December 23rd, 2019

FDA Defers Approval of First Long-Acting HIV Therapy, Surprising Everyone

We HIV/ID specialists are lucky. For over two decades, steady progress in HIV treatment brings regular excitement to our field.

Some of these advances are incremental, but others represent major leaps forward. One such example of the latter is long-acting injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) for maintaining viral suppression. This strategy — two injections every 4 or 8 weeks — obviates the need to take antiretroviral therapy daily.

Based on the results of the phase 3 efficacy studies called ATLAS and FLAIR, we know that injectable CAB/RPV is safe, well-tolerated, and (among those who chose to participate in the studies), highly popular. Patient-reported outcomes in study participants consistently showed they vastly preferred the long-acting therapy to the pill or pills they took previously.

It has been widely known for several months that FDA review of this injectable cabotegravir/rilpivirine strategy would take place before the end of this year. Most people (including me) expected FDA approval.

(Jeepers, the treatment even already has a brand name — Cabenuva, which sounds like a beach resort town in Mexico.)

However, recently we learned that the FDA sent a “complete response letter” (CRL) back to the filing company ViiV without approval. The reason?

The reasons given in the CRL relate to Chemistry Manufacturing and Controls (CMC). There have been no reported safety issues related to CMC and there is no change to the safety profile of the products used in clinical trials to date.

With the caveat that we don’t have the actual copy of this “CRL” (what strange code language in this announcement), it’s reassuring that no additional concerns have come up in this review regarding safety.

What’s tricky is the “CMC” part. I confess that aside from understanding what the individual words chemistry, manufacturing, and controls each mean in plain English, I didn’t fully grasp what CMC means when specifically applied to drug approvals.

Fortunately, my local Boston ID colleague (and our former ID fellow!) Dr. Katy Stephenson does:

CMC means chemistry, manufacturing and controls. It’s the regulatory section where you describe how the drug substance and drug product is made and tested for quality control. For example, when a drug is licensed and released with an expiration date, where does that date come from? It comes from product testing by the company and that data is submitted in the “CMC” portion of the FDA application. It even includes info on the packaging.

One can envision how this aspect of quality control could pose challenges for this treatment strategy. Storage, distribution, and packaging of cabotegravir and rilpivirine will be completely different from other antiretrovirals.

Meanwhile, HIV clinicians and our patients will need to wait a bit longer for approval of this regimen. Until we hear more details, we won’t know how long. But the data from clinical trials are solid enough that approval should be forthcoming eventually.

Which will then lead several fascinating questions, and (silver lining) we now have a bit more time to think about them:

  • What proportion of those who are suppressed on simple therapy (one or two pills a day) will want to make the switch?
  • The clinical trials only included people with no treatment failure or resistance — will we expand the treatment beyond this group?
  • What will it cost?
  • Will it require prior approval? If so, how will we make the case to the payers for a person who is doing well, which will by definition be essentially all the eligible patients?
  • How will we “operationalize” it in the clinic? (Just writing “operationalize” gives me, a college English major, substantial pain — but it hurts a little less when I put it in quotes.)
  • What pharmacies will dispense it?
  • Will it be placed on hospital formularies? (Thinking probably not.)
  • Is the oral lead-in necessary?
  • What will we do about people who miss doses, or are lost to follow-up?

In other words, when — not if — CAB/RPV gets approved, this will be quite a bit different from any HIV treatment we’ve had before, with all sorts of questions and challenges.

Meanwhile, for those of you clinicians working the holidays, here’s what it’s like for us ID doctors:

4 Responses to “FDA Defers Approval of First Long-Acting HIV Therapy, Surprising Everyone”

  1. Tobias Pusch says:

    What a surprise!
    HIV med trials have become so standard and predictable. the FDA is like a volatile stock that you can’t predict it seems.
    we have to wait for details if minor tweaks will suffice or if this is a major “NoNo” that the FDA discovered.
    while some people (Gilead stock holders) will take a deep joyful sigh, the reminder of us are taken for a ride and progress is stalled for a while – manufacturers will await of what went on before enthusiasm continues with injectables for PreP etc.
    it never gets boring…

  2. Jeff Berry says:

    Thank you Paul! I saw the announcement right before I went on holiday break, and wondered what it was about, particularly when the data in the studies looks so good. This makes it much more clear and understandable, and will help me when explaining it to people who are asking what it all means. Thanks again!

  3. Buster says:

    Knowing the FDA, I just wonder if politics or loyalty to a competing pharma company has something to do with this rejection….
    Gilead money…?

  4. Allister says:

    What does this mean for European approval? Is it likely to slow things down at the EMA, or will they have completely different standards?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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