Hsp90 Inhibitor Program

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MPC-3100 and MPC-0767 are Hsp90 inhibitors we are developing for the treatment of cancer. An open-label, dose-finding, multiple-dose clinical trial of MPC-3100 in patients with refractory or relapsed cancers has been completed.  MPC-0767 is a novel L-alanine ester pro-drug of MPC-3100, which was designed to have improved aqueous solubility compared to MPC-3100. We expect to submit an investigational new drug application, or IND, on MPC-0767 in the first quarter of 2012.

 

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About Heat Shock Protein 90

Heat shock protein 90, or Hsp90, is a chaperone protein that plays an important role in regulating the activity and function of numerous signaling proteins, or client proteins, that trigger proliferation of cancer cells. Hsp90 binds and stabilizes these client proteins and inhibition of Hsp90 leads to degradation of the client proteins important for growth and, sometimes, survival of the tumor. Some mutant oncogenes become reliant or "addicted" to Hsp90 to maintain their activity, making them particularly sensitive to Hsp90 inhibitors [1].

Targeted therapies against Hsp90 client proteins for example, ALK, HER2, FLT3 and B-RAF have proven very efficacious in the clinic. We believe that by hitting these targets through a different mechanism, it may be possible to improve efficacy and duration of response with an Hsp90 inhibitor alone or in combination with these targeted therapies to Hsp 90 client proteins.

Early Hsp90 inhibitors were analogs of the natural product molecule geldanamycin that demonstrated promising preclinical and clinical proof of concept activity, but have been challenging to develop because of drug related toxicities, including hepatotoxicity, nephrotoxicity and pancreatitis. These toxicities appear to be 'off target' effects and not related to inhibition of Hsp90. Additional limitations to geldanamycin derivatives include poor solubility, metabolic stability and difficulty in administration.

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MPC-3100 and MPC-0767: Preclinical Development

MPC-3100 and MPC-0767, a pro-drug of MPC-3100, are fully synthetic, orally bio-available, non-geldanamycin Hsp90 inhibitors that have shown significant and broad preclinical anti-tumor activity in mouse models of human cancers[2][3][4][5]. MPC-3100 has not demonstrated the same hepatic or renal toxicity in vivo as the geldanamycin analogs. MPC-3100 inhibits Hsp90 by binding to the same site as geldanamycin and has displayed potent anticancer activity in several in vitro and in vivo models. MPC-3100 significantly and dose-dependently reduced tumor growth in multiple studies conducted in mice implanted with a variety of human cancer cell lines, including colon, prostate, myeloid leukemia, small-cell lung, gastric, breast, and ovarian cancers[4][5][6]. We recently reported data demonstrating that the combination of MPC-3100 with other targeted therapies, including erlotinib and sorafenib, showed greater in vivo anti-tumor activity compared to either agent alone, suggesting the potential of combining MPC-3100 with these targeted cancer therapies in the clinic [6].

We also presented a preliminary assessment of the novel L-alanine ester pro-drug of MPC-3100, MPC-0767, which was designed to have improved aqueous solubility compared to MPC-3100 [7]. Animal studies showed that the pro-drug displayed pharmacokinetics comparable to MPC-3100 and equivalent efficacy, inducing significant tumor regressions. We expect to submit an IND on MPC-0767 in the first quarter of 2012.

MPC-3100: Clinical Development

We have completed a first-in-human Phase 1 clinical study to investigate the safety and tolerability of MPC-3100 [8]. The phase 1 study was an open-label, dose-escalating, multiple-dose, study in which 26 patients with recurrent cancer or cancer refractory to available systemic therapy were treated with MPC-3100. Patients received oral MPC-3100 either once daily for 21 days followed by seven days off (cohorts 1-5, at doses of 50, 100, 165, 245, and 340mg/m2, respectively) or continuously for a 28-day cycle at doses spaced 12 hours apart (cohorts 6-7, at total daily doses of 480mg and 640mg, respectively). The primary objectives of the Phase 1 study were to assess the safety and tolerability of MPC-3100 and to define the maximum tolerated dose (MTD). Secondary objectives were to characterize the pharmacokinetic parameters of MPC-3100, to assess antitumor activity, and to evaluate pharmacodynamic biomarkers for Hsp90 inhibition. The study demonstrated that MPC-3100 was generally safe and well tolerated at doses below 600 mg per day. The most common adverse events were gastrointestinal, including diarrhea, nausea, and vomiting. Pharmacokinetic analysis indicated that the Cmax and AUC(0-12h) increased proportionally to the dose of MPC-3100. The terminal plasma half-life of MPC-3100 ranged from 4.8 to 21.4 hours with a mean half-life of 11.2 hours. The best clinical response was stable disease (12/26; 46%), with a median duration of 11.1 weeks (range 3.0-52.3 weeks). On target activity of MPC-3100 was confirmed by biomarker analysis, which suggested effective and persistent in vivo inhibition of Hsp90.

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MPC-3100 and MPC-0767: Future Clinical Development

We are conducting non-clinical studies as well as other technical, regulatory and market assessments with the objective of identifying optimal cancer indications and drug combination regimens to potentially advance one or both of our Hsp90 inhibitor compounds into Phase 2 clinical development. Our current plan is to initiate a Phase 2 study of MPC-3100 in one or more specific populations of patients with cancer in the second quarter of 2012. However, the timing of a Phase 2 trial and the compound to be tested may change depending upon the results and timing of the clinical development of MPC-0767.

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Recent Presentations

 

ab2617
 MPC-3100, a synthetic Hsp90 inhibitor, induces biomarker changes in vitro and in vivopdf-icon-small
AACR 102nd Annual Meeting
April 2-6, 2011
San Diego, CA
7.5 MB

References

1. Trepel J. et al. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 2010 Aug;10(8):537-49. View Abstract

2. Wettstein D. et al. MPC-3100: A non-natural product Hsp90 inhibitor with anti-tumor activity in preclinical models. 20th EORTC-NCI-AACR, October 21-24, 2008 in Geneza, Switzerland. Poster PDF pdf-icon-small

3. Yu M.K. et al Pharmacokinetic and pharmacodynamic data for MPC-3100, a fully synthetic, orally bioavailable HSP90 inhibitor, in cancer patients. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, November 18th, 2009 in Boston, MA. Poster PDF pdf-icon-small

4. Baichwal V.R. et al. Anti-tumor Activity of MPC-3100, a Synthetic, Orally Bioavailable Hsp90 Inhibitor, in Animal Models. 101st Annual Meeting of the American Association for Cancer Research (AACR), 2010 Poster PDF pdf-icon-small

5. Baichwal V.R. et al. MPC-3100, a synthetic Hsp90 inhibitor, induces biomarker changes in vitro and in vivo. 102st Annual Meeting of the AACR, 2011. Poster PDF pdf-icon-small

6. Baichwal V.R. et al. Anti-tumor Activity of MPC-3100, a Synthetic Hsp90 Inhibitor, in Combination with Erlotinib and Sorafenib . 102st Annual Meeting of the AACR, 2011. Poster PDF pdf-icon-small

7. Papac D. et al. Evaluation of the Pharmacokinetics and Efficacy of a Novel Pro-Drug of the HSP90 Inhibitor,MPC-3100, Designed with Improved Solubility. 102st Annual Meeting of the AACR, 2011. Poster PDF pdf-icon-small

8. Samlowski W.E. et al. Phase 1 study of the HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer. EORTC/NCI/AACR Molecular Targets and Cancer Therapeutics Symposium. Poster PDF pdf-icon-small

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