New FDA Approval: Trogarzo

New FDA Approval: Trogarzo

Drug

Ibalizumab-uiyk

Indication

In combination with other antiretrovirals, Trogarzo is indicated for the treatment of HIV-1 in heavily treatment-experienced adults with multi-drug resistant HIV-1 who are failing their current therapy. 

Put another way, this is salvage therapy. Or a treatment of last resort. 

How it Works

This is the cool part.

Trogarzo is the first monoclonal antibody on the scene to treat HIV. For a long time, drug development has focused on the ways we already knew how to stop HIV. We got new integrase inhibitors, new NRTIs, new NNRTIs. Trogarzo is the first HIV drug with a novel mechanism of action to be approved in something like 10 years. 

How does it work?

The short answer is that Trogarzo blocks HIV from getting inside your CD4+ T-cells.

But I wouldn't be me if I didn't also give you a long answer.

To really understand how Trogarzo prevents HIV from entering your T-cells, you have to first understand the usual process HIV uses to get itself inside.

 Your T-cell after HIV has attached to it ( Image )

Your T-cell after HIV has attached to it (Image)

In a nutshell, a glycoprotein on the viral envelope of HIV (gp120) binds to a CD4 receptor on your T-cell. That's called attachment

This new gp120/CD4 complex causes a conformational change of CD4 receptor, which allows gp120 to also bind to a second receptor on your T-cell.

This second receptor is called a co-receptor, and if HIV doesn't bind to it, it can't get into your T-cell. 

BTW, the co-receptor is either chemokine receptor-5 (CCR5) or CX chemokine receptor-4 (CXCR4). Which one? It depends on you. A trophile test can be performed to find out which receptor you're working with.

Some of us have CCR5 receptors on our T-cells, and some of us have CXCR4. Some of us actually have both (this is called dual or mixed trophic). 

You may also remember that we already have a drug that inhibits HIV binding to CCR5. Prior to the approval of Trogarzo, that drug (maraviroc) was the only drug used in HIV therapy that had a human target.

Anyway, so once HIV's gp120 has bound to both CD4 and CCR5 (or CXCR4), another protein from the HIV envelope (gp41) inserts into the T-cell membrane. This causes fusion of the viral envelope and the T-cell membrane, and ultimately HIV enters the cell. You may also remember that we have a (rarely used) drug named enfuvirtide that inhibits this step. 

Got it? Good.

So Trogarzo is a humanized monoclonal antibody (remember, the 'zu' part of the name ibalizumab tells you it's humanized) that binds to your CD4 receptor. Specifically, it binds to domain 2 of CD4. Why does that matter? Because your macrophages (and other MHC Class II cells) bind to domain 1.

Remember that CD4 is an important receptor for your T-cells. There's a lot of downstream cytotoxic functions of your immune system that we wouldn't want to block. These patients have HIV, so they already have a suppressed immune system. We don't want to make that worse. So the challenge here is to find a way to stop HIV from binding (or getting into) your T-cell, while allowing your T-cell to still carry out its normal immune functions.  

And by binding specifically to domain 2, Trogarzo seems to fit the bill. Your other immune cells can still bind to domain 1 and do their thing. Interestingly, HIV can also still bind to your CD4 receptors. So Trograzo doesn't actually stop HIV from binding to your T-cells. It stops the step that happens after binding (where CD4 goes through a conformational change so that HIV can bind to it's CCR5 co-receptor). 

Pretty cool, huh?

Notable Adverse Effects

All in all, Trogarzo seems very well tolerated. The most significant adverse effect seems to be on your wallet (we'll get to that in a bit)...

In term's of "actual" side effects, the most common reported (>5%) are diarrhea, dizziness, nausea, and rash. 

It's a monoclonal antibody, so of course there's always a risk of an infusion reaction, but severe rash was only reported in 1 patient. 

Additionally, Immune Reconstitution Inflammatory Syndrome (IRIS) is a potential serious concern. In the clinical trials, IRIS only occurred in one patient...but then again, Trogarzo has only been studied in 292 people so far. 

But really, that's about it. Significant immunosuppression hasn't been noted (as mentioned above). There aren't any expected drug interactions (though that hasn't been specifically studied as of yet). 

So compared to some of our other drugs for HIV (I'm looking at you, zidovudine), Trogarzo seems pretty well tolerated.

Current Place in Therapy

And now the fun part. Where exactly does Trogarzo fit in?

As noted way back at the top of this post, it's only indicated for salvage therapy at this point (and it's not monotherapy, you still need a complete HAART regimen). So think of Trogarzo for your heavily "treatment-experienced" HIV patient that has failed multiple regimens and/or has a high mutational burden. 

Why is that? Well, for a lot of reasons. Let's start at the top with it's dosing. As a preface, remember that these are all IV doses and have to be administered in a health care facility such as an infusion clinic. 

You give a 2000 mg load followed by 800 mg IV every 2 weeks. So automatically, when you sign on for Trogarzo, you're signing on for a visit to the infusion center every 2 weeks for life or until treatment failure. In addition to the time of the infusion, you're also going to need to be monitored after the infusion (because of the risk of infusion reaction). That's an additional 1 hour of waiting for your first dose, but it reduces to 15 min for your subsequent doses. 

What's worse. If you miss one of those maintenance doses by more than 3 DAYS, you have to re-load the patient. Think about that, only 3 days. That's just a scheduling mishap and a 3 day holiday weekend away from messing with your therapy. 

Alright, so the dosing schedule more or less sucks. How effective is it?

After 24 weeks, only 43% of patients achieved suppression of HIV viral load (you can read more about that in our guide here). At first flush, that seems bad. But remember the treatment population you're working with. These are people that have failed everything else. It's salvage therapy. We don't really have any other options. In my opinion, 43% is better than 0%, so that's not so bad. Additionally, there doesn't seem to be any cross-resistance with other HIV drugs, so even patients with a high mutational burden can benefit from ibalizumab. 

But what about the cost? How much does Trogarzo cost?

 The WAC price is wack ( Image )

The WAC price is wack (Image)

Holy crap is ibalizumab expensive. The Wholesale Acquisition Cost (WAC) is right around $118,000 annually.

By the time you add on a few other drugs to make a complete HAART regimen, you're looking at a whole lotta money.

Per Lexicomp, each 200 mg vial weighs in at $1362.00 (so you REALLY want to avoid having to re-load...again, you've gotta keep the patient's infusion schedule on point). That being said, almost no one pays the WAC price. 

Also, the WAC price of $118,000 annually doesn't factor in rebates and other price reductions. To their credit, Thera Technologies has said that "the majority of patients will pay less than $25 per infusion in out-of-pocket costs for Trogarzo."

Of course, even if the patient isn't paying all of that extra money, someone is. And through increased healthcare costs, we all are paying for it eventually. That money doesn't just come from a magical pot of gold. 

But that's a conversation for another day and another post. 

For now, if you're one of the ~25,000 people with multi-drug resistant HIV, you've got a new treatment option in ibalizumab (as long as you're an adult, Trogarzo hasn't been studied in peds yet). This was deemed important enough by the FDA to give Trogarzo Fast TrackPriority Review and Breakthrough Therapy designations. It also got an Orphan Drug designation.

So, for salvage therapy, when you don't have any other options, Trogarzo seems like a decent step forward in HIV treatment. 

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