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Opioids Novel Opioid, Investigational Antagonist, Combo Pill In Development

Tchort

Bluelight Crew
Joined
Mar 25, 2008
Messages
2,392
Nektar Therapeutics is a biopharmaceutical company developing novel therapeutics based on its PEGylation and advanced polymer conjugation technology platforms. Nektar has a robust R&D pipeline of potentially high-value therapeutics in oncology, pain and other areas. In the area of pain, Nektar has an exclusive worldwide license agreement with AstraZeneca for NKTR-118, an investigational drug candidate, being evaluated in Phase 3 clinical studies as a once-daily, oral tablet for the treatment of opioid-induced constipation. The agreement also includes NKTR-119, an earlier stage development program that is a co-formulation of NKTR-118 and an opioid. NKTR-181, a novel mu-opioid analgesic molecule wholly-owned by Nektar, is being evaluated in Phase 1 clinical studies.

http://www.marketwatch.com/story/ne...ncial-markets-2011-10-26?reflink=MW_news_stmp

So they are close to putting out a new peripherally acting opioid antagonist for opioid-induced constipation to compete with Methylnaltrexone.

Even more interesting is they have a novel mu agonist opioid in development, as well as a combination formulation containing a mu agonist and the investigational peripheral-antagonist to deal with constipation only.

NKTR-181 is a mu-opioid analgesic investigational drug candidate with a novel molecular structure designed to provide potent pain relief while reducing the serious side effects of respiratory depression, sedation and abuse potential associated with conventional opioids.

NKTR-181 was uniquely designed to cross the blood-brain barrier at a substantially slower rate than other opioid therapies. With a reduced rate of entry into the CNS, NKTR-181 has the potential to eliminate not only the euphoria that underlies opioid abuse liability and dependence but also the serious CNS-related side effects of respiratory depression and sedation. The unique molecular design of the polymer drug conjugate also prevents conversion of NKTR-181 into a rapid-acting abusable form of an opioid. As a result, NKTR-181 has the potential to be a highly effective analgesic with a highly favorable safety profile and reduced abuse potential.

NKTR-181 is currently in Phase 1 clinical development to assess its pharmacokinetics, pharmacology, safety and efficacy.

A second Phase 1 study, a multiple-dose trial evaluating efficacy and safety of NKTR-181 in healthy subjects, is underway and expected to be complete by end of 2011.

http://www.nektar.com/product_pipeline/cns_pain_nktr-181.html

Here's a link to the study data from the first test done on NKTR-181:

http://www.nektar.com/pdf/pipeline/NKTR-181/pr_20110607.pdf

It contains some disturbing information if it turns out to work the way they say it does:

With slower entry into the CNS when compared to historical oxycodone data, NKTR-181 has the potential to greatly reduce the euphoria that underlies opioid abuse liability and dependance, as well as serious CNS-related side effects of respiratory depression and sedation. The unique molecular design of the polymer drug conjugate also prevents conversion of NKTR-181 into a rapidly-acting, more abusable opioid

Quite disturbing.
 
Slower onset just means more people in pain have to suffer for a longer time waiting for their meds to kick in.

And not to rain on anyone's parade or anything, but I never found oxycodone to be "abusable" in the same way heroin is. *shrugs* I just think the people who gravitated towards using prescription opiates aren't going to say no to this one, no matter if it can't be crushed and injected or even if it can.

Pharmaceutical companies just want in on the "next big thing", no matter how unwanted, unnecessary, or irrelevant it is in terms of the grand scheme of modern medicine.
 
Any data on the structure, CASno, or properties of these drugs, or are they "top secret" for now?

It appears that everything is in-house; the only data released that I could find came from press releases and company sponsored puff pieces. It sounds like a kind of opioid Vyvanse if it works the way they say (but obviously with a very different mechanism).

Slower onset just means more people in pain have to suffer for a longer time waiting for their meds to kick in.

