Apadaz: The Best Case Scenario for FDA Labeling & Approval

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BACKGROUND WISDOM

(Ticker: KMPH) KemPharm, Inc filed an NDA for KP201/APAP in September of last year with an expected decision date on or around February 23rd, 2018.

KP201/APAP is an immediate release (IR) combination product of KP201 + APAP; better known by its trade name of Apadaz. Apadaz is intended for the short term management of acute pain.

APAP is just another name for acetaminophen (aka paracetamol), the active ingredient found in Tylenol, another kind of pain reliever.

As for KP201, this is a chemical called benzhydrocodone hydrochloride, and it’s a prodrug of hydrocodone. Hydrocodone is an opioid/narcotic that is often abused.

The fact that KP201 is a prodrug means that it is an inactive chemical that doesn’t become a functional pain reliever until it is activated by the body’s biochemical processes. Specifically, Apadaz is converted into an active drug via digestive enzymes, proteins that speed up biochemical reactions, found in the intestinal tract.

KEMPHARM MUST MAKE THE CASE

Crushing, grinding, smoking, or vaporizing Apadaz will not release the active hydrocodone. This helps deter the product’s abuse. Other than its potential ability to deter abuse, Apadaz is basically no different than similar products out on the market, such as Norco. This means, from a therapeutic/side-effect perspective, it has no real advantage over well-established competitors.

Ergo, KemPharm must prove to the FDA that Apadaz’s formulation does, in fact, deter its own abuse. If KemPharm succeeds in doing so, it can put abuse-deterrent language on its product label. This will give it a huge competitive advantage as doctors will choose to prescribe it over its well-established, but non-abuse-deterrent, competitors.

If KemPharm fails to prove this, then it’s basically all over.

WHY THE FDA REJECTED APADAZ

Given the opioid abuse crisis in the country, the FDA has acknowledged the need for such abuse-deterrent pain relievers. It even granted Apadaz priority review status in early 2016.

Several months later an FDA advisory panel (FAP) agreed, by majority decision, that Apadaz was an effective pain reliever. Nevertheless, the FAP did not believe that Apadaz deters abuse in any significant way; again by a majority decision.

At least on the point of abuse-deterrence, the FDA agreed with the advisory panel’s decision and issued a complete response letter (CRL) in mid-2016 and thus failed to approve the drug.

KemPharm appealed the decision but their appeal was unsuccessful. Nevertheless, an amended NDA was submitted and accepted with an approval decision date of February 23rd, 2018.

Overall, the main issues that KemPharm needed to address were whether or not Apadaz actually deterred abuse and should be labeled as an abuse-deterrent as a result.

We say this carefully, as press-releases are not always truthful nor fully forthcoming on all of the problems raised in a CRL. There may have been other concerns behind the FDA’s decision as well, such as some (relatively minor) safety concerns specific to Apadaz’s unique make-up.

From hereon, we examine KemPharm’s arguments for receiving abuse-deterrent labeling as well as how likely it is that they have the goods, scientifically speaking, to warrant FDA abuse-deterrent approval the second time around.

CATEGORY 1 LABELING

Let’s start with category 1 labeling; that of abuse-deterring chemical and physical properties that minimize the risk of intravenous (IV) abuse. This category utilizes lab-based studies that test the ease by which a chemical can be manipulated in a way that promotes drug abuse.

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Partly as a result of Apadaz’s intrinsic chemical make-up, it’s very unlikely that Apadaz itself would be abused intravenously; but it has to run the category 1 testing gauntlet anyways. This is because Apadaz might be chemically manipulated in a way that makes it easier to abuse nonetheless.

To keep the very large amount of data brief, KemPharm made the scientific case that it’s quite difficult to extract a usably safe and/or appreciable amount of hydrocodone from Apadaz for IV use in a relatively short space of time. The same could not be said for its comparator drug, Norco.

Overall, KemPharm did quite a bit of due diligence in their testing and their results laid out a pretty solid case for category 1 labeling.

But some alternative testing by the FDA has actually shown that, given a not unreasonable amount of effort, enough hydrocodone could be extracted for IV use. Even safe, store-bought, supplements could potentially be used to this end (with currently unknown effects).

CATEGORY 2 & 3 LABELING

For category 2 and 3 label language, the premise boils down to the following in this case. KemPharm needs to prove, using studies with people, that it won’t be abused by the oral and/or intranasal (snorting) routes.

KemPharm stumbled here. They admitted outright that Apadaz will not prevent abuse via the oral route (which is difficult to prevent for this kind of drug in any event). Yet KemPharm believed that the intranasal route of abuse is adequately important and that they had the relevant data to prove their product prevented intranasal abuse.

This dug KemPharm into a hole because there were some problems with their evidence and reasoning therein.

1. THE FDA DOESN’T AGREE

The FDA generally believes the oral route is the most significant (but not the only relevant) route of abuse for immediate release combination product opioids like Apadaz. There is no solid data to suggest otherwise and KemPharm failed to provide any significant data to the contrary.

Furthermore, the FDA believes that even if a drug deters intranasal abuse, it may not reduce overall abuse via other routes in any significant fashion.

And at least in the case of Apadaz, the intranasal and oral routes of abuse might actually be significantly intertwined.

How so?

Apadaz may not interact physiologically with the airways in any meaningful way to cause a “high”.

Instead, some of the snorted Apadaz will make it to the back of a person’s throat, get swallowed, and then be absorbed into the body via the digestive system. It’s likely that it’s this swallowed portion that will result in the “high” abusers feel when they snort the medication.

In fact, KemPharm’s own studies and results suggest as much.

2. KEMPHARM’S PROOF IS INADEQUATE

Regardless, KemPharm tried to back-up its claim of abuse deterrence with three human-based studies. Two of their studies were, overall, well-designed and credit must go out to them for their honest and significant efforts.

