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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 28, 2010

Acorda and Ampyra

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Posted by Derek

I had not been following the progress of Acorda's recently approved drug Ampyra for MS. (Well, more specifically, it's to improve gait and walking speed in MS patients). Opinion seems to be rather divided about how successful it'll be. On the one hand, new therapies for multiple sclerosis are certainly needed, but there's also room to argue about just how efficacious Ampyra really is.

I'm not going to fight that one out here, because we'll have the judgment of the market pretty soon. What I find interesting is the structure of this new drug: it's 4-aminopyridine. If there's a more simple, lower molecular weight structure approved within the next few years as an oral drug for anything, I'll be quite surprised.

This brings up several interesting topics relating to drug development and intellectual property. For one thing, this compound has been known for many years as a ligand for neuronal voltage-gated potassium channels, which is the mechanism by which it seems to work for MS patients. Some of these patients have experimented with it themselves over the years; the idea of using it for multiple sclerosis is certainly not new. (Here's a good history, taking things back a good 30 years through many players, with Elan a prominent one).

Secondly, it's not like the compound's chemical structure can be patented as such, either, since it's nowhere near novel. I have no idea of when 4-aminopyridine first makes its appearance in the chemical literature, but it's surely back into the 19th century. Nor is it anything like a rare chemical. For many years it was used as a bird-control poison. (High doses are fatal, but lower ones cause bird seizures that cause the rest of the flock to leave in consternation). We've got some on the shelf in our stockroom; I see in my Aldrich catalog that they're selling the 99% grade for $18/gram. And Aldrich is not exactly the world's low-cost chemical supplier. A railroad car full of the stuff could surely be arranged through someone, although it wouldn't exactly be pharmaceutical grade.

So. . .how then, some might wonder, does Acorda Therapeutics (partnered with Biogen Idec) get to charge several thousand dollars a year for Ampyra? (I don't think the actual price is known yet, but that's the best guess I've seen). One key factor is the bird-repellant aspect. Messing with ion channels in nerves is a tricky business, and 4-aminopyridine can and will cause trouble in humans if it's not dosed carefully. It's also (I believe) cleared pretty quickly, as you'd expect from something with that structure. Ampyra is a time-release formulation, an attempt to get enough of the compound into circulation over a long enough period, but without crossing over the line to too high a concentration, which could set off seizures and worse. Taking 4-aminopyridine from that railroad car and using that instead would be very much not recommended, considering what's waiting out there at inappropriate doses.

And that's Acorda's intellectual property. Plenty of work was done to find a good formulation for the drug, and Acorda spent the time and money to test one for safety and efficacy. They get to reap the fruits of their labors, if fruits there are. And that's what the market will decide for them. . .

Comments (28) + TrackBacks (0) | Category: Patents and IP | The Central Nervous System


COMMENTS

1. Dave on January 28, 2010 9:40 AM writes...

A question this brings up -- do patents on the formulation process work in the same way as those on the chemical matter? Or how hard is it for generics companies to copy the branded formulation?

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2. SP on January 28, 2010 9:54 AM writes...

What is the lowest MW drug on the market? Hydroxyurea?

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3. HappyDog on January 28, 2010 10:22 AM writes...

I have an answer to Derek and SP. The lowest MW drug on the market I can think of off the top of my head (well, besides potassium) is nitric oxide. The manufacturers of Ampyra could have taken out a use patent. When my daughter was born at 24 weeks of pregnancy, she wasn't expected to survive her first 24 hours because her lungs were so immature. One of the treatments the neonatologists use is nitric oxide to help expand the blood vessels in the immature lungs of very small preemies. The results are also extremely dramatic. My wife and I watched her blood O2 saturation levels go from the 50 - 60% range into the high 90% range. Nitric oxide certainly isn't novel. In fact, there are lots of environmental regulations on the books limiting its production as a pollutant. (It comes out of your car's tail pipe for crying out loud.) But the supplier apparently had a use patent and charged a lot of money for it. The nurses in the NICU said that some insurance carriers had even called the hospital and told them to discontinue its use in some patients on the grounds that it was 'experimental'.

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4. David on January 28, 2010 10:53 AM writes...

With respect to Dave's question (1.)...

There are a number of patented extended release formulations available for license, which I'm guessing Acorda did because they have no patent of their own for an extended release formulation. Can someone copy that exact same formulation while it's still under patent protection? No. However, a generic competitor could develop their own extended release formulation that doesn't violate the patented formulation, and then would only need to show bioequivalence with the approved drug. Sounds easy, right? But it's not. These extended release formulations are pretty challenging, especially for drugs with low half-lives. Take a look at Alza's OROS osmotic controlled release system for a nice example.

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5. PharmaHeretic on January 28, 2010 11:03 AM writes...

What about Lithium for Mania?

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6. sgcox on January 28, 2010 11:03 AM writes...

Lithium for bipolar disorder ?

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7. anon the II on January 28, 2010 11:04 AM writes...

This packaging price differential thing isn't so rare. I have a friend, a ChemE, who makes Ritalin (methylphenidate) commercially. He says it cost about $5/kg. Concerta, a time released version of methylphenidate, cost about $6/pill (54 mg) without a co-pay. I calculate about a 22,000 fold markup.

Maybe that's why it's still made in the US.

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8. sgcox on January 28, 2010 11:05 AM writes...

Lol, simultaneous posts !

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9. qetzal on January 28, 2010 11:30 AM writes...

@SP -

Sterile water for injection is considered a drug by FDA. MW 18. Even a medical gas like NO or O2 isn't quite that low.

I suspect that's the lowest possible for a true molecule. (Surely there's no medical use for H2 gas?)

Helium is also a medical gas subject to FDA regulation. It's not truly a molecule, but if you'll forgive that, we're down to a weight of 4.

If you'll accept He, despite not being a molecule, what about the electron - "MW" ~ 0.0005? For that, you'd have to agree that electricity delivered in treatments such as deep brain stimulation (for Parkinson's) is a form of drug.

Finally, there's the photon (used in various forms of phototherapy). Rest weight = 0.

;-)

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10. Chemjobber on January 28, 2010 12:02 PM writes...

Well, this gives the partial lie to Kevin Trudeau's
"too cheap to patent" shtick. Or does it? ! ! !

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11. qetzal on January 28, 2010 12:38 PM writes...

RE: lithium -

According to Drugs@FDA, lithium is actually sold as lithium carbonate (MW 73.9) or lithium citrate (MW 209.9).

If we're going to count the Li+ ion itself as the drug, we could equally count H+ (e.g. when delivered as part of an acid to treat severe alkalosis).


RE: Chemjobber #10 -

Yes I think it does, at least where the substance is public domain but there are other barriers to selling the drug product. Those might include formulation IP (as in this case), method of use IP, process IP, maybe others. I think it mainly comes down to how easily a competitor can circumvent your IP using the same substance.

In reality, the same applies even to patented substances. In that case, competitors have to find a different substance that has a similar effect but isn't covered by IP. And of course, that happens all the time, at which point Trudeau-types start griping about "me-toos."

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12. Will on January 28, 2010 1:05 PM writes...

The FDA will also award exclusivities for a new use/formulation of an old compound. During the exclusivity period, the FDA won't approve an ANDA from a competitor. It's not as long of a period as a patent, but if you're development costs are low enough (which may be the case here) you may make enough $$$ over the shorter FDA exclusivity period to make it worthwhile.

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13. Hap on January 28, 2010 1:10 PM writes...

If the compound is readily available and easily formulated, exclusivity probably doesn't help (because people could get it other ways or for other indications), but with something like this it would.

I would have figured that the biggest portion of the development cost is the trials, rather than the formulation and development. Maybe the trials are simpler with old compounds, but I don't know why or if that would be the case.

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14. cynical1 on January 28, 2010 1:32 PM writes...

As a medicinal chemist, (former) MS researcher and spouse of a multiple sclerosis patient, I'll put my two cents in on this one. Not surprisingly, I know quite a bit about this particular drug.

The structural simplicity of this drug and its 30 year history to market is more a reflection of the utterly pathetic amount (and quality) of effort that has been put forth for multiple sclerosis drug research and development. I remember trying to initiate MS research at my former employer (which has a 3-letter acronym). The mere suggestion of working in this area was instantly reviled by research management and the marketing groups alike. Why? "There's no money in MS and everyone knows it." And by implication, I was an idiot. Ironically, my wife was also an employee there at the time working in reg. affairs on their neurology line. (There's a very long gripping story that follows this but I can tell you Hollywood won't make that movie because it doesn't have a happy ending. No Harrison Ford playing me on the silver screen, alas.)

