NRP104 Abuse Liability Studies

By robin_himself · Jun 19, 2006 · ·
  1. robin_himself

    New River Pharmaceuticals Inc. (Nasdaq: NRPH) announced today that it anticipates that results will be presented from its three clinical abuse liability studies on NRP104, a compound being developed as a treatment for attention-deficit/hyperactivity disorder (ADHD).

    Dr. Donald Jasinski, Professor of Medicine, Chief Center for Chemical Dependence, Johns Hopkins Bayview Medical Center, the principal investigator for the three clinical abuse liability studies, is expected to present results from the studies in two separate presentations at the annual meeting of the College on Problems of Drug Dependence (CPDD) in Scottsdale, Arizona.

    Data from the A01 study and the top line data on the A03 study will be presented at an oral presentation scheduled to begin Sunday, June 18 at 1:45 pm. MST. The A01 presentation, Pharmacokinetics of oral NRP104 (lisdexamfetamine dimesylate) versus d-amphetamine in healthy adults with a history of stimulant abuse, will discuss the pharmacokinetic effects of NRP104 in stimulant abusers. The A03 study, Study to Evaluate the Likeability, Safety, and Abuse Potential of NRP 104 in Adults With Histories of Stimulant Abuse, evaluated the likeability of NRP104 compared to positive controls and placebo in stimulant abusers. Data from the A02 study, Safety, Tolerability and Abuse Liability Study of Intravenous NRP104 in Adults With Stimulant Abuse Histories, will be presented at a poster session scheduled to begin at 1:30 p.m. MST on Tuesday, June 20.

    Data from the three studies have been submitted to the FDA as part of the new drug application for NRP104 as a treatment for pediatric ADHD. The company anticipates that these data, along with all the other clinical and non-clinical abuse liability studies conducted by New River, will help inform the FDA and the U.S. Drug Enforcement Agency in assigning an appropriate controlled substance schedule to NRP104. NRP104 has not been scheduled for its use during clinical trials, although the DEA is expected to assign a schedule before the drug is made available for commercial sale.

    Under review by the U.S. Food and Drug Administration as a potential treatment for pediatric ADHD, NRP104 is the subject of a collaboration agreement between New River and Shire plc (LSE: SHP; Nasdaq: SHPGY; TSX: SHQ).

    New River and Dr. Jasinski plan to organize a conference call several business days following the presentations at CPDD to elaborate upon the studies and their results. Details regarding the conference call will be provided in a later press release.

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  1. robin_himself
    Swim's questions are: "what is NRP104?" "can it be used recreationaly?" if yes... effects, dose etc please
  2. robin_himself
    I'll awnser it myself actually :p

    NRP104, is a conditionally bioreversible derivative (CBD) of amphetamine, a stimulant widely used to treat ADHD. ADHD is a well-studied childhood psychiatric disorder that has been recently recognized in adults as well. ADHD interferes with an individual's ability to regulate activity level and behavior and to sustain focus on tasks in developmentally appropriate ways. Estimates of the number of children affected by ADHD vary, but the American Psychiatric Association estimates that 3% to 7% of all children are affected with the disorder. According to Frost & Sullivan, research indicates that rates of treatment fall at the lower end of that range, suggesting that many children with the disorder may go undiagnosed or untreated. ADHD has only recently been recognized in adults, but Frost & Sullivan estimates that 4% of adults in the United States, or approximately 8 million people, have the disease.

    Treatments for ADHD have traditionally consisted of behavioral modification, drug therapy or both. Drugs used to alleviate the symptoms of ADHD are broadly segmented into stimulant and non-stimulant therapies, with the stimulant therapies dominating the market. Common stimulants are methylphenidate (Ritalin®, Concerta®), dextroamphetamine, pemoline (Cylert®) and a combination of four different amphetamine forms. Also recently approved to treat ADHD is a new type of non-stimulant medication such as atomoxetine hydrochloride (Strattera®). Stimulants are more widely prescribed than non-stimulant alternative therapies.

    We are developing NRP104 as a CBD of amphetamine for the treatment of ADHD. NRP104 is an amphetamine conjugated to a specific amino acid. NRP104 is intended to provide better overdose protection and a reduced potential for addiction than currently-marketed amphetamine products while providing effective treatment of ADHD symptoms when taken as directed. We also believe NRP104 may minimize the possibility of a patient abusing the drug and the risk of drug diversion.
  3. robin_himself
    NRP104 Pipeline Update, New Old Drug for ADHD


    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.
  4. robin_himself
    Abuse Liability Study Results Lisdexamfetamine Dimesylate (NRP104) Presented At CPDD

    Abuse Liability Study Results Of Lisdexamfetamine Dimesylate (NRP104) Presented At CPDD

    Shire plc (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) announced that results of three abuse liability studies with lisdexamfetamine dimesylate (NRP104), an investigational drug for the treatment of ADHD, were presented last week at the 68th annual meeting of the College on Problems of Drug Dependence (CPDD) in Scottsdale, AZ. Principal investigator Donald Jasinski, Professor of Medicine, Chief Center for Chemical Dependence, Johns Hopkins Bayview Medical Center, presented these results.

