The Long and Winding Road to Drug Approval

[catbirdseat]

A drug that I worked on in the late 1980's was finally approved by the FDA for use in the United States to treat Parkinson's Disease.

 

The following is probably only of interest to tech geeks so be forwarned. I'm posting this because this approval is very gratifying to me, even though I left the project almost 20 years ago. My grandfather died of Parkinson's complications in 1983. Mohammed Ali suffers from this disease. It is a horrible disease.

 

Neupro is the brand name for the rotigotine patch. The drug had its origin at a company called Nelson Research, founded by Eric Nelson on the UC, Irvine campus as a sort of spin off of Allergan Pharmaceuticals. I hired on there in 1986 under Richard Phillips. We built up an analytical services group from scratch.

 

The earliest form of the drug was designated N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin). It was racemic (mixture of two optical isomers). The drug was found to be very potent. A stereoselective synthesis was developed for the active (-) isomer, which was then designated N-0923. This was twice as potent as N-0437.

 

N-0923 was so potent its active dose was about a milligram, and plasma concentrations were on the order of a mcg/mL. I worked on a sensitive HPLC method using electrochemical detection so we could conduct pharmacodynamic studies in monkeys and later humans.

 

They had a rather interesting way of testing the drug. They'd induce "hemi-Parkinson's" in monkeys by giving MPTP to one side of the brain and selectively killing off the dopamine producing cells in the substantia nigra of only that side of the brain.

 

One side of the monkey was paralyzed and the other normal. The monkeys could only turn towards the paralyzed side. They never turned the other way. If you gave an effective dose of drug, the monkey could turn either way as a normal animal would. They'd have people watching with clicker counters. One for left and one for right. Subract the left count from the right count and you'd have the net turns. You were shooting for a net of zero.

 

One of the hallmarks of N-0923 was "first pass metabolism", that is it goes directly from the gut, where it is absorbed, to the liver where it is metabolised. Because of this, the half life of the drug was very short indeed. The drug could have died here but it didn't.

 

It was pure serendipity that Nelson Research was experienced in dermal drug delivery and it occurred to them to try administration by skin as opposed to the oral route. This avoids first pass metabolism. It so happened that the drug was really well absorbed through the skin and the idea of a patch was discussed. Nicoderm had been recently introduced at this time, so patches were all the rage, as it were.

 

One of the interesting things about this drug, a Dopamine D-2 Agonist, was that it not only reduced Parkinson's symptoms it made people feel REAL GOOD. In tests on rats it was much more addicting than cocaine. You'd think this would have killed the drug's chances, but did not because of two factors. Patches provide steady state levels, which tends to reduce addiction. Second, patients were generally old people with severe disease poorly treated by existing drugs (including L-Dopa).

 

Nelson was bought by Ethyl Corporation around 1988 and the name was changed to Whitby Pharmaceuticals. In 1990, quite abruptly, Ethyl decided they wanted to move the company to Richmond Virginia. I gave serious consideration to making the move but decided against it as Richmond would be a bad place to find oneself out of work as a chemist. This was where I parted company and soon ended up in Seattle.

 

About half of my colleagues made the move to Richmond where they worked for about a year when Ethyl decided to get out of pharmaceuticals and let everyone go. A group of scientist from Whitby got together and started their own company Discovery Therapeutics and bought from Ethyl the patent for N-0923.

 

They labored through the 1990's on N-0923 which eventually was issued the generic name rotigotine by the FDA. Discovery eventually entered into a partnership with Schwarz Pharma, a Swiss company, since the costs of full scale clinical trials are beyond what a small company could afford.

 

So now here it is 2007 and the drug is finally approved in the US, about 22 years after it was first synthesized by a chemist. It's a long road. Is it any wonder drugs cost as much as they do?

 

 

[ken4ord]

I don't wonder what-so-ever why they cost so much, it was an interesting read, especially since I am in the pharma field as well.