For those of you who have been in research for awhile, how many of you can recall a MS-focused research project 10 years ago? Five years ago? Or even now?

It wasn't until Biogen was raking in several billion dollars a year treating a tiny fraction of the patient population that the MBAs running these ships starting paying any attention at all. Ironically, Novartis, who used to be run by a physician, just filed the NDA for fingolimod for MS. If the safety data holds up, they are going to make a ton of money and they're going to charge a lot more than $3K a year. MS patients will mortgage their house for something that actually works. I know my wife and I would.

Ask yourselves if a crap drug like 4AP would ever get approved for type II diabetes, obesity, MED, asthma, osteoarthritis, osteoporosis, ect. ect. But the FDA will allow any POS drug on the market because MS patients don't have anything else. Interferons and copaxone? Crap. Mitoxantrone and Cladribine? Really toxic crap. Tysabri? Great, if you don't mind playing Russian roulette and dying of PML with every infusion.

Derek, do you think you will have a similar post when Biogen launches dimethylfumarate, currently in Phase III. How many medicinal chemists does it take to esterify fumaric acid. It’s not even the ethyl ester for pity sake!

4-Aminopyridine is a very sad testament of the dismal failure of our industry (particularly Big Pharma) to give a damn about a horribly underserved patient population even when they could (and can still) make tons of money on it. Ampyra is a perfect example of what is wrong with our industry and why MBAs should not be running the show.

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15. HelicalZz on January 28, 2010 1:35 PM writes...

I'm no patent lawyer, but suspect the formulation patent is certainly enforceable, but of limited value. Depends on how hard it is to mimic the bio-availability profile.

So that leaves one with 5 years data exclusivity on the trial data (unless someone wants to run efficacy trials for a generic). Only 5 years to recoup the development investment though does tend to justify a high price, regardless of the cost of the API.

Zz

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16. retread on January 28, 2010 2:01 PM writes...

There were a lot of papers on the clinical use of 4 amino pyridine starting nearly 30 years ago [J. Neurol. Sci. vol. 60 pp. 353 -362 '83 ]. Initially such high doses were used that some had convulsions. 70% of patients experienced side effects (tingling, dizziness) after each dose. A trial on 70 patients showed improvement on the Expanded Kurtzke Disability Scale, but like the improvement with Cognex in Alzheimer's disease, it was too small to be clinically meaningful [ Ann. Neurol. vol. 32 pp. 123 - 130 '92 ].

Cynical1 is right, there certainly wasn't much for MS while I was practicing ('67 - '00), but I don't think it was from neglect. The neurological literature was full of trials of various immunomodulators (corticosteroids, interferons) for MS. The results I saw, like Cynical1, were clinically negligible.

If "in the Pipeline" shows nothing else, it shows that throwing large amounts of money and/or effort at a particular disease is no guarantee of a useful result. That's not a reason to quit.

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17. darkdogzzz on January 28, 2010 2:18 PM writes...

Ampyra is an orphan drug so it has 7 years market exclusivity. You need a drug that has better patient compliance, is safer, or has a different efficacy profile in order to file another 4AP for this indication within 7 years.

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18. Alejandros on January 28, 2010 3:01 PM writes...

I would suspect its patentability comes down to two things. Firstly, Swiss use claims, and, in the US, method of treatment claims. A known compound used to make a medicament for a new use is specifically allowable. You can't claim the compound, but you can claim its use.

Secondly, selection invention. I meet this quite a bit: the prior art disclosed millions of variations on a compound, but the current application made, say, 10, and found they had better properties than you would expect from the earlier document, then the 10 compounds are novel.

But this is all done while eating breakfast and knowing little about the case. Also, I'm not from the US, so US law is undoubtedly different in some ways to the one I work under.

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19. Bingo on January 28, 2010 4:27 PM writes...

@HelicalZz

I don't know about the specifics of this product, but your timeline doesn't reflect the realities of data exclusivity.

If an ANDA is filed with no Paragraph IV certification (no attempt to obtain approval before patent expiry) it cannot be *submitted* to FDA before the expiration of the NCE exclusivity.

