Research & Development
Hepatitis C
PYN17 to Relieve the Symptoms of Chronic Hepatitis C (CHC)
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 five 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 being planned.
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”
PYN18 for Hepatitis C Virus (HCV) and Dengue Fever Virus
In contrast to Relivergen™, PYN18 is a potential treatment for reducing the activity of the hepatitis virus. PYN18 is a single plant extract that has shown anti-viral activity against HCV in pre-clinical tests. Phynova recently screened several different fractions of this extract and found that one in particular showed very distinct activity against the hepatitis C virus in a surrogate viral replicon assay. PYN18 showed good antiviral activity, with EC50 value of 2.5μg/mL and EC90 of 7μg/mL. Additionally, PYN18 had a large therapeutic window with the first signs of cytotoxicity only being evident at almost eighty times the effective concentration.
In addition to its activity against HCV, PYN18 has shown significant in vitro activity against the dengue, another flavivirus. In vitro screening of PYN18 against dengue virus showed potent activity against the virus with EC50 values of <1.2μg/mL. Flow cytometry and real time-PCR indicated that PYN18 inhibited the production of infectious virus rather than total viral levels suggesting that PYN18 was not targeting viral absorption, replication, formation or secretion of progeny virus. PYN18 appears to interfere with viral maturation such that progeny virus is not infective to host cells. Such a mechanism is beneficial in acute viral infections as it slows the progression of the virus sufficiently to allow the host organism to mount an immune response.