Chemical structure of XMT-1001
Our lead candidate, XMT-1001, is currently in Phase 1 in cancer patients with refractory solid tumors. XMT-1001 is a conjugate of Fleximer and camptothecin (CPT), a broad-spectrum cytotoxic that inhibits the enzyme topoisomerase I, causing DNA damage to cancer cells. In prior Phase 2 trials (not sponsored by Mersana), the free drug CPT demonstrated evidence of anti-tumor activity, but also exhibited safety concerns, including severe bladder toxicity. Nonclinical studies of XMT-1001 in oncology models have shown significant improvement over the clinically active CPT and irinotecan, evidenced by broad-spectrum activity with better efficacy and safety. CPT analogs reached over $1 billion in annual sales globally in 2007. Furthermore, XMT-1001 provides lower development risk than a typical new chemical entity, with the benefit of full patent life.
Results from nonclinical studies with XMT-1001 in oncology models demonstrate the following:
- Increased therapeutic efficacy in preclinical models compared to CPT and irinotecan
- Greater therapeutic window than irinotecan
- Fleximer backbone extends half-life of CPT and provides controlled release
- Enhanced tumor distribution and accumulation - CPT is 75x more concentrated in the tumor when conjugated to Fleximer, compared to when administered alone
The ongoing Phase 1 trial is an open-label, dose-escalation study of XMT-1001 administered as an intravenous infusion once every three weeks in patients with advanced solid tumors. The objectives of the study are to determine the maximum tolerated dose (MTD) as well as to assess safety and pharmacokinetics. Preliminary Phase 1 data presented at the 2009 American Society of Clinical Oncology (ASCO) meeting and the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference demonstrated that the Fleximer-conjugated drug was well tolerated, with favorable pharmacokinetics and prolonged stable disease in numerous patients with advanced refractory tumors.
Early results from the XMT-1001 Phase 1 study reveal:
- Sustained release of free CPT in plasma and the formation of the expected release products in both plasma and urine
- Low levels of free CPT in urine
- To date, no hemorrhagic cystitis or severe diarrhea
