The Rest of the Story

I haven't written about neuroscience for a long time.  Since Tuesday, to be exact.  That has got to change.  Yesterday, I found some information about NRP104.  Due to clamoring demand from hordes of readers, all curious about NRP104, I'll tell all I know.

For decades, amphetamine has been one of the two main treatments for ADHD.  Amphetamine and methylphenidate are old molecular entities, so the only marketing action has been in repackaging them into various intermediate and long-acting forms. 

When I read that yet another company is coming up with yet another way to deliver amphetamine to the human brain, I thought there couldn't be much substance to it.  Perhaps I was wrong.  A company called New River Pharmaceuticals has developed what they call Carrierwave™ technology.  Basically, this is a method of modifying existing drugs to alter their pharmacokinetics: where they go in the body, how fast they get there, and how quickly they go away.  Of course we have to have a long Latin-sounding name for that.  (NEJM has a good, free, but somewhat technical review of the clinical implications of pharmacokinetics here.)

In the case of NRP104, they take a molecule of amphetamine and stick an amino acid on it.  That's all.  They take a perfectly good molecule and render it inactive.  That may sound like a bad idea, but it can make sense.  NRP104 is another one of those prodrugs.  It is not active until it undergoes a chemical reaction in the body to make it active again.  In this case, an enzyme sits and waits somewhere, usually in the liver, until the prodrug floats by.  It then snips the amino acid off the amphetamine. 

Other than finding a way to patent something again, after the original patent has expired, is there any benefit?  Perhaps.  The idea is that the body only has a certain amount of the enzyme that converts the prodrug into active drug.  That enzyme operates at a fixed rate.  Thus, the active drug is produced at a steady rate over the course of the day.  In cases where the active drug has a significant abuse potential, the fixed rate of conversion might make the substance less appealing to those who might want to abuse it.  It also might provide some degree of safety in cases of overdose.  This would be effective only if the rate of conversion is in the correct range.  If the prodrug is converted fairly quickly, it might only make the drug safer for those who abuse it, but not make it less appealing to abusers.  If the rate is too slow, the drug will not have the desired effect.  It might just make it hard to sleep at night, without actually improving daytime functioning.  We already have lots of drugs that do that.

New River just reported the results of a phase II study:

A total of 52 children aged 6-12 with Attention Deficit Hyperactivity Disorder (ADHD) were enrolled in a double-blind, placebo- and active- controlled, randomized, 3-treatment, 3-period crossover study that compared NRP104's and Adderall XR's efficacy, duration and incidence of adverse events to placebo.

The primary efficacy endpoint in this study was SKAMP-Deportment (Swanson, Kotkin, Agler, M.Flynn and Pelham rating scale). In the study, patients treated with NRP104 showed a statistically significant improvement on primary endpoint compared to placebo across all three doses (p values <0.0001). We believe that the studies also demonstrated that efficacy results of NRP104 when compared to placebo and Adderall XR when compared to placebo were similar in terms of primary and secondary endpoints and should support the filing for the inclusion of a dose conversion table in the label of NRP104.

The significant therapeutic effects of NRP104 continued throughout the last assessment time point (i.e., 12 hours post morning dose), compared to placebo, suggesting a 12-hour duration of drug action.

Ok, that sound promising.  No doubt they have phase III studies underway.  New River says that, so far, the DEA has not required that the drug be considered a controlled substance.  If that holds up, it will be a big advantage in the marketplace. 

The only problem that I might anticipate with this product is that there tends to be a lot of variability in the amount of enzyme activity from person to person, for any given enzyme.  Some people have a lot of the enzyme, or have a mutated version that works faster than expected (rapid metabolizers).  Some people have multiple copies of the same gene, and produce more enzyme that other people.  Others have less, or have relatively slow-acting version of the enzyme.  In either case, a prodrug might not have the desired effect.  Below is an illustration from the NEJM article, showing this effect for a different drug.  The illustration shows how great the individual differences can be:


Personally, I would like to see the company address this issue before they put the drug on the market.  Regarding the variation in rates of conversion from prodrug to active drug, both the rapid metabolizers and the slow metabolizers might be unusually susceptible to adverse effects.  Rapid metabolizers could develop unusually high peak drug levels after each dose.  Slow metabolizers could have the drug build up with successive doses.  If they could devise a widely-available, reasonably-priced way to identify those people before treatment is attempted, it could save a lot of trouble.  If that is not feasible, then perhaps testing blood levels in people, after they have been on the drug for a while, could serve the same purpose.

Why worry?  Well, at about the same time that New River was reporting the favorable results of their phase II trial of NRP104, Health Canada was in the process of suspending sales of Adderall XR (an extended-release amphetamine).  This was not done in the US, in a move that no doubt will generate some controversy.

There have been 20 cases of sudden death reported worldwide.  Fourteen occurred in children.  These numbers are not large, considering the number of children and adolescents who have taken Adderall.  Of course, there probably have been others, cases that occurred but were not reported.  However, sudden death is so unusual in children and adolescents that I suspect most cases were investigated and reported.   The details are summarized here.  Of note:

Twelve cases of sudden death were reported between 1999 and 2003, all of which were males between ages 7 and 16. Five of the youngsters had significant cardiac risk factors, some of which were identified only on autopsy, such as abnormal coronary artery anatomy or abnormal valve structure. Seven of the youngsters had no abnormality, but at least one had a family history of cardiac ventricular arrhythmias. It also notes that several of the youngsters had unexplained and unusually high levels of the drug in their system, in the absence of any evidence indicating overdose.

The connection is this: several patients had unexpectedly high levels of drug, but were not thought to have overdosed.  If they were people who metabolized the drug slowly, such that it was not entirely cleared for the body after each dose, they could build up higher than expected drug levels. 

There have been many instances in which variations in pharmacokinetics were linked to unexpected outcomes.  Soon, we may be seeing a drug that has kinetics that are more complex than what is seen with the original drug.  This is somewhat speculative, but plausible: let's say there are some people who convert the prodrug into active drug very quickly, but who metabolize the active drug slowly.  Just picture the blood concentration curve in your head for a moment.  What you see is that they will have a certain baseline concentration of the drug in their blood before each dose.  Then, on top of that, they will get an unusually large peak after the dose.  For some drugs, such things don't seem to matter.  But for some, it matters a lot. 

Remember the illustration that shows the wide variation in metabolism of nortriptyline?  When that drug is used clinically, it is quite common to check blood levels of the drug.  It's a test that is widely available.  At this point in time, though, blood levels of amphetamine are not widely available. 

In order to really know whether this effect is going to be clinically significant, one would have to do pharmacokinetic testing in a large number of people.  That probably has not been done yet, since the NRP104 still is in stage II testing. 

Nobody knows, at this point, if amphetamine, when used as directed, actually does increase cardiac risk.  But if it does, then NRP104 could be safer for some people, but more dangerous for others, depending upon their individual differences in drug metabolism.