Nektar Therapeutics: Old Company, New Drugs

Near the end of March 2017, Nektar Therapeutics ($NKTR) will present data from their most recent Phase 3 trial. Nektar has already brought two drugs through the entire FDA process, so this is not their first rodeo.

As I’m sure you’ve heard, prescription drug abuse is becoming a huge problem across the world. Nektar’s newest drug, under the working title NKTR-181, is supposed to be an abuse-resistant opioid. If things go well, NKTR-181 will start to take market share away from drugs like oxycodone and morphine.

The success or failure of the NKTR-181 Phase 3 trial will hinge on two things:

  1. Whether it is at less risk for abuse than other opioids
  2. Whether it can significantly decrease pain (versus a placebo)

With that in mind, let’s dive into the data.

Question 1: Is NKTR-181 less likely to be abused?

The short answer to this question is “probably.” The ultimate answer to this question can only really come from seeing how the public reacts to the drug, but the researchers have done what they can by testing rats.

In the NKTR-181 Phase 1 trials, the researchers found that NKTR-181 probably enters the central nervous system (or “CNS”) much more slowly than drugs like Oxy or morphine. The idea here is that the “high” feeling from oxycodone comes from how rapidly it hits the CNS. If NKTR-181 takes hours (instead of minutes) to hit you, you’re much less likely to feel high from it.

NKTR enters the CNS much more slowly than oxycodone
From “NKTR-181 efficacy in multiple preclinical models of pain”, Choi et al.

The researchers also found that rats will stop trying to get NKTR-181 at about the same time that they will stop trying to get saline. Graph A below shows that if you make a rat press a lever more than 25 times to get NKTR-181, the rat will give up. For oxycodone, on the other hand, the rat will keep pressing that lever. Graph B shows that if you take a rat trained to press a certain lever when it “feels” oxycodone, the rats will only start pressing the correct lever once they get a pretty high dose of NKTR-181. That’s a bit dense, but essentially it means that it takes a lot of NKTR-181 to make a rat feel like it does on just a little Oxy.

Rats are much less likely to keep self-administering NKTR-181
From “NKTR-181 efficacy in multiple preclinical models of pain”, Choi et al.

On the whole, these are all reasonable ways for researchers to say that NKTR-181 is probably less prone to abuse and addiction than oxycodone. Self-administration and drug-discrimination studies are both very common in behavioral research. On to question 2.

Question 2: Does NKTR-181 significantly decrease pain (versus a placebo)?

This is where I got a little more worried.

The Phase 2 study design was a little curious, but not unusual for opioids. Every patient in the study started by taking the drug to establish how much of the drug they needed to decrease pain. After this short “titration” period, some of the patients switched from the drug to placebo. This is called a “withdrawal” study, because the researchers withdraw the drug and replace it with a placebo.

NKTR-181 failed the Phase 2 trial. It failed because when patients withdrew to the placebo, their pain never came back. This was great for the patients, of course, but not great for the researchers at Nektar Therapeutics. Such an event is actually not uncommon in Phase 2 opioid trials, as the trials tend to be pretty short and the patients don’t have a chance to rebound.

To their credit, the researchers noted all of this and doubled the length of the Phase 3 trial. Making the trial twice as long gives patients a lot of time for their pain to come back, and should take care of the issue that tanked the Phase 2 trial. However, the Phase 3 trial is also testing a different type of pain.

Low-back pain – the type of pain being treated in the Phase 3 trial – is probably the trickiest type of pain to treat. In many cases, patients who have real, measurable lower back disorders like bulging discs will be completely pain free. In other cases, patients who have no discernable pathology will suffer from chronic lower back pain. As such, low-back pain is also one of the most responsive types of pain to placebo treatments. I can remember at least one recent study (Carvalho et al., 2016) which found that giving patients a placebo and telling them it was a placebo still had a measurable beneficial effect on lower back pain.

All of that makes me worry that the final study is going to have the same placebo problem that caused the Phase 2 trials to bomb.

Conclusion: The NKTR-181 Phase 3 study will probably be long enough

I’m a little worried about the Phase 3 study, since they are using low-back pain and following the same withdrawal design that flummoxed the Phase 2 study. However, doubling the length of the trial will probably be enough to help NKTR-181 reach significance. I’m also encouraged by the fact that – as the researchers pointed out – only 3% of the patients in the Phase 2 trial were unable to achieve pain relief.

Prediction: Phase 3 Pass

Although I still have concerns about using lower back pain for the pivotal trial, a length of 12 weeks is probably enough to eliminate the weird placebo rebound issue that buggered Phase 2. With that, NKTR-181 answered both of my questions and I think there’s better than even odds of a pass.




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