The Scientific Issues Surrounding ZTlido’s Upcoming PDUFA Date

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BACKGROUND WISDOM

ZTlido is the trade name for a patch containing lidocaine 1.8%. The trade name stands for the ‘Z’ero H20 ‘T’transdermal ‘Lido’caine Patch.

The active ingredient in this patch, lidocaine, is a drug that’s often used as an anesthetic/pain reliever. The percentage (1.8%) signifies there is 18 milligrams (mg) of lidocaine for every gram of adhesive material in this patch; with the adhesive material being the substance within which the lidocaine is suspended.

As such, ZTlido is indicated for the treatment of postherpetic neuralgia. This is nerve pain as a result of shingles (aka herpes zoster), a condition caused by the varicella-zoster virus. This virus also leads to the more familiar chickenpox.

Once applied to the body, the lidocaine in this patch passes through the outermost layer of the skin. After doing so, it acts on nearby damaged nerves and minimizes their ability to transmit, or start the transmission of, pain signals to the brain.

PATCH PROPERTIES

ZTlido is a very thin, single-layer, and flexible patch (a benefit to patients applying it on contoured areas of the body). The patch also uses what’s known as hot-melt, pressure-sensitive adhesives. In short, these are substances that can form a sticky and effective bond with the skin upon the application of light pressure.

Furthermore, ZTlido is an anhydrous patch. In other words, its formulation doesn’t need water, helping to minimize the costs of manufacture as a result.

ZTLIDO VS. LIDODERM

ZTlido is meant to be a competitive, improved, yet bioequivalent answer to Endo Pharmaceutical’s Lidoderm, a lidocaine 5% patch indicated for the same purpose as ZTlido.

When compared to Lidoderm, ZTlido is marketed as improving patient compliance (proper use of the medication), decreasing environmental waste, and improving the safety of children and pets.

How so?

Lidoderm contains 700 mg of lidocaine in each patch but only 1%-5% of it is ever absorbed by a person’s body. This means that upwards of 99% (693 mg) of the medication remains unused and is thrown out, needlessly increasing environmental waste and contamination.

Furthermore, ZTlido is engineered to stick to a person’s body even during moderate exercise, helping to improve patient compliance by decreasing the chances the patch will fall off and need replacement.

In contrast to Lidoderm, each ZTlido patch contains only 36 mg of lidocaine. While this seems like a relatively small amount, ZTlido’s manufacturer claims the drug is delivered more effectively than Lidoderm, minimizing the amount of lidocaine needed per patch.

This also means that if a ZTlido patch falls off accidentally, a child or pet who comes into contact with the patch will be exposed to a relatively low amount of lidocaine when compared to Lidoderm. The smaller amounts of lidocaine per patch may help reduce the potential for side-effects as well.

As a result of novel adhesive and delivery mechanisms, ZTlido is a patch that weighs less than, and is half as thick as, a Lidoderm patch.

NDA TIMELINE; SCILEX & SORRENTO

ZTlido’s initial NDA was submitted to the FDA in mid-2015 by Scilex Pharmaceuticals. In May of 2016, Scilex received a complete response letter (CRL) and thus their application was rejected for numerous reasons outlined in the next section.

In August of 2016, Scilex met with the FDA to discuss the CRL and, thereafter, believed it would be able to resubmit their NDA relatively quickly, expecting an FDA action date in mid-to-late 2017.

By late 2016 Scilex was acquired by Sorrento Therapeutics (Ticker: SRNE). The former resubmitted their NDA for ZTlido in late August of 2017 with an expected PDUFA action date of February 28th, 2018.

WHY DID THE FDA REJECT ZTLIDO?

As per the CRL, the FDA mentioned the need for at least the following upon re-submission of the NDA:

  • A new pharmacokinetic (PK) study was requested. PK refers to the ways by which the body absorbs, distributes, metabolizes (chemically changes), and eliminates the drug. In short, Scilex was requested to show what the body does to the drug with a new study.
  • A new 3-month-long animal study analyzing the drug’s toxicity. It’s not explicitly clear if this was recommended or actually required by the FDA.
  • The need to address several issues related to quality assurance.

