According to the WHO, Hepatitis C (‘HCV’) is comparable to a 'viral time bomb'. The WHO estimates that about 200 million people are infected with HCV with a global 170 million chronic suffers at risk of developing liver cirrhosis and/or liver cancer which are the primary reasons for liver transplants. Only a minority of patients receive a long-term benefit from the treatments currently available. Many drop out or decline the treatment because of side effects. The unmet medical need remains very high and the market potential for a new effective treatment is substantial.

Recent studies have demonstrated the link between poor Health Related Quality of Life (“HRQoL”) and chronic hepatitis C (“CHC”). Current standard of care in CHC comprises pegylated interferon therapy combined with ribavarin. Patients responding to interferon/ribavarin treatment and showing sustained virological response (“SVR”) have been shown to achieve improved HRQoL, as measured by the widely used and validated “SF-36” HRQoL questionnaire. However, SVR rates in CHC treatment remain around 50% in patients with genotype 1, the commonest form of the hepatitis C virus and many patients do not finish treatment because of side effects.

Phynova’s lead drug, PYN17 combines potential antiviral, anti-inflammatory and anti-fibrotic properties in a “multivalent” approach that is designed to alleviate the symptoms associated with poor HRQoL in CHC, and the concurrent liver inflammation.

Phynova has completed a small UK based, six month, double-blind, placebo controlled, randomized, parallel-group Phase II study of PYN17 in patients with CHC. The trial was carried out in CHC patients who were refractory to, or unwilling or unable to take interferon/ribavarin.  PYN17 treatment resulted in a downward trend in serum transaminase levels (i.e. ALT), an accepted marker of inflammation in CHC and in improvement in 6 of the 8 HRQoL domains of the SF-36 questionnaire. Within the SF-36 questionnaire, the vitality score improvement seen after PYN17 treatment  was above the level regarded as being clinically important  (i.e. above the “MCID” of 4.2 points ) (Spiegel et al1).The vitality score can therefore be used in monitoring patient outcomes in both clinical practice and clinical trials. 

Analysis of the results of the UK study encouraged Phynova to seek FDA approval to carry out a larger Phase II study of PYN17 in the USA. An IND for a Phase I/IIa study was approved in January 2007 and the study was carried out in 5 major US hepatology centres between May and September 2007. Patients were randomised to treatment for one month with PYN17 or a placebo. The primary objective was to assess the safety and tolerability of PYN17. The preliminary results showed that PYN17 was indeed well tolerated with only a relatively low level of minor adverse events, identical to that seen with the placebo. A pivotal Phase IIb efficacy and safety study on PYN17 is planned to begin during the first half of 2008.

Phynova believes that PYN17 is the only drug in clinical development designed specifically to target the symptoms associated with CHC including, impaired HRQoL and liver inflammation.

There may be significant commercial opportunities in the development of PYN17 both for use in patients that have failed to, or that are unable to take interferon/ribavarin therapy (~50% patients in genotype 1 infection) and as a potential adjunct therapy with interferon/ribavarin.

 Reference
1 Spiegel et al; Hepatology 2005; 41:790-800 “Impact of Hepatitis C on Health Related Quality of Life: A Systematic Review and Quantitative Assessment”.

Non Alcoholic Fatty Liver Disease ("NAFLD") is a common and increasing problem world wide. It encompasses a spectrum of liver disorders ranging from fatty liver to non-alcoholic steatohepatitis (‘NASH’), the latter being associated with liver inflammation and fibrosis. NAFLD may progress through NASH to cirrhosis and heptocellular carcinoma. Currently there is no effective drug therapy in use for NAFLD/NASH. Treatment focuses on reducing body weight by diet and exercise and for more severe cases associated with morbid obesity, bariatric surgery. PYN22 is a single plant extract that has been selected as a candidate for the treatment of NAFLD/NASH, based on preclinical work in both China and the UK that suggests PYN22 may have a direct effect on body weight, liver and blood fat levels. Phynova has plans in development for a clinical study with PYN22 that it expects to initiate during 2008.

PYN9 is a preclinical candidate for the treatment of post operative ileus ('POI'), developed in China by Botanic Century (Beijing) Ltd ('BCCL'), a botanical drug development company in which Phynova has a 45% equity stake. POI is a form of bowel obstruction/hypomotility associated with surgery and/or the use of opiate pain killers that is widely seen after abdominal surgery and is an important cause of post-operative morbidity and delayed hospital discharge. BCCL’s candidate has shown promising efficacy in preclinical studies targeting increased bowel movement in conditions where the bowel motility has been impaired. BCCL has filed an IND to begin clinical studies in China. Once regulatory approval to begin a clinical study is given, BCCL expects to complete the clinical phase of development within 2 years. Phynova is currently exploring the potential for PYN9 in markets outside China.

An estimated 100,000 patients in the UK contract an antibiotic resistant infection while in hospital each year. The reported cost to the NHS of treating these infections is in excess of £1 billion. With the sharp increase of so-called "super-bugs" such as MRSA in hospitals, there is a major need for new anti-bacterial treatments. PYN6 is a fraction isolated from a single plant that has been found in pre-clinical screening assays conducted both in China and in the UK to have activity against clinical isolates of MRSA and against the bacterium associated with the development of acne, Propionobacterium acnes. PYN6 appears to be active against MRSA at one tenth the concentration of the commonly used topical antibiotic, mupirocin. In laboratory studies extending over three weeks of MRSA strain culture with PYN6, none of the MRSA strains tested could be converted to PYN6 resistance.  Phynova is now planning formulation studies to assess the potential of PYN6 for topical application in both MRSA and acne.

PYN18 is a single plant extract that has shown considerable antiviral activity in laboratory assays against both the Hepatitis C Virus and against the virus that causes Dengue Fever (both Flaviviruses). There is a clear need for new drug candidates for the treatment of hepatitis C, given the low viral clearance rates seen using the combination approach of interferon with ribavarin and the continuing disappointing side effects that are emerging with some of the newer clinical candidates that include protease and polymerase inhibitors. Likewise, there is an outstanding need for drugs that could treat Dengue Fever, which is endemic in many (particularly) southern hemisphere countries infested with the virus-carrying Aedes aegypti mosquito. There are no current effective treatments for Dengue Fever and control measures largely comprise attempting to reduce mosquito populations.

The collective title ‘PYN7’ refers to a series of single molecules isolated from active fractions of a plant used in China. Professor Lawrence Young, head of the Institute of Cancer Studies at the University of Birmingham is acting as Oncology consultant to Phynova on PYN7. The Institute has conducted a series of studies for Phynova using cell-based assays of anti-cancer activity that demonstrated interesting potential. Phynova plans further mechanism of action studies in the first half of 2008.