Exactly; it sounds like it's either going to be a piss poor analgesic, or it'll have to act as well as drugs like Morphine, Oxycodone, etc in extended release formats. And we all know what a crock anti-abuse mechanisms are- including drugs that have been called un-abusable (Concerta, TEVA OxyContin, OpanaER, Vyvanse, etc).
 
^Like what happened with OPs?

I know its not the best comparison, but a good deal of people I know who got switched to Vyvanse by their doctors went back to Adderall or went to Dexedrine because the Vyvanse didn't work anyway.
 
I think Vyvanse is a good comparison really. And my personal opinion regarding analgesia from opioids is that it is an all-around deal. The euphoria, mild sedation, and every other primary, secondary and peripheral effect from the drug taken contribute to the pain relief as a palliative. This is why opioids like Propoxyphene, which are technically no more effective analgesics than Aspirin, are given out regularly (particularly to the elderly with non-specific pains/pain unrelated to a particular illness)- the euphoria, sedation, etc act as palliatives that make it a subjectively 'better' analgesic than Aspirin.
 
I wonder what "novel" side affects this drug will have.

These drugs with uber specific site receptors always have the craziest side affects.

Like compare the side affects of a regular benzo to a z-drug. Z-drugs are fuckin nuts

id try to explain my view a lil more but i'm kinda ferked derped right now. But I think a more accurate analogy for this new drug is comparing it to benzos to z-drugs. Like Oxycodone is the benzo and this "NKTR-181" is the z-drug. You follow my logic?
 
The NKTR-181 Phase II study is expected to complete before the summer is over.

The company still hasn't stated what the molecule is. Most likely it is pegylated oxycodone. In layman's terms, that means turning oxycodone into a large molecule so that it crosses the blood-brain barrier much more slowly. In theory, it's like having oxycodone s-l-o-w-l-y dripped. The time from peak plasma concentration to peak brain concentration is measured in hours, instead of minutes like with oxycodone. It is thought that the very slow build minimizes the addiction, euphoria and the CNS side effects that come from the opioid brain rush without compromising the pain killing ability much. It was injected directly into the carotid artery of rodents without inducing the typical immediate opioid responses. It looks like there is nothing you can do physically to it to make it more abusable. Chemically, the company has stated there is no way to break the peg off the base opioid without destroying the molecule. NKTR-181 will still bring the standard peripheral side effects like constipation.

If NKTR-181 pans out and comes to market, it will probably be the first opioid prescribed to patients. It doesn't have to be tremendously effective to be a big seller. It's for the average Joe's with temporary or chronic pain who don't want to become accidental addicts or deal with opioid sedation.
 
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Whatever happened to Oxytrene? As a chronic pain patient on ocycodone, I was very interested in that drug. I haven't heard anything for a long time though...
 
Company just reported outcome of NKTR-181 human abuse liability study. NKTR-181 was dissolved in liquid for fastest absorption in digestive tract and compared to oxycodone and placebo. Even at the highest dosage, NKTR-181 was much, much closer to placebo than oxycodone in "likability". Same result for sedation. Efficacy results in a 200 patient study with opioid-naïve patients with osteoarthritis of the knee is due before the summer is over.

Edit, adding links to conference call transcript and presentations.

http://seekingalpha.com/article/151...ty-study-for-nktr-181-transcript?source=yahoo

http://www.nektar.com/pdf/pipeline/NKTR-181/CPDD_NKTR-181_Hal_Study_Presentation.pdf

http://www.nektar.com/pdf/pipeline/NKTR-181/NKTR-181_CPDD_Poster.pdf
 
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NKTR-181 failed its Phase II efficacy study but in an unusual way.

First, some background. Most drugs are evaluated for efficacy in multi-armed, randomized, double blind placebo controlled studies. Multi-armed and randomized means that people entering the study are broken into groups at random. For example, a study may have three groups, one gets a low dose of the drug, another a high dose of the drug, another gets placebo. Double blind means that neither the patient nor the physician knows what the patient is getting. Data is collected during the study. After the study is complete, the data is sent to a monitoring committee (who do know what the patient was given) and statistical analysis performed. The idea is to eliminate all forms of bias in the study.

