Clavis and Clovis collaboration to tackle problem of Gemzar (gemcitabine) resistance - New hope for pancreatic and non-small cell lung cancers
11th March 2010 16:47
According to our 2009 feature Commercial Insight: Cytotoxic Therapies, the cytotoxics market was worth $13.8 billion in 2008 across the seven major pharmaceutical markets, and is forecast to grow to $18.7 billion by 2018, achieving a CAGR of 3.1%.
In 2008, Taxotere (docetaxel; Sanofi-Aventis), Eloxatin (oxaliplatin; Sanofi-Aventis) and Gemzar (gemcitabine; Eli Lilly) were the top three cytotoxics, with sales over $1 billion.
Today’s editorial focuses on one of these blockbuster cytotoxics, gemcitabine, or to be more precise, a fatty acid derivative of this agent, CP-4126 which is currently being developed by Clavis Gemcitabine was initially launched in the 1990’s as a treatment for non-small cell lung cancer (NSCLC) and pancreatic cancer and it is now part of first line treatment for both. Gemcitabine is also indicated for other cancers such as metastatic breast cancer, ovarian cancer and bladder cancer.
The cancer pipeline is burgeoning, driven by the continued incidence of the disease, continued unmet needs and patent expiries. The majority of the cancer pipeline is comprised of targeted therapies and improved cytotoxics. Gemcitabine is a good example of the current status of oncology R&D. With generics already on the market following patent expiration in some markets and acquired drug resistance limiting the continued efficacy of gemcitabine the clinic is ready for a super-gemcitabine. This is particularly the case given continued unmet needs for improved treatments of indications for this drug.
Our 2008 feature Pipeline Insight: Non-Small Cell Lung Cancer - Emerging Therapies highlights the problems around NSCLC. In 2008, the incidence of NSCLC was estimated to have exceeded 367,000 new cases in the seven major pharmaceutical markets. The prognosis for patients with the disease remains poor. In one pivotal study median survival time was just 9 months in combination with cisplatin.
Pancreatic cancer is far less common than NSCLC but remains a significant problem all the same. Estimated incidence is 91,000 across the 7 major markets. According to a report published last year Pancreatic Cancer - Gemzar Dominance Will Continue Among High Levels of Persistent Unmet Needs, only 15-20% of pancreatic cancer patients have resectable disease, therefore most receive systemic therapy. Gemcitabine forms the current standard of care for advanced disease. Despite this, no treatment is truly effective, with five-year survival at 5% for all stages of disease. Gemzar is only associated with median overall survival of 5.7 months and a one-year survival rate of 18%, statistics even more dismal than for NSCLC.
It is therefore clear that treatment of NSCLC and pancreatic cancer continues to be plagued by high levels of unmet need. Clavis is taking this need to task with CP-4126.
Activation of gemcitabine requires phosphorylation by deoxycytidine kinase; the active metabolite is incorporated into DNA and RNA. After its incorporation into DNA one or some more nucleotides can be added, after DNA polymerization stops. The nucleotide dFdCDP is also a potent inhibitor of DNA-synthesis inhibiting ribonucleotide reductase, which is the only enzyme providing the cells with deoxynucleotides which are essential for DNA synthesis. Resistance to gemcitabine may occur because it is hydrophilic therefore requiring active transport into tumor cells. One way of circumventing this problem is to develop fatty acid ester cytotoxic derivatives
Clavis Pharma has already gained success through this approach with esterified cytarabine derivative, CP-4055 which is in Phase 2 development for AML. Today we focus on CP-4126, a fatty acid derivative of gemcitabine. Both molecules were developed using the company's lipid vector technology.
In the January issue of Investigational New Drugs, Bergman et report the preclinical profile of CP-4126. Across a wide variety of cancer cells CP-4126 and gemcitabine displayed similar potencies (IC50 approximated to 100nM). Of importance, while inhibition of nucleoside transport decreased sensitivity to gemcitabine by up to 200-fold, CP-4126 suffered little effect.
The authors proceeded to evaluate CP-4126 in various xenograft models and found efficacy similar to gemcitabine in melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts. Importantly and in contrast to gemcitabine, CP-4126 could be administered orally.
We have seen a recent trend towards developing orally active forms of existing oncology agents. For example, Capecitabine, has been developed as an oral version of 5-fluorouracil. CP-4126 might show significant benefit as a future oral alternative for gemcitabine in addition to its ability to circumvent resistance resulting from cellular access. Clavis has been developing CP-4126 clinically as oral and iv formulations. CP-4126 has recently received orphan drug designation in the US and EU (Press Release) and is currently in a phase 2 trial (link to clinicaltrials.gov entry) of newly diagnosed, advanced pancreatic cancer. The study was initiated in April 2009 and results are expected in H1 2012. Of interest we understand that Clavis has been exploring the development of a biomarker diagnostic method for determining which patients would benefit from the drug. We presume that this test will probe the nucleoside transporter.
LeadDiscoveryexpects investigation in other indication to follow and this is likely to be accelerated given recent news that Clavis and Clovis Oncology has signed a US$380 million partnership agreement for the development and commercialisation of CP-4126. Under the terms of the agreement, Clovis Oncology will take over responsibility for product development and manufacturing of CP-4126 as CO-101, and for filing of marketing approvals in the United States, Europe, Canada, Central and South America. Clovis Oncology will also be responsible for commercialisation of CP-4126/CO-101 in those territories.
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