We go over these in order but do be aware that these are the problems we know about overtly and other issues are, of course, possible.

A NEW PHARMACOKINETIC (PK) STUDY

The FDA requested a PK study to help determine if  ZTlido and Lidoderm are bioequivalent or not.

Scilex completed the additionally requested PK study and announced its results at the end of 2016. The company mentioned that a primary endpoint and a secondary endpoint were met.

They were likely referring to the following two PK/bioequivalence endpoints:

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Endpoint #1: Cmax. This measure refers to the maximum concentration the lidocaine reaches in a person’s blood. If ZTlido’s Cmax is similar to Lidoderm’s, this can help indicate that the two drugs share similar maximal therapeutic effects and/or similar risks of side effects.

Endpoint #2: The total exposure to the drug (a.k.a area under the curve or AUC). This is a reflection of the concentration of lidocaine in the bloodstream over a period of time. It tells us the extent to which a person is exposed to a drug. Generally speaking, when two drugs have similar AUCs, this means they are similarly effective and safe over a longer time-frame.

It should be emphasized that Scilex said that “a”, not “the”, primary endpoint and “a” secondary endpoint were met in their new PK study. These were probably deliberate phrasings.

That’s because the same press release mentioned Scilex was analyzing the same study’s results further to see if any other endpoints were met.

Some news outlets accidentally reported this press release in a manner that implied that all the endpoints were met, potentially misleading some investors.

THE OTHER ENDPOINT: TMAX

It’s unclear exactly which other endpoints were requested by the FDA and investigated by Scilex.

However, given the nature of the study and active ingredient in question, one of these endpoints was almost certainly Tmax. Tmax is the time it takes for lidocaine to reach its maximum concentration in the body.

This is an endpoint for which Scilex was silent about during their initial PK study (for the first NDA), their second PK study for their resubmission of the NDA, and their third PK study for their European bioequivalence (BE) tests thereafter.

Either they failed to demonstrate BE on this point or they didn’t think it was important enough to report on three separate occasions. That may be because Cmax and AUC are often considered to be the more important endpoints in PK BE studies.

The importance and usefulness of Tmax, on the other hand, has been argued back and forth between researchers. For our discussion, this debate is irrelevant.

What’s far more important for us is what the FDA thinks about Tmax. And, to the FDA, Tmax is not an unimportant endpoint for products such as these.

There are multiple reasons for this, including the fact that the FDA relies partly on Tmax to gauge the rate at which a drug is absorbed into the body. If ZTlido is absorbed too quickly or slowly, then the FDA may deem that ZTlido is not bioequivalent.

It’s possible that, despite equivalency with respect to AUC and Cmax, BE cannot be established due to a difference in Tmax.

THIS MIGHT NOT BE A PROBLEM, UNLESS…

If Scilex has failed to demonstrate equivalency of Tmax, then you should be aware this doesn’t completely doom and gloom the chances of FDA approval.

This is because the FDA allows for an out in such a scenario. Scilex is permitted to provide sufficient data (other than AUC or Cmax) to show that, despite a difference in Tmax, the safety and efficacy of ZTlido is not significantly compromised. If it manages to do so, then the FDA may move to approve ZTlido anyways.

Failing that, the FDA will issue a CRL and send Scilex home to reformulate ZTlido, its method of manufacture, or to gather additional safety and/or efficacy data.

There is also plenty of other data the FDA may want to take a peek at other than Tmax, including any important variations found between test subjects as well as the elimination rate constant and the drug’s half-life. Both of these latter measurements, in their own ways, help ascertain how quickly the drug is broken down or cleared by the body.

Significant differences between Lidoderm and ZTlido in any of these could obviously harm the chances of approval. Scilex has not publicly commented on any of them.

WHY THE NEW ANIMAL STUDY?

The FDA also suggested Scilex perform a 3-month-long animal toxicity study prior to the resubmission of the NDA.

Scilex actually performed an animal toxicity study for the initial NDA so it’s unclear why the FDA opined on potentially including another one. Either the FDA deemed the first one inadequate, found a concern, or saw reason enough in a human study to suggest conducting another toxicity study for something unaddressed in the first one.

JUST A HYPOTHESIS

Here’s a working hypothesis for the FDA’s request based on what we know.

One of the initial studies for ZTlido mentioned the fact that various severities of side effects were noted. We also know that ZTlido caused irritation in a manner that was quantitatively worse than Lidoderm. Scilex claimed this irritation wasn’t clinically significant but said nothing of statistical significance.

The outcome of the latter is very important to know because the FDA emphasizes establishing BE in such products using statistical significance as opposed to clinical significance.

Either ZTlido was statistically significantly more irritating than Lidoderm (bad news), Scilex failed to mention that it wasn’t statistically different (why hide a good result?), or the number of subjects in their study was so large that it truly found a statistically significant yet clinically irrelevant event (unlikely).

Another possibility is that the apparent increase in irritation was based on different ways by which such irritation can be measured. One such measurement can show that an increase in levels of irritation is clinically irrelevant while another one will show that it is clinically relevant.

This begs the question of why Scilex would report the increased irritation in the first place, yet try to brush it aside with the clinical relevancy comment, if a better way of measuring it showed no such problems to begin with.

Regardless, this irritation/side-effect issue might imply that if Tmax (or another) endpoint equivalency wasn’t reached, then equivalent safety and efficacy wasn’t established by other means either. Hence the CRL and the need for another PK study, a toxicity study, or even something else that was never disclosed to the public.

THE FDA’S RATIONALE

There’s a reason why, for lidocaine patches such as this, the FDA requires new products to be no more irritating than Lidoderm (or an equivalent medication). This is because a transdermal drug’s safety and even efficacy partially depends on the extent to which it irritates the skin.

In other words, significant irritation of the skin can affect the rate at which a drug is (un)safely absorbed and the extent to which it reaches its site of action (to exert a therapeutically beneficial effect).

By extension, significant irritation might predispose a patient to serious toxic effects that should be addressed in animal models first.

In its own NDA roughly 20 years ago, Lidoderm demonstrated the fact that it was safely absorbed even when applied to inflamed/irritated skin. This is something that ZTlido may now need to prove as well.

While PK studies performed in humans are the most important ways by which bioequivalence is established in lidocaine-based transdermal technologies such as this, the FDA has the legal right to ask Scilex to determine BE via other studies if it finds reason to do so.

QUALITY ISSUES

The final known issues Scilex/Sorrento have to deal with have less to do with any scientific research questions and more to do with quality control and assurance. These concerns, outlined in the CRL, that you should be aware of include:

  1. Providing information about the levels of impurities found in ZTlido in order to ensure they aren’t excessive.
  2. Showing the FDA that the amounts of excipients found in ZTlido are safe as well. Excipients are supposed to be inactive/inert substances that modify the properties of the drug.
  3. Resolving all issues raised by the FDA during facility inspections.
  4. Giving the FDA the necessary information they need on drug quality. This includes assessing the company’s management, design, and purchasing controls.

In other words, the last point boils down to the need for the company to prove that everyone involved in the chain of manufacture, from executive management to suppliers and contractors, has systems and policies in place that assure ZTlido’s quality; and that everyone works actively to prevent any future potential issues.

These systems are critical, for the FDA is unable to routinely inspect and evaluate every facility and process, so it needs reassurance that Scilex has systems in place to do so on its own.

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Read our article disclaimer.

Published: 2/13/2018

Updated on: 2/15/2018 – the article’s content was not altered; only the article disclaimer was modified on this date.

No one associated with this article has any financial stake in, or ties to, SRNE.

2018-12-05T16:12:55+00:00