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LAB ROUNDS research & clinical updat e Harvoni: Why hepatitis C focus is a plus for Benitec With Gilead’s announcement in October of FDA approval for Harvoni, Benitec’s Senior Vice President of Research & Development, Dr David Suhy, explains why putting Hepatitis C in the spotlight is good for Benitec. Hepatitis C: snapshot Hepatitis C is a liver disease caused by the hepatitis C virus (HCV). According to the World Health Organisation, 130-150 million people suffer from the disease worldwide with 350,000 to 500,000 dying each year1. There are about 13 million sufferers in the Americas and Europe, with the highest disease prevalence in the Middle East, Africa and Asia2. In the USA, over 50% of intravenous drug users suffer hepatitis C3, which is spread via the blood. Harvoni: what Gilead says Harvoni is a once-a-day tablet treatment for Hepatitis C Genotype 1, which was approved by the US FDA in October 20144. Harvoni combines ledipasvir and sofosbuvir (trade name Sovaldi) to block replication of the virus. Harvoni eliminates the need to also take Ribavirin and Interferon, previously part of double or triple therapies with Sovaldi, and is currently prescribed to be taken over 12-24 weeks5. Treatment combinations containing Ribavirin and Interferon have been noted to cause fatigue, headache, nausea, insomnia and anemia6 which increased patient withdrawal and decreased cure rates. Harvoni has cure rates of between 99.1% and 94%7 and a treatment period of eight, 12 or 24 weeks. The duration of prescribed treatment depends on the patients’ treatment history, cirrhosis status and viral load; the eight week period could be applied to treatment-naïve patients without cirrhosis and with a low baseline HCV viral load8. While the side effects of Harvoni are said to be less severe than the Ribavirin, Interferon and Sovaldi treatment, the Prescribing Information confirms they still include fatigue, headache, nausea, diarrhea and insomnia9. Contact us: www.benitec.com (02) 9555 6986 When considering the impact of Harvoni on the potential hepatitis C market for TT-034, factors such as cost, compliance, re-infection and mode of action need to be examined. A sizeable price tag In the USA, a 12-week course of Harvoni will cost US $94,500 or US $1,125 per day10 compared to Gilead’s predecessor Sovaldi (US $84,000). “...present focus on hepatitis C serves to hint at the scale of the opportunity for Benitec” For those with private health insurance, the Journal of the American Medical Association estimates that the cost of new HCV therapeutics could increase each person’s premium by up to US $300 per year over the next five years11. For the uninsured in the United States, about 750,000 hepatitis C sufferers receive state-funded healthcare through Medicaid or the prison system. Based on Sovaldi pricing, earlier this year Express Scripts estimated that the USA would foot a bill of US $55.2 billion if all States made that regimen available12. Given the higher price for Harvoni, one would assume the bill for the newer treatment would also be higher. 1.Hepatitis C Key Facts; WHO 2.Ibid 3.High Risk Groups Hepatitis C in the USA; Epidemic.org 4.U.S. Food and Drug Administration Approves Gilead’s Harvoni; Gilead; Oct 10, 2014 5.Ibid 6.Patient Information; Sovaldi; Gilead Sciences; Dec 2013 7.Gilead; Op Cit 8.Gilead; Op Cit 9.Prescribing Information for Harvoni; Gilead; Oct 2014 10.Harvoni wins FDA Approval; New York Times; Oct 10, 2014 11.The Journal of the American Media Association; reported by Seattle Post-Intelligencer 12.State Governments May Spend $55 Billion on Hepatitis C Medications 1 Express Scripts; Jul 17 2014. Harvoni: Why hepatitis C focus is a plus for Benitec Because it has only recently gained regulatory approval, it’s not clear how many US insurance companies will offer reimbursement for the Harvoni treatments. With Sovaldi, some insurers offer cheaper alternatives that have more side effects and less efficacy, and offer the more expensive drug only to the most severe cases13. With Harvoni and other multiple-dose treatments, if patients become re-infected, they will have to commence a new course. This obviously increases the cost and duration of treatment. Benitec’s intention has always been to develop effective drugs that will be accessible in target markets. Whilst it is far too early to be specific, we expect a single dose of TT-034 to be priced competitively to 56-168 doses, the number of pills required for a 8-week or 24-week course of Harvoni. The mode of action of Benitec’s TT-034 is quite different and overcomes the problem of patient re-infection. TT-034 directs patients’ liver cells to continuously produce their own molecules to ‘turn off’ replication of HCV, for as long as the liver cells live. Thus, TT-034 is designed not only to clear the infection from the liver, but to provide prophylaxis and protect the patient’s liver from re-infection by HCV for months or even years, from a single dose. Compliance: reality bites Hep C: a hint of things to come A key factor in treatment efficacy is compliance (continuing to take the drug) and it has to be quite high; for instance, with anti-retroviral drugs for HIV, compliance needs to be 95% or above for the drugs to be effective at suppressing AIDS14. During all clinical trials, patients are very closely monitored, so compliance rates and therefore cure rates are usually very high. It is accepted that once drugs reach the market, compliance tends to drop. Once drugs are approved and out in the community, a wide variety of other factors may come into play that effect compliance: forgetting, being away from home, being busy, changes in daily routine, psychiatric disorders and substance use/abuse15. If patients fail to comply yet wish to be cured, they must wait a period and start the treatment again, thereby potentially doubling the cost, increasing the treatment period and, presumably, skewing the cure rates. For Harvoni, patients must take multiple doses (56, 84 or 168 over eight, 12 or 24 weeks) and maintain high compliance to achieve cure. By contrast, Benitec’s TT-034 for hepatitis C is administered in a single infusion, thus compliance or lack thereof will not be a factor in treatment success. Re-infection: <25% in some populations Another factor for success is patient re-infection. With Hepatitis C in gay men, the re-infection rate is up to 25%16with secondary re-infection reported at 23%17. Contact us: www.benitec.com (02) 9555 6986 Approval of Harvoni has moved hepatitis C, its prevalence and significant cost of cure into the spotlight. However, when compliance and cure rates are put into perspective, the benefits of a lower cost, single dose alternative therapeutic like TT-034 become clearer. The added benefit of protection against re-infection is compelling. The implications for Benitec of a successful TT-034 clinical trial are far broader than hepatitis C. Small molecule drugs like Harvoni are designed to treat one disease. TT-034 is too, but it’s based on ddRNAi, Benitec’s broad platform for genesilencing. Once ddRNAi technology is proven safe in man via the TT-034 clinical trial, it can be applied to many more disease-causing genes, through a simple sequence change. Clearly, ddRNAi has sizable potential beyond hepatitis C. In fact, present focus on that disease serves to hint at the scale of the opportunity for Benitec. This is already occurring: our other inhouse programs based on ddRNAi - hepatitis B, drug resistant lung cancer, age-related macular degeneration - are progressing towards the clinic, by leveraging off the knowledge gained with TT-034, the first in man Hepatitis C therapeutic. David Suhy PhD November, 2014 13.New York Times; Op Cit. 14.Determinants of non-compliance to ARV therapy among adults; JBI Library of Systematic Reviews 15.Ibid 16.Hepatitis C Reinfection Rising Among HIV Patients; Medscape Medi cal News, Jul 11, 2013 17.Hepatitis C virus reinfection incidence and treatment outcome 2 among HIV-positive MSM. PubMed. Oct 2013