 

It is really funny that I am where I am now. In college back in the '94 I read my first article on microbicide research. At that time I thought it was such a cool idea, to create a compound that would block HIV infection. I would have liked to have gotten involved with microbicide research then, but nobody near me was doing that research. I think I recall doing a publication review of the research out there for one of my classes. At that point all of the work was still just done the lab and animal testing hadn't even been started, and there was no solution to how one would conduct a clinical trial where the drug compound was estimated to be only a maximum 60% effective. Furthermore there was no to very little market for a product that is 60% effective when condoms were found to be almost 100% effective.

 

Around the same time the genocide or should I say "acts of genocide" were taking place in Rwanda. I recall seeing congressional deliberations on whether or not it was a genocide. It was frustrating, and I also thought quite disgusting that they wasted so much time while 1000's of people were being hacked apart (in the end it was close to 1 million people killed). At the same time who could blame them, just the year before we had a bunch of Marines who were ambushed and were thrown into a situation that they weren't prepared for in Somalia.

 

Fast forward to 2005, my girl friend was offered a job and I was decided to come out to be with her. Within 2 weeks of being in Rwanda I find myself with a job setting up a microcide research site with the intentions of conducting clinical trials. Still with no money making market for microbicides, research is now funded by non-profits. With statisticians help they were able to devise plans for conducting trials that would provide data needed to know whether or not a compound is effective enough to reduce transmission of HIV. Ethics issues on conduction a trial have been resolved by making sure that even if the compounds don't work that HIV transmission is reduced through counseling, education, and condom promotion. And now the compounds are more effective ~80% and promising indications that these new compounds can be formulated with other to increase effecacy and also work in prevent other STD's. We are still looking at another 10 years of clinical trial work before we will see first generation microbicides possibly hit the market, but it satifying to know progress is being made.

[archenemy]

You people are amazing.

[Dechristo]

Mighty cool.

 

And, there are people in place, currently, performing "Mother Theresa-type" work in easing peoples' sufferings while they die.

 

We live on a busy little ball.

[catbirdseat]

FDA News

FOR IMMEDIATE RELEASE

P07-84

May 9, 2007

 

FDA Approves Neupro Patch for Treatment of Early Parkinson's Disease.

 

The U.S. Food and Drug Administration (FDA) today announced the approval of Neupro (rotigotine transdermal system), a skin patch designed to treat symptoms of early Parkinson's disease.

 

Rotigotine is a drug not previously approved in the United States. Neupro is the first transdermal patch approved for the treatment of symptoms of Parkinson's disease.

 

Parkinson's disease, which belongs to a group of conditions called motor system disorders, results from the loss of dopamine-producing brain cells. Rotigotine, a member of the dopamine agonist class of drugs, is delivered continuously through the skin (transdermal) using a silicone-based patch that is replaced every 24 hours. A dopamine agonist works by activating dopamine receptors in the body, mimicking the effect of the neurotransmitter dopamine.

 

The effectiveness of Neupro was demonstrated in one fixed-dose response study and two flexible-dose studies. The parallel group studies were randomized, double-blinded, and placebo-controlled, and involved 1,154 patients with early Parkinson's disease who were not taking other Parkinson's medications.

 

The most common side effects for Neupro included skin reactions at the patch site, dizziness, nausea, vomiting, drowsiness and insomnia, most of which are typical of this class of drugs. Other potential safety concerns include sudden onset of sleep while engaged in routine activities such as driving or operating machinery (sleep attacks), hallucinations, and decreased blood pressure on standing up (postural hypotension).

 

Neupro Patch is manufactured by Schwarz Bioscience of Research Triangle Park, N.C.

 

According to the Parkinson's Action Network, more than 1 million Americans live with Parkinson's disease and 60,000 new cases are diagnosed each year. The four primary symptoms of Parkinson's are trembling in hands, arms, legs, jaw, and face (tremor); stiffness of the limbs and trunk (rigidity); slowness of movement (bradykinesia,); and impaired balance and coordination (postural instability). As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks.

 

For more information

National Institute of Neurological Disorders and Stroke

http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm