Seeking FDA Approval for a Botanical Prescription Drug:

Case Study of PHY906

 

Shwu-Huey Liu¹, Zaoli Jiang¹, Tah-Mun Su¹, Robert Tilton¹, Edward Chu^2,3 and Yung-Chi Cheng³

¹PhytoCeutica Inc. New Haven, CT; ²Department of Medicine and ³Pharmacology, Yale University School of Medicine, New Haven, CT;

 

The Guidance for Industry: Botanical Drug Products published by the U.S. FDA in June 2004 forms the basis for the development of botanicals in the United States.  Although the uptrend has been very encouraging, proponents of botanical medicine must still overcome several hurdles to become fully integrated into mainstream medicine.  The challenges facing botanical drugs lie with manufacturing, preclinical and clinical studies, education and legislation.

 

PHY906, a traditional Chinese botanical formulation consisting of 4 different herbs, was first described nearly 1800 years ago for common gastrointestinal distress.  It has since been shown to reduce chemo-induced toxicity and to enhance the therapeutic efficacy of a broad-spectrum of common anticancer agents in a variety of tumor-implanted in vivo animal models.  PHY906 is being developed as an FDA-approved botanical prescription medicine that would offer a new approach to cancer supportive care.

 

A phase I/IIA double-blind, randomized, placebo-controlled, cross-over, dose escalation clinical study of PHY906 as a modulator of irinotecan-based chemotherapy with advanced colorectal cancer has been carried out.  The primary objectives of this study were to define the safety, tolerability, and effective dose of PHY906 when co-administered with the Saltz regimen (weekly schedule of CPT-11, 5-FU and LV) as first-line treatment or with CPT-11 alone as second-line treatment of patients with advanced colorectal cancer.  The secondary objectives were to compare the effect of PHY906 or placebo on the pharmacokinetic profiles of CPT-11 and 5-FU as well as on gastrointestinal side-effects, specifically the late-onset grade 3/4 diarrhea caused by CPT-11-based regimens.  Pharmacokinetic analysis indicated that PHY906 neither altered significantly the plasma levels of CPT-11 and its active SN-38 metabolite nor that of 5-FU.  As to the remediation of late-onset diarrhea, preliminary results show that the frequency of using rescue medication such as loperamide during the PHY906 treatment period was less than that during the placebo treatment period. We intend to confirm these preliminary findings with another clinical study that will involve a larger patient pool and that will expand upon the study objectives to include the effect of PHY906 on the antitumor activities of CPT-11 in advanced colorectal cancer.

 

A second phase I/II clinical study evaluating the effect of PHY906 on the enhancement of the therapeutic efficacy of capecitabine chemotherapy in patients with advanced unresectable hepatocellular carcinoma was launched in 2003 and currently ongoing at several medical centers in the U.S. The objectives of this study are to determine the safety and tolerability and effective dose of PHY906 in combination with capecitabine and to evaluate the objective antitumor response rate and the time to disease progression.

 

While clinical trials address the safety and efficacy of the drug candidate, we have also developed various new physical/chemical and biological analytical methods to address the critical issues of quality control and assurance of botanical drugs.  Both three-dimensional LC/MS chemical fingerprint profiles with molecular resolution and genomic profiles of cellular bio-response are employed to generate a quantitative signature pattern to ensure batch-to-batch consistency of the study drug used in both pre-clinical and clinical studies.

 

Our twin-approach of using both controlled clinical studies and modern advanced physical/chemical and biological analytical methods for quality control of the study drug can transform ancient botanical drug formulations into new and useful regimens for treating unmet medical conditions such as cancer.

 

20^th Natural Medicine Conference

Taipei, Taiwan, June 24-25, 2005