In a comment to yesterday's post, William Knight says:
"While the initial challenges of developing and delivering therapeutic proteins are no doubt far greater, it seems to me that in the long run, proteins, peptides and nucleic acids are the right tools for the job, not small molecule analogues."
Well, I don't quite agree, but he's not the first person to think that way. An awful lot of money has been thrown at the problem of using antisense DNA therapeutically, for example, and I think that a similar amount is in the process of flowing into RNA interference. On the protein front, things have been more successful. There are quite a few protein-based therapeutics out there, starting with insulin and ethythropoetin.
One problem, as he correctly states, is delivery. There have been any number of ingenious approaches to oral delivery of large biomolecules, but there's still no solution in sight. We have enough trouble dosing small molecules and getting them absorbed and distributed; the problems facing large proteins and oligonucleotides are still worse. The gut is designed to rip these things apart, and the gut wall is designed to not absorb them. There are alternate dosing routes, but those are no stroll to riches either, as witness the multiyear campaigns to develop an inhaled form of insulin.
You'd think that biomolecules would be less toxic and more efficacious than small molecules, too - this was one of the early promises of the whole biotech industry. But that's been tricky to realize. A recent example is found with Amgen's attempted use of glial-derived neurotrophic factor for Parkinson's disease. Early results were promising, despite the fact that the protein had to be administered directly into the brain. But things haven't worked out:
"One of the most promising experimental therapies for Parkinson's disease could be shelved after scientists revealed today that a clinical trial has been stopped because of safety concerns. . .Hopes for the treatment soared last year when it was announced that the first five people treated with GDNF experienced a dramatic recovery in their movements. But on Tuesday, Anthony Lang of Toronto Western Hospital in Canada revealed that a second, more extensive clinical trial of GDNF has been halted because the drug showed little signs of working and some potentially dangerous side effects."
Those included neuronal death in monkey studies, and the appearance of antibody responses to GDNF in several of the patients. Raising antibodies to close relatives of your own proteins is not something you want to do. They're still trying to figure out what went wrong - it could be that GDNF was never much good from the start. A five-person trial is capable of producing just about any result under the heavens.
But this illustrates some of the problems. For now, until we understand things much better, biomolecules will have more liabilities than small synthetic ones, and just as good a chance at failure. Perhaps, eventually, the odds will shift.
1. qetzal on October 5, 2004 11:02 PM writes...
Protein drugs do have one fairly consistent advantage - they're much better suited for gain-of-function type therapies than small molecules. You alluded to this in your previous post, of course.
Note that in this regard, antisense and RNAi are much more like small molecules - their immediate function is to inhibit some protein. True, they do so by interfering with the production of the protein in question, but I think the general kinds of therapeutic mechanisms they can have will be much more like small molecules. Assuming anyone ever gets them to work reliably.
One other problem with protein drugs that I didn't see mentioned. Generally, they're only useful if they can function outside a cell. It's really hard to inject a synthetic protein into a person and get it inside some target cell type. Unless it turns out that the target cells already have a built in mechanism to internalize the protein.
Personally, I think this is a much bigger limitation for protein drugs than cost of production or inability to dose orally. We seem to be learning that there really aren't that many proteins that have therapeutic potential due to gain-of-function, and can perform that function extracellularly. Most of the good ones are already developed (insulin, epo, clotting factors, interferons).
Permalink to Comment2. William Knight on October 6, 2004 1:51 PM writes...
The article about the Amgen trial of GDNF is interesting, but perhaps a little short on details about the dangerous side effects, the most serious that I saw mentioned were breakdown of monkey brain cells in related studies. I'm no expert, but there do appear to be other studies that show significant introduction of GDNF to monkey brains with little damage (Ai et al, 2003, J Comp Neurol.).
It would be nice to see a more comprehensive survey and comparison of negative side effects of therapeutic protein trials vs. conventional drugs. Of course, the data may be rather limited for proteins.
In trying to understand factors related to side effects, I am wondering about the question of drug lifetime and metabolism. Do small molecule drugs hang around longer and are they metabolised/removed more slowly than proteins? And if so, is this a significant cause of dangerous side effects?
If protein-based drugs are by nature more transient, and transience reduces the possibility of negative side effects, then this a good reason to focus more on delivery technologies.
By trying to deliver transient protein drugs to specific targets, the outcome would be polarized into two distinct camps of 'desired effect' or 'no effect', rather than a spectrum of strong desired effects and undesired side effects that result from more persistent and potent small molecule drugs.
Permalink to Comment3. just a science guy on October 6, 2004 7:41 PM writes...
The way I see it, the real advantage of protein-based drugs is their molecular specificity -- little or no off-target activity. So if you get the biology right -- and I mean really right -- you should never get surprised in the clinic. With small molecules, you also have to get the biology right, but then you've also got to cross your fingers and hope your drug doesn't find some other way to wreak havoc.
Permalink to Comment4. Derek Lowe on October 6, 2004 8:37 PM writes...
That's a good point, and I think it's what W. Knight was getting at, too. it's just that I think that the fraction of biology that we have really, really right is still rather small. Those pathways are worth going after with biomolecules, as are cases where there are just no small molecules to be had. But on a level playing field, small molecules still win out, and will until we know more about how to make administer the large ones.
Permalink to Comment5. Peter Ellis on October 7, 2004 3:26 AM writes...
Even *if* there's no off-target activity, you can still get surprised, if it turns out your target pathway has some secondary function you didn't know about in some other tissue...
Permalink to Comment6. just a science guy on October 7, 2004 9:46 AM writes...
Agreed, Peter. But that's part of getting your biology *really* right. I didn't say it was easy!
But you've got the same problem a small molecule drug, too. The latter adds the issues associated with unpredictable off- and near-target activities, metabolism, general tox, etc., which, in general, proteins don't have.
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