If an ANDA includes a Paragraph IV certification to on of the Orange Book patents, it may be submitted one year before the expiry of the NCE exclusivity. However, assuming the patent holder wishes to assert its patent, there is a stay of approval of the ANDA. If there is no NCE exclusivity, that stay is 30 months from the date the NDA holder is notified of the challenge. If there is an NCE exclusivity, that stay runs 30 months form the expiration of the NCE. That is to say, the absolute minimum exclusivity a NCE gets is 7.5 years from approval unless the patents are not asserted or don't hold up in court.

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20. bmartinmd on January 29, 2010 11:16 AM writes...

The market for Ampyra is yet to be known, but I suspect that clinicians--spooked by the risks of seizure and acute confusion--will reserve the drug for those still-ambulatory MS patients who don't take current disease-modifying agents (ie, interferon beta or glatiramer acetate). We're talking about a minority of MS patients in the United States--probably half of those patients who don't have relapsing-remitting disease, or ~30,000.

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21. cynical1 on January 29, 2010 1:30 PM writes...

@bmartinmd: There are ~300-500,000 MS patients in the US. Approximately, 45% are relapsing-remitting, 45% secondaary progressive and 10% primary progressive. (Relapsing-progressive is a rather useless clinical distinction IMO since the only way you get to secondary is by starting with RR-MS.) I would say that the majority of the 2nd progressives have very limited ambulatory capacity so I think that they will be targeting the RR group mostly. I agree that most neurologist will be reluctant to prescribe the drug but my friend told me that their phones have been ringing off the hooks since the approval. I am sad to say that MS patients are likely to be sorely dissappointed, once again.

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22. tedstube on January 30, 2010 12:03 AM writes...

Hmmm... basically taking DMAP as a drug. That should accelerate acylation reactions in the body. Let's say that the drug reacts with acetyl-CoA to give an activated acid that would have a much broader reactivity scope that acetyl-CoA itself. Sounds like trouble!

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23. Henry O'Hara on January 30, 2010 1:37 PM writes...

I have participated in the Clinical Trial for Fampridine (now known as Ampyra) through Jefferson Hospital in Philadelphia. I believe that it is helpful in my personal situation. I wanted it to be the "magic bean" that we all hope for. I use a walker to get around when I am not using my power wheel chair. I think that my use of fampridine (ampyra) does exactly what was represented to me. It improves my walking speed when I use the walker. I cannot imagine what a fair and reasonable price for this might be.

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24. Christine on March 31, 2010 11:53 PM writes...

I have just started ampyra and hope that it improves my walking abilities and pray that I can run again!!! That's all that I can hope and pray for!!

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25. Mike on May 6, 2010 6:33 AM writes...

My Wife has been injection with Beta seron for over 15 years and it DOES help her. She has been on Ampyra for about 2 weeks now and actually has noticed some improvement - no foot drop and her ankle that used to turn when she walked, doesn't. I am sure there may be many factors for this improvement, but it can't be coincidence that her walking has improved from taking the walking pill.

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26. Giovanni on May 20, 2010 6:53 PM writes...

My brother-in-law has MS. He started Tysabri infusions about 2 years ago..After 3 infusions he no longer needed his walker.. He did have some problems with foot-drop . After a couple of weeks he walks with NO problem. The interferons did little for him. Tysabri is a Godsend and Ampyra was icing on the cake!!

Gio

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27. gearhead on July 19, 2010 10:17 AM writes...

MY MS presented is April 2006 with a vengence
that required 7-months of chemo and then I went on Avonex at-home self-administered injections.

I just recieved Tysabri infusion # 34 (I think)
and my relapsing-remitting MS has reciently been
upgraded to secondaary progressive MS so my Neuro
suggested Ampyra....

I have been tormented over this decision for many
weeks!

My final decision is a resounding is NO!

I know paitents recieving this who cannot even
tell me the cost....and are confused about the
results themselves!!!

I have ENOUGH to worry with PML hanging over my
head every month as it is....plus I can get by
for now with a cane when I need it.

SERIOUSLY folks...wise up...the added risks of
seizures and acute confusion....4-amino pyridine
starting testing nearly 30 years ago and NOW it is the new-fix?????

Then there is the $280.00 per MONTH co-pay with Medicare Plus Blue PPO.. I think I'll pass...

I'll take my chances where I'm at for now and
see "how" this plays out.....

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