However, this design often works poorly in opioid studies. The reason is that many people cannot tolerate opioids. In the past, so many patients assigned to an opioid group have dropped out due to side effects to render the study statistically worthless. Opioid drugs are now evaluated using a withdrawal study design. In a withdrawal study, all patients are given the opioid drug in increasing doses until sufficient pain relief is achieved and maintained, called the titration phase. The patients are then randomized in a double blind manner. Some patients are maintained on the opioid and others are switched to placebo. The idea is that pain will return to patients switched to the placebo. After a period of time (called the withdrawal phase), the pain scores of the patients are evaluated. Success is measured by the difference in pain between patients remaining on the opioid to those switched to placebo. This eliminates the dropout problem from patients who cannot tolerate opioids. They are dropped during the titration phase prior to the evaluation.

The NKTR-181 Phase II study was with osteoarthritis patients who could not achieve adequate pain relief using NSAID's. Patients were given NKTR-181 in increasing doses until 40% pain relief was achieved and maintained. 40% pain relief is considered clinically significant. The patients were randomized to continue NKTR-181 or switch to placebo in a double blind manner. They were evaluated over a six week period. The endpoint was the difference in pain scores between the two groups after six weeks.

During the titration phase, only 18% of the patients dropped out due to side effects, which is very low for an opioid. 97% of patients achieved and maintained 40% pain relief or better after titration. The unusual results occurred during the withdrawal phase. After six weeks, the pain scores of patients who continued on NKTR-181 improved another 6%. However, the patients who were switched to placebo maintained their 40% improvement in pain six weeks after being taken off NKTR-181. There was no statistically significance difference in pain scores between the two groups, so the study failed.

What does it mean? Is it all placebo effect? Is six weeks long enough for a withdrawal period? Is there some additional long lasting benefit that NKTR-181 provides in osteoarthritis? The company is looking at options about how to proceed. Stay tuned.

Links.

Press release: http://finance.yahoo.com/news/nektar-announces-preliminary-topline-results-201000567.html

Conference call transcript: http://seekingalpha.com/article/171...r-nktr-181-conference-transcript?source=yahoo

R&D Day presentation: http://www.nektar.com/pdf/NKTR-R&D_Day_2013_Pain.pdf

R&D Day transcript: http://seekingalpha.com/article/173...-amp-d-day-conference-transcript?source=yahoo
 
That's not a fair characterization. I wouldn't call NKTR-181 unwanted or irrelevant. Quality pain relief in a drug that is less addictive and with lower side effects like somnolence would be a welcome improvement for average Joe's who don't want the baggage that comes with other opioids. I'm not sure if it will pan out, but the motivation is righteous.
 
Who cares if big pharma is just trying for the next big thing? That's what they're supposed to do. Morphine was once the next big thing, so was aspirin, benzos, my neurological meds. I got major gripes with big pharma, but them looking for the next big thing is hopefully what they're going for. It can't become the next big thing unless it's super useful. Especially since this med is supposed to be an opioid without the addiction potential. Which is interesting in that they usually are trying to get you to take addicting substances not safer alternatives.
 
Why would you need an opioid antagonist for constipation? You take Dexedrine and an hour later you're shitting bricks.
 
Ksa,

You're confusing NKTR-118 (for opioid induced constipation) with NKTR-181 (opioid pain killer). That happens a lot, actually.
 
If the pharm companies wer smart they would try and make more euphoric drugs.. I have a feeling this is going to be another huge waste of $$$ and time, People will just bitch to their doc that they dont work and such..

I think this hits the nail right on the head. They can say the mechanism of action should do this and that and every other great thing, but in the end it comes down to what the patients being prescribed it say.
 
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