Could generic lansoprazole become the next major advance for hepatocellular cancer

27th April 2010 23:52

Hepatocellular carcinoma (HCC) is the seventh most common cancer in the world.  The close association with hepatitis (both HBV and HCV) means that HCC is common in developing countries where these infections are endemic. Consequently the incidence of HCC is very high in China and other Asian countries. HCC is currently uncommon in the US where a reported 8,500 to 11,000 new cases diagnosed each year, comprising just 2% of all malignancies. HCC will however remain a significant, if not growing, problem in the US for the foreseeable future as hepatitis is becoming increasingly chronic.

HCC patients are poorly served by existing treatment options, with only a small proportion amenable to curative therapy such as surgical resection and liver transplantation (see Hepatocellular Carcinoma - Opportune indication for novel therapies ). Prognosis is poor for unresectable patients and so R&D interest in HCC is relatively high.  This has lead to recent advances, notably for example with the launch of sorafenib (Nexavar) in 2007.  This pan-kinase inhibitor is currently the first-line option for patients with HCC.

One aspect of cancer biology that has received steady interest is tumor acidity.  V-ATPase activity is elevated in tumors leading to proton extrusion into the extracellular medium as well as accumulation of protons within intracellular organelles. Abnormal acidity within the extracellular environment promotes activation of various proteases and destruction of the extracellular matrix.  This in turn supports the acquisition of metastatic cell phenotypes.  Increased acidity is also believed to impair the uptake of weakly basic chemotherapeutic drugs.  Inhibiting V-ATPase activity may therefore not only reduce tumor progression directly, it may also diminish drug resistance.

The proton pump inhibitors (PPIs) have been used for decades as treatment of gastroduodenal ulceration.  The normal target for PPIs such as omeprazole and lanzoprazole is the H+-ATPase protein expressed by the lumen of gastric parietal cells. However, PPIs also inhibit the activity of V-ATPases and so the PPI class could play a new role in the treatment of cancer, a suggestion supported by in vitro and in vivo data demonstrating the ability of lansoprazole to inhibit tumor cell growth and enhance survival in mouse models of cancer alone, and in combination with doxorubicin.

Today's issue of DailyUpdates features news from NexMed that the FDA has authorized the start of a Phase 2 trial of the company's candidate, PrevOnco.   PrevOnco incorporates lansoprazole (Prevacid).  The Phase 2 study will assess the safety and efficacy of lansoprazole plus doxorubicin as a first line treatment of patients with advanced unresectable HCC at up to 10 study sites throughout the US. The primary objective of the study is to assess the response rate to doxorubicin and lansoprazole. Subjects will be treated with oral lansoprazole 90mg twice daily and iv doxorubicin 60 mg/m2 administered every 21 days. Subjects will continue to receive doxorubicin plus lansoprazole, if tolerated, up to a maximum of six consecutive cycles of doxorubicin, as long as there is no evidence of progressive disease. A total of between 15 and 70 subjects are expected to be enrolled in the study for a period of up to 12 months in the absence of disease progression or intolerance. Total study duration is anticipated to be one to three years, depending on the rate of enrollment and number of patients enrolled.

Of interest the FDA has also suggested moving PrevOnco directly into a Phase 3 trial in combination with doxorubicin for those patients who have failed Nexavar therapy. This accelerated development of PrevOnco as a second line treatment would, according to NexMed, save at least 12-24 months in development time.

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