    New River Pharmaceuticals Inc. (NASDAQ: NRPH) designed lisdexamfetamine dimesylate as an inactive prodrug in which d-amphetamine is bonded to l-lysine, a naturally occurring amino acid. Lisdexamfetamine dimesylate remains inactive until converted and active d-amphetamine is gradually released. On January 31, 2005, New River signed a collaborative agreement with Shire to develop and commercialize the product and on December 6, 2005, filed a New Drug Application with the U.S. Food and Drug Administration to evaluate lisdexamfetamine dimesylate for the treatment of ADHD. This application is currently under review.

    Results of "Pharmacokinetics of oral NRP104 (lisdexamfetamine dimesylate) versus d-amphetamine in healthy adults with a history of stimulant abuse"

    The A01 study was designed to evaluate the safety, tolerability, and abuse liability of lisdexamfetamine dimesylate in twelve healthy adult volunteers with histories of stimulant abuse.

    In this single blind, placebo- and active-controlled, single-dose escalation study, lisdexamfetamine dimesylate tended to be less euphoric than d-amphetamine sulfate 40 mg, and had a later peak effect. The systemic exposure to active d-amphetamine sulfate (AUC and Cmax) was dose proportional following a single administration of lisdexamfetamine dimesylate in doses between 30 mg and 130 mg and was attenuated between 130 mg and 150 mg. Overall, doses of lisdexamfetamine dimesylate from 30 mg to 150 mg were well tolerated in healthy adults with previous history of stimulant abuse.

    Results of "Abuse liability of intravenous L-lysine-d-amphetamine (NRP104)"

    The A02 study was designed to evaluate the safety, tolerability and abuse liability of intravenously administered lisdexamfetamine dimesylate in twelve healthy adult volunteers with histories of stimulant abuse. In this double-blind, three-way crossover study, 50 mg lisdexamfetamine dimesylate taken intravenously produced a lesser degree of euphoria or amphetamine-like subjective effects, when compared to a molar weight-basis equivalent amount of 20 mg d-amphetamine sulfate taken intravenously. At the end of the study, when participants in a second cohort were asked which treatment they would take again, six participants chose intravenous d-amphetamine sulfate, two chose none of the treatments, and one chose lisdexamfetamine dimesylate.

    Results of "Study to Evaluate the Likeability, Safety, and Abuse Potential of NRP104 in Adults With Histories of Stimulant Abuse"

    The A03 study was designed to evaluate the "likeability" of lisdexamfetamine dimesylate compared to placebo and two active controls (d-amphetamine sulfate 40 mg, a Schedule II stimulant, and diethylpropion HCl 200 mg, a Schedule IV stimulant) in thirty-six volunteers with histories of stimulant abuse. In this double-blind, randomized, placebo and active cross-over study, lisdexamfetamine dimesylate (50 mg and 100 mg) produced liking effects that were not significantly different from placebo and were less than d-amphetamine sulfate 40 mg and diethylpropion HCl 200 mg with respect to the primary end point (DRQS Liking Score). The amphetamine content in lisdexamfetamine dimesylate 100 mg is equal to that of d-amphetamine sulfate 40 mg on a molar weight basis.

    In the same study, a higher dose of lisdexamfetamine dimesylate (150 mg) produced liking effects that were significantly greater than placebo. The liking effects of lisdexamfetamine dimesylate 150 mg were not statistically significantly different from either d-amphetamine sulfate 40 mg or diethylpropion HCl 200 mg, although the amphetamine content in lisdexamfetamine dimesylate 150 mg is 50 percent more than the amphetamine content of 40 mg of d-amphetamine sulfate on a molar weight basis. Also, lisdexamfetamine dimesylate 150 mg demonstrated a delay in peak liking effects by two hours when compared to both d-amphetamine sulfate 40 mg and diethylpropion HCl 200 mg.

    The results of these three human abuse liability studies suggest that the abuse liability and abuse potential of lisdexamfetamine dimesylate is less than d-amphetamine sulfate.
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