New FDA Approval: Vemlidy

New FDA Approval: Vemlidy

Drug

Tenofovir alafenamide [Vemlidy]

Indication

The treatment of adults with chronic hepatitis B virus (HBV) with compensated liver disease

Note that Vemlidy is NOT indicated for HIV infection at the time of this writing (1/12/17)

Otherwise, you can think of Vemlidy as a more "hipster" version of Viread (tenofovir disaproxyl fumarate). 
 

I feel like this drug already exists...

We've written about this before, but it kind of does already exist. Vemlidy is the latest in a series of "tenofovir 2.0" drugs. That list now also includes: 

  • Descovy (emtricitabine + tenofovir alafenamide) 
  • Odefsey (rilpivirine + emtricitabine + tenofovir alafenamide)
  • Genvoya (elvitegravir + cobicistat + emtricitabine + tenofovir alafenamide)

So what's the deal?

Up until now, we've used tenofovir disoproxyl fumarate (TDF) in HIV and HBV treatment (remember that tenofovir also covers HBV). In fact, TDF has been one of the more commonly used agents in both disease states. It's indicated as monotherapy for chronic compensated HBV, and it's a common part of the NRTI backbone that constitutes HAART therapy.

*If you want more information, here's our super handy article on HIV

Anyway, suffice it to say, we have a lot of data (from a lot of patients) with TDF. And it's very well tolerated. But it has two common strikes against it. 

  1. It can worsen renal function -- even leading to the rare-but-serious Fanconi Syndrome (the same Fanconi Syndrome you can get by taking expired tetracyclines).
  2. It can cause bone loss 

Both of those can be legit side effects...especially in a patient predisposed to kidney failure and/or bone loss. Especially when you consider the "chronic" nature of well-managed HBV and HIV treatment. Patients could be taking tenofovir for decades.

So, Gilead has been on a sort of mission to rebrand and reformulate all products with tenofovir. Not coincidentally, the patent on TDF happens to expire this year (what, me cynical?). 
 

How it Works

For starters, realize that both TDF and the new tenofovir alafenamide (TAF) are prodrugs. They deliver the active drug (tenofovir diphosphate) to liver cells infected with HBV and to CD4 cells infected with HIV. The difference is that TAF is a lot better at getting into liver cells and CD4 cells. A lot better. 

The dose of TDF in every available formulation is 300 mg.

The dose of TAF in every available formulation is 25 mg.

So, for less than 10% of the original dose of tenofovir, you're getting the same efficacy in both HBV and HIV. And because you've got less than 10% of the dose floating around in the blood stream, those nasty side effects of kidney failure and osteoporosis are less likely to occur. 

In terms of what TAF does once it's actually inside of an HBV or HIV-infected cell....

Just like TDF, TAF is a Nucleotide Reverse Transcriptase Inhibitor (NRTI). So as the HIV (and HBV) virus is replicating, NRTIs insert themselves into the viral genome. They "look" just like the regular nucleotides that are supposed to be there. But they aren't functional. 

So viral replication fails, and HBV and HIV become sad pandas.

  

Notable Adverse Effects

TAF is pretty similar to TDF across the board. I mean, at the end of the day it's the same drug, right? Even when you look at the adverse event and discontinuation rates in the Vemlidy trial, they're practically identical. Vemlidy had a 1% discontinuation rate compared to 1.2% for Viread (TDF).

In fact, in the Viread vs. Vemlidy trial, Vemlidy had slightly better success at normalizing ALT levels (indicating better efficacy at stopping liver damage). 

So you can think of Vemlidy as similar to its cousin, Viread. Vemlidy has the same Black Box Warning for lactic acidosis and hepatomegaly/steatosis. 

We've written about the improved bone and renal side effect profile previously when we covered Descovy, so instead of re-creating the wheel, here's the tl;dr from that...

Early data is decent. In one study where 1436 participants switched from TDF to TAF, there was an increase in bone density of 1.79% in the TAF arm (compared to a decrease of 0.28% in the TDF arm). As for renal function, there were also improvements in urine protein : creatinine ratio (a decrease of 21% for the TAF arm). They are using "different" markers for renal function because this particular study was done with Genvoya. Genvoya contains the PK enhancer cobicistat. Cobicistat can increase serum creatinine (but does not seem to actually cause kidney harm). 

 

Current Place in Therapy

Again, let me emphasize that Vemlidy is currently only indicated for HBV. That being said, whether it eventually gets approved for HIV or not, you know it's going to be used there. Gilead has already established that TAF works with the combination drugs Descovy, Genvoya, and Odefsey. Vemlidy now will let practitioners use TAF without attaching it to emtricitabine. 

When we first wrote on Descovy, I wasn't sure what the final place in therapy was going to be. Gilead doesn't seem to be going for all of the indications that TDF has (probably because that costs a lot of money and they don't need to). As an example, Descovy is still not indicated for pre-exposure prophylaxis (PrEP), whereas Truvada is. 

From what I've seen (disclaimer: I'm not a purchasing agent, so I can only look at list prices), Gilead is pricing the new TAF formulations at the same price as current brand TDF. That definitely helps soften the financial impact a little, but of course with TDF losing a patent this year it remains to be seen where the difference in price between TAF and TDF will end up. 

In terms of the side effect profile, we will soon have more post-marketing data to evaluate how clinically meaningful the adverse event rates are for TAF vs TDF. Vemlidy not needing a renal adjustment until CrCl < 30 ml/min is a real benefit compared to TDF's 50 ml/min, especially considering the chronic nature of HBV and HIV. 

From my anecdotal experience, I've seen increasing amounts of subscribers moving to TAF formulations. Right now, that makes complete sense (and is a savvy business move by Gilead). If TAF and TDF cost exactly the same, but TAF is better tolerated, why wouldn't you start your patient on that? 

Will it still be worth it in a few months when TDF generics start coming out? I suspect for some patients (elderly, pre-existing kidney/bone disease etc...) it will be. For a young, newly diagnosed and otherwise healthy patient with HBV or HIV...maybe, maybe not. 

For your convenience, here's a handy list of the "cousins" that currently exist. The TAF brand is on the left, and the TDF brand is on the right:

  • Vemlidy = Viread
  • Genvoya = Stribild
  • Odefsey = Complera
  • Descovy = Truvada

 

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