These two studies scored some limited victories. For instance, they managed to show that Apadaz is better than Norco in minimizing some of the biochemical and physiological elements involved in drug abuse and addiction.

However, more important endpoints in these two studies showed that, by and large, Apadaz’s chemical make-up does not help deter its own abuse any better than Norco when taken orally (not unexpected) nor when taken nasally (bad news for KemPharm).

KemPharm tried to lay out the case that, despite these findings, Apadaz deters abuse via the nasal route because the high from snorting probably comes from swallowing the inhaled drug.

By extension, there’s no incentive to snort the drug if you can just swallow the pill to get high. So, in a way, all of this indirectly deters intranasal abuse despite the poor study results. At least, that’s what KemPharm wanted the FDA to believe.

The FDA, of course, remained unconvinced. First, that’s probably because KemPharm never proved conclusively that the high comes from swallowing snorted Apadaz as opposed to some sort of mechanism involving the airways.

Second, and irrespective of that, KemPharm’s own data failed to prove any meaningful difference in drug deterrence between Apadaz and Norco when both were snorted.

THE “BETTER” STUDY

As for the third study, the “better” one in terms of favorable meaningful results for KemPharm, there was a problem. In its methodology, KemPharm failed to use at least two preferred (and important) FDA study design standards from the outset. So this study’s results are questionable, at best, although KemPharm tried to spin it otherwise.

Moreover when a more stringent approach was used to assess the data from the third study (which the FDA is likely to do again), any meaningful benefit even this faulty study found unfortunately disappeared.

Hence the class action lawsuit claiming KemPharm misled investors during the IPO by knowingly conducting a less than ideal study that would likely sink its chances of FDA approval (with respect to abuse-deterrence claims).

CAN KEMPHARM OVERCOME THESE PROBLEMS?

The above was a long discussion but it was necessary to help fully emphasize the fact that KemPharm must overcome quite a few things in order to gain the labeling it wants.

The good news is that Apadaz has a high chance of FDA approval solely based on its efficacy and safety. The bad news is that this alone gives it no competitive advantage over very well-established alternatives like Norco and Vicodin.

Remember, KemPharm has been touting the abuse-deterrent properties of Apadaz, not its ability to better manage a person’s acute pain compared to competitors. Failing to gain abuse-deterrent language on its label, even if approved otherwise, will be a humongous blow.

ROXYBOND THROWS A SMALL LIFELINE

On the positive side of things, the FDA recently approved an immediate-release, abuse-deterrent, narcotic (RoxyBond) for the first time. This occurred after Apadaz’s CRL. For its NDA, RoxyBond provided information that can be used to boost Apadaz’s chances of category 1 approval.

That being said, RoxyBond isn’t a combination product opioid like Apadaz so saying that the former’s label approval is a massive boon for Apadaz’s chances would be misleading.

Intranasal rates of abuse are more profound for single-entity immediate release opioids like RoxyBond. This means, all else equal, the FDA is more interested in intranasal abuse deterrence for RoxyBond than it is for Apadaz.

WHY APADAZ’S CHANCES ARE LOWER THAN ROXYBOND’S

There is a bigger issue here though; and so we’ll put the (counter)-arguments about the relative importance of intranasal abuse for various opioids aside.

The far more important thing is that upon submission of their data to the FDA, RoxyBond had very solid evidence that proved that RoxyBond deterred intranasal abuse in numerous meaningful, patient-important ways. That’s really the key here.

In contrast, Apadaz’s own evidence, which actually stemmed from sound study designs, showed that it does no such thing.

We then have to question how likely it is that, given another quality study of the same meaningful endpoints, Apadaz would find better results the second time around for category 2 and 3 labeling approval. It’s not likely.

In fact, it appears that KemPharm may push for approval by trying to tweak exactly how it phrases its abuse-deterrent language on its product label instead of focusing on trying to prove patient-important outcomes with better studies.

In other words, KemPharm may have realistically thrown in the towel for category 2 and 3.

THE ROUTES APADAZ COULD TAKE TO WIN APPROVAL

So it boils down to this:

  1. It’s likely the FDA will approve Apadaz in terms of efficacy/safety but this offers no long-term competitive advantage to KemPharm.
  2. KemPharm’s best hopes appear to be winning category 1 language on its product label. Even here, we must hope they have better data to allay some of the many concerns raised by the FDA in terms of intravenous abuse potential.
  3. Assuming FDA approval for efficacy/safety, it’s unlikely that category 2 and 3 abuse-deterrent language will be allowed.

#3 is important in a financial way.

Even with category 1 language, Apadaz will be at a disadvantage compared to RoxyBond. RoxyBond is labeled as an IV and nasal abuse-deterrent while Apadaz’s best chances lie solely with IV abuse-deterrence.

Apadaz’s only saving grace may be that it’s a combination product and doesn’t overlap with RoxyBond’s patient base entirely as a result.

This means Apadaz, even with a lower category abuse-deterrent label, can still carve out a significant-enough market share for itself. That’s because combination opioid products like Apadaz are prescribed more so than stand-alone opioids, such as RoxyBond.

Of course, this is a double-edged sword. Because this is the case, the FDA will be less likely to label Apadaz as an abuse-deterrent without significant proof thereof precisely because it will be so widely used if approved as such.

It should be emphasized that the FDA fears mislabeling Apadaz as an abuse-deterrent in such a large market with such a high potential for abuse. A false sense of security is the last thing physicians need when prescribing addictive drugs.

Ergo, the bar that Apadaz must overcome is in some sense higher than that of RoxyBond’s but the rewards are potentially greater.

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Read our article disclaimer.

Published: 2/9/2018

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, KMPH.

2018-12-05T16:13:00+00:00