Phase-0/Microdosing: Intra-Target Microdosing (ITM) in actual drug development – recent developments

Dear All,

With Intra-Target Microdosing (ITM) a microdose (calculated on a total body basis) is administered locally into a small area of the intended target such that it is sufficient to generate therapeutic-level exposures in the target.  For example, if a microdose that is 1/100th of the therapeutic-level dose is administered into the radial artery, the hand, which is just about 1/100th of the body mass, will be exposed momentarily to therapeutic-level exposures sufficient to collect PD, biomarker, and mechanism-of-action (MOA) data from the target while exposing the rest of the body to microdose-level exposures.

Recently, several applications using these principles in actual drug development have been reported:

1. Sjogren et al, used microdose administration of 3 novel analgesics in microdose (calculated on whole body basis) into rat skin, therefore generating momentarily local analgesia.

2. Presage together with BMS and Celgene reported in press release shared earlier this summer using Phase-0/Microdosing to test new drugs in cancer patients. The intervention combines principles of Intra-Target-Microdosing and cassette microdosing by administering multiple drug candidates simultaneously into the intended target, in this case – tumors.

The press release (attached) indicates that the technology is “designed to deliver up to eight different microdoses of drugs or drug combinations directly into the tumor. Each drug or combination is injected alongside fluorescent tracking microspheres, which allow investigators to track each dose. This way, the tiny doses don’t disperse into the body, and investigators know exactly where in the tumor each drug was injected and where it went after that. It’s an efficient way to run combination studies—rather than testing a two-drug cocktail in one patient, one half of it in another patient and the other half in a third patient… allows for the simultaneous microdosing… into a single tumor,”

3. Perhaps most interesting is the work new Network member Oliver Jonas from Harvard Medical School and his team are doing.  They are using micro devices injected into tumors (using standard biopsy needles) with multiple (up to 16) simultaneous microdose of different agents.  As the microdoses diffuse into the tumor tissue they generate therapeutic-level exposures locally, and associated PD, biomarker, and MOA data. Drugs that get to the systemic circulation generate safe microdose exposures. After a while the device plus core tissue around it are removed to study drug effects.  This is also an example of Intra-Target Microdosing principles together with cassette microdosing and is a testament both to the flexibility available in the regulations and the creativity inherent in marrying technological advances with pharmaco-physiological principles.

References

1. Sjogren, E., M. M. Halldin, O. Stalberg and A. K. Sundgren-Andersson (2018). “Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.” Eur J Pain.

2. Jonas, O., H. M. Landry, J. E. Fuller, J. T. Santini, Jr., J. Baselga, R. I. Tepper, M. J. Cima and R. Langer (2015). “An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors.” Sci Transl Med 7(284): 284ra257

3. Jonas, O., M. J. Oudin, T. Kosciuk, M. Whitman, F. B. Gertler, M. J. Cima, K. T. Flaherty and R. Langer (2016). “Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.” Clin Cancer Res 22(24): 6031-6038.

4. Davidson, S. M., O. Jonas, M. A. Keibler, H. W. Hou, A. Luengo, J. R. Mayers, J. Wyckoff, A. M. Del Rosario, M. Whitman, C. R. Chin, K. J. Condon, A. Lammers, K. A. Kellersberger, B. K. Stall, G. Stephanopoulos, D. Bar-Sagi, J. Han, J. D. Rabinowitz, M. J. Cima, R. Langer and M. G. Vander Heiden (2017). “Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors.” Nat Med 23(2): 235-241.5. Burt, T., R. J. Noveck, D. B. MacLeod, A. T. Layton, M. Rowland and G. Lappin (2017). “Intra-Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing.” Clinical and Translational Science: 1-14.

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