Hi ####,

With GT2 pretty much anything with Sofosbuvir is likely to be curative.

The original trials used Sofosbuvir+Ribavirin in all genotypes. The results we excellent in GT2 so although things like Sofosbuvir+Ledipasvir became the default for GT1, the treatment guidelines for GT2 stayed with Sofosbuvir+Ribavirin. Now to understand exactly why you need to understand this.

When Pharmasset invented Sofosbuvir (an NS5B inhibitor) they were working with Bristol Myers Squib who had a drug called Daclatasvir – a pan-genotypic NS5A inhibitor.

When Gilead bought Pharmasset they cut off relations with BMS and used their own NS5A inhibitor – Ledipasvir – and thus was born Harvoni. Now Ledipasvir does not work for GT2 or GT3 but with GT1 being the most common genotype…..

With the price of both Sofosbuvir and Daclatasvir being very high few trials were done with it. Couple that with GT2 being <10% and there is/was not that much data about it outside GT3. When we started using it in GT2 the total published trials data was about 49/50 SVR12 - encouraging but small numbers. The largest single trial was 22/22. We currently have 33/33 so it clearly works well - somewhere in the high 90s.

Velpatasvir is Gilead's Daclatasvir knock off. On paper it is 25 times stronger, but it is only absorbed about 1/4 as well, but it is given at a 50% stronger dose so practically speaking it's probably about 10 times stronger. This is just enough to make a significant difference because resistant variants are usually 10x 100x or 1000x resistant - ie you need 10x 100x or 1000x as much drug to do the job so for a new drug to be "much better" it needs to be 10x or 100x more potent than an old drug.

The only practical problem with Velpatasvir is that the only data we have comes from the drug company and we know this is always the best case data. For example, Harvoni was supposed to give a 97% SVR rate in treatment-naive low fibrosis GT1 patients but when the Veterans Administration gave it to 4200 veterans the SVR rate was 91.3%

With Velpatasvir only getting approved in July last year the first of the real world SVR12 results are just starting to arrive and nothing has been published. I expect the results to be good, but also expect they may not quite live up to the values quoted for the trials - nothing ever does.

So getting to where we are now. Sofosbuvir+Daclatasvir clearly works well and has a good real world track record. Sofosbuvir+Velpatasvir should be just a little better, but that remains to be proven outside clinical trials. Either option is likely to deliver SVR.