 108 evaluable patients (33 percent) had a complete or partial response on two consecutive occasions at least four weeks apart. Final results will be made available sometime in 2009, when all patients have at least six months of follow-up.
This month, the biotech enrolled the first patient in a Phase III trial called EMILIA that will compare T-DM1 to lapatinib (GlaxoSmithKline's Tykerb) in 580 HER2+ metastatic breast cancer patients who have progressed on a standard Herceptin regimen.
Genentech also has conjugates in all stages of preclinical and early clinical development for a number of solid tumor and hematological cancers, according to materials presented at the meeting. The company has licenses to use ImmunoGen's TAP technology against five undisclosed targets in addition to HER2-targeting T-DM1.
The rest of ImmunoGen's partnered clinical lineup
ImmunoGen is expecting a flow of data this year from partnered and internal compounds, some that will inform go/no go decisions and some that could garner milestone payments, attract partners or at least add validation of the ACC technology.
In the case of the lead candidate under ImmunoGen's five-year collaboration with Sanofi-Aventis, validation could be due not for the company's TAP platform, but for its abilities as an antibody company. AVE1642 is a "naked" IGF-1R binding antibody, developed and humanized by ImmunoGen that works by blocking a pathway used by cancer cells to survive chemotherapy. Phase II results are expected later this year.
A second Sanofi candidate, SAR3419, is an entirely ImmunoGen-made compound. The Phase I anti-CD19 conjugate was cobbled from an ImmunoGen antibody and cell-killing agent linked by ImmunoGen technology.
Two of ImmunoGen's partnered compounds entered the clinic in mid-2008. Biogen Idec licensed ImmunoGen's TAP technology in 2004 for use with its antibodies that target the cell-surface signaling molecule Cripto and is advancing BIIB015. German plasma company Biotest is advancing BT-062, in development against multiple myeloma. ImmunoGen has opt-in rights for U.S. development and commercialization on the Biotest compound.
Another candidate that entered Phase I last summer involves an integrin-targeting antibody ImmunoGen licensed from Johnson & Johnson's Centocor division. ImmunoGen is studying the anti-angiogenesis conjugate, IMGN388, for use against a number of tumor types and plans to make a go/no go decision on its further development in the fourth quarter. Centocor has opt-in rights for that compound.
Building an internal pipeline
ImmunoGen aims to advance one new novel anti-cancer compound a year into preclinical development starting in 2009, with the goal of putting together IND-ready packages for internal development or outlicensing.
The company's first strictly de novo compound, however, probably won't enter the clinic until 2011, Junius said. The limiting factor is the time it takes to develop a manufacturable antibody with the desired characteristics, he said. Meanwhile, he did not rule out the possibility the company would speed up the process by inlicensing an antibody, as it did in the Centocor deal.
But the pace of internal development depends on income from partnering, and with a big enough development deal on the table, ImmunoGen might be forced to set aside its internal interests altogether in favor of the collaboration, a contingency Junius called an appropriate, but difficult, tradeoff.
ImmunoGen will be making go/no go decisions on two proprietary compounds during this year. IMGN242 is in Phase II testing against CanAg+ gastric cancer, and IMGN901 is in Phase I studies in patients with heavily pretreated CD56+ multiple myeloma. It likely will advance first in that indication, but it has shown activity against small-cell lung cancer as well. Both compounds are partnering candidates.
Looking ahead, ImmunoGen reported it has new linking systems and new cytotoxins ready to be deployed.
A new family of hydrophilic (POL) linkers is designed to resist efflux in cancer cells, allowing sufficient toxins to build up and kill the cell. They will be particularly useful in multi-drug resistant cancers that express the target antigen at low density, according to ImmunoGen.
The new linkers attach a cytotoxin to an antibody that, as with current products, will circulate in the bloodstream and release toxins only after gaining entrance to the cell via the antibody's binding power.
A new family of "highly potent and specific" DNA-alkylating agents that will provide new cell-killing options is set to be unveiled at the coming American Association for Cancer Research meeting.


Hopeful