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EASL Slides - 94.4% SVR4 Overall 7 years 7 months ago #14555

  • DrJames
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Here's my notes for the presentation and the presentation as a PDF and PPTx

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And here I am giving the presentation with my eyes closed!

--- Title
REDEMPTION-1 is an ongoing open label study assessing the safety and effectiveness of generic direct acting antiviral Hepatitis C medication. This is an interim analysis of the all results available to date.

--- A Global Tragedy
Hepatitis C, Hepatitis B, HIV, TB and Malaria are the 5 major causes of infectious disease death worldwide.

In a breakthrough that rivals the invention of penicillin, drugs that cure hepatitis C, with minimal side effects and high success rates, have reached the market.

Across the world 150 million people are infected with Hep C and it causes over ½ a million deaths each year, but, in what must be one of the greatest tragedies of modern times, these life saving medications are not being deployed on a mass scale.

It is sobering to reflect that more patients died last year than received the new treatments.

--- The Deployment Problem Is Price
The deployment problem is price.

Although the ingredients for a 12 week course of Sovaldi cost less than $100, the US retail price is a $84,000

To put that price in perspective if Apple put the same 100,000% markup on a new iPhone it would cost $1 million dollars.

--- Background
So the staggering prices of these new medications prevent patient access to safe and highly effective treatment.

But… Generic versions are being mass produced for under 1% of the current US retail price, in countries where the patents have been rejected.

And… Under the laws of Australia, the UK, and many other countries, individuals have the right to import a three month supply of medication, for their personal use

--- The Legal Basis Of Personal Importation
Patents provision monopoly rights that are open to abuse, however other laws provision other rights.

Article 60 of the World Trade Organization TRIPS agreement makes small consignments exempt, and in line with Article 60 most countries allow some form of personal medication importation.

The fixhepc website was set up to help patients safely access generic medication and the forum there has over 1000 patients discussing their generic treatment experiences in real time.

--- Methods
When the first patient asked for help, stating he was going to import generics with or without me, I concluded I could improve his safety if the medications he sourced were shipped to me first for testing. The deal was if they passed testing he could take them, and if not they were going in the garbage. The medications tested correctly, the patient took them, and he’s now past SVR24 and cured.

That single patient might have been my only patient, but the news leaked and 1 became a dozen, who in turn became hundreds. Thus was born REDEMPTION.

Consecutive patients were enrolled and assessed pre-treatment, during treatment and then for SVR

The objective was to answer the two key clinical questions – do generics work? and are they safe?

--- Sofosbuvir NMR
For interest here is an NMR spectrum of some generic sofosbuvir. NMR is one of a range of techniques, such as High Performance Liquid Chromatography, Mass Spectrometry and X-ray crystallography that can establish the precise nature and purity of a medication.

--- Over 400 Patients Worldwide
Although REDEMPTION is based in Australia the gp2u Telemedicine platform allowed patients from around the world to enroll

--- Baseline Characteristics
On the right you can see the genotype breakdown with the majority genotype 1, just under 1/3 genotype 3 with smaller percentages of the other genotypes.

448 patients enrolled.

There is a roughly 50:50 split between SOF+LDV and SOF+DCV with just over 10% also using ribavirin

This is a relatively unwell cohort with nearly 50% treatment experienced, over 30% cirrhotic, and a significant number who had previously been rejected from at least one clinical trial.

There was a slight male bias, an average age of 54 and a mean viral load of 2.8 million

--- Viral Response
Let’s look at the on treatment viral kinetics The scatter plot dots are the viral load at various time points, and the size represents the log number of patients. Blue is Ledipasvir and Pink is Daclatasvir.

Unlike the usual reporting which stops at < LLOQ (<15) we have differentiated < LLOD as another data point and I think this makes evident a 2 stage kinetic decay – the first stage is rapid, but the second is substantially slower and it’s this slower second stage that dictates the minimum treatment duration.

The 3 grey lines are from data published in the Lancet in 2014 about the on treatment kinetics for SOF+PEG+RBV. As you can see the response for both the generic combinations used was substantially faster than this demonstrating the impact of effective NS5A inhibition. The difference between the SOF+LDV and SOF+DCV kinetics, where Daclatasvir looks slower, is an artifact due to it’s higher use in GT3 where the kinetics are slower than in GT1. If we look only at GT1 with SOF+DCV we see the response is slightly better that SOF+DCV and it crosses <LLOQ a little earlier.

There was one virological breakthrough.

--- SOF+LDV+RBV for GT3?
So now to the first of the results.

In 2015 Professor Ed Gane published an interesting study about the use of SOF+LDV+/-RBV in GT3

One group – treatment naïve patients who also had RBV did very well with a 100% (26/26) SVR rate.

We’ve duplicated that result with generics suggesting it is repeatable and should perhaps be investigated at a larger scale.

Here we can see that at the end of treatment 99.6% of patients were <LLOQ. One virological breakthrough reduced the result for LDV

The overall SVR4 rate was 94.4%.

Looking at GT1 only the results of LDV and DCV were similar, with the LDV result again suffering from that breakthrough patient (S282T RAV)

--- Published SVR12 Results
Dr Andrew Hill and his research student Anna Savage aggregated all the clinical trials data we could find for the DAA combinations SOF+LDV and SOF+DCV, and they are presented here.

And if we compare this to the results of generics…

--- REDEMPTION-1 Overall SVR4 Results
We don’t see a lot of difference.

The 100% results in GT2,4,5,6 are of course pretty meaningless given the tiny numbers, but for GT1 and GT3 the results are in line with expectations.

We do expect a handful of patients who passed SVR4 to fail SVR12 but don’t expect that to cause a huge change.

--- Patient Safety
No new or unknown side effects were reported with headache, fatigue and insomnia being the most common

3 patients with compensated cirrhosis temporarily decompensated on treatment initiation but continued with treatment

4 patients who enrolled have since died, all from HCC

--- Summary
So in this interim analysis treatment with legally imported generic DAAs produced similar SVR rates to what we would expect from the clinical trials of their branded counterparts.

Doctors prescribing and monitoring patients taking generics can take comfort from the fact that, like the HIV generics that came before them, HCV generics deliver robust clinical results.

--- Conclusions
Generic cure for Hepatitis C is available now for $1000 and works as expected

Given current production costs, $200/patient treatment with SOF+DCV is possible, not in the future, but right now

It’s sad to reflect that at a price of $200/patient the entire world – all 150 million patients - could have been treated for less than the $31.5 billion dollars in profits made from the Sovaldi franchise in the last 3 years.

Without treatment the future for millions of patients infected with HCV looks like this…

--- RIP

Today over 1000 of our fellow citizens will die from a disease we have the power to cure.

We have the power to FixHepC.

The real question is do we have the will power? The will power to think global, but act local, and see cure deployed on a mass scale?

Generics work. Let’s deploy them and wipe Hepatitis C off the face of the planet, just like we’ve done with smallpox and polio.
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