I'm a technology guy. I investigate and understand the technology behind any biotech in which I invest. It helps that I have a background in cellular biology.
Last night I was investigating other cancer drugs in development, and something led me to a paper that hit me over the head. Curis's lead drug GDC-0449 is a Hedgehog Pathway inhibitor. More specifically in binds a protein called Smoothened, or SMO. Very recently, scientists at Howard Hughs Medical Institute who were screening known drugs for activity in the Hedgehog Pathway found something. They found several drugs in fact, and one of them--itraconazole--blocked the very same protein as GDC-0449. It blocks SMO.
This is a generic drug that has been used for about twenty-five years as an antifungal. It's well-tolorated and very well studied. Trials are either being enrolled or underway for the use of itraconazole against cancer.
Here is an excerpt from the paper I found published in Cancer Cell last month.
"These small molecules [drugs like GDC-0449] have been effective in blocking Hh pathway-dependent growth of transformed cells,both in vitro (Taipale et al., 2000) and in vivo (Berman et al.,2002;Dierks et al., 2008; Romer et al., 2004; Yauch et al., 2008; Zhaoet al., 2009), thus stimulating major efforts to develop small molecule antagonists of the Hh pathway as cancer therapeutics. However, drug development is time-consuming and costly (DiMasi et al., 2003; Frank, 2003), and we sought to circumvent this delay and expense by identifying Hh pathway antagonists among drugs that have been tested for toxicity in humans or even approved for human use by the US Food and Drug Administration (FDA)."
They sought and they found. Itraconazole. It's safe, it appears to work as well as any other SMO blocker, it's already FDA approved, and it's GENERIC. I can't see how this won't be an enormous blow to Curis. For that reason I am selling my shares immediately. I strongly suggest that anyone long on Curis engage in his own due dilligence.
Here's a link to the article in Cancer Cell. You can read the summary without purchasing the entire article:
<<snip>>Look at the GDC-0449 resistance mutation and ask why do they demonstrate that it is also resistant to KADD-cyclopamine?<<snip>>
Um, because both drugs bind the same sight on SMO? (which has an altered amino acid in the mutant form that prohibits binding). And since they bind the same sight on SMO they're competitive inhibitors of same. Um, yeah, got that. Not seeing your point here.
And if it's true that as cyclopamine goes so goes GDC-0449, that's not particularly good news is it? Not if you're referring to the adverse effects profile of a drug which is widely held to be virtually useless anywhere but in research.
I guess I'm missing your point.
GDC-0449 is a competitive inhibitor & analog of cyclopamine, except it's 10X more potent. So as goes cyclopamine, so goes GDC-0449, so once again it is essential for you to understand this point. Your cited paper uses an assay that will work for both cyclopamine and GDC-0449 because they bind the same region of SMO. Look at the GDC-0449 resistance mutation and ask why do they demonstrate that it is also resistant to KADD-cyclopamine? Think and ask if you know the structure-Activity-Relationship of cyclopamine & GDC-00449 vs SMO. I can tell you don't.
And if your grandmother had testes she'd be your grandfather. The hypothetical was and is for the case in which the drug with the higher relative potency is unacceptably toxic.
If cyclopamine is too toxic for general use (and it appears to be), then its relative potency is a non-issue.
The hypothetical was only to make a point. "If there's a hurricane blowing [hypothetical], then wearing a hat won't keep you more or less dry." To which you answered "Ha! But what if it's sunny out!"
Well, that's not what we were talking about, is it? We were discussing the relative benefits of hat/no hat in a hurricane. We were discussing the relative benefits of potent/less potent for a drug that's too toxic to use, e.g. cyclopamine.
The degree to which a CYP3A4 inhibitor like itraconazole interferes with another drug metabolized primarily by that same enzyme will vary according to that second drug's hepatic extraction ratio. Drugs with a low HER, in the range say of .3 to .5 are likely going to be affected by that CYP inhibition. Drugs with a higher ratio, .8 to 1.0 say, are usually not. This is not one study, this is just standard PK.
I don't know off the top of my head the various HER's of the front line chemos out there. If they're typically low, then CYP3A4 inhibition may be an issue. Of course many drugs have secondary metabolizing pathways. ADME studies can only show so much. The data will have to come from the clinic.
>>My point was only that since cyclopamine is described is as being unacceptably toxic in this application, that the relative dosages between it and itraconazole (the dosages needed to achieve effective Hh pathway blocking) wouldn't appear to matter here. If cyclopamine is essentially unusable, what difference does relative potency mean? Fentanyl is about a hundred times more potent than morphine, but that wouldn't mean a thing if fentanyl were intolerably toxic<<
Stubborn wins! What if Fentanyl is less toxic & more stable in vivo than morphine; which would be the proper analogy of GDC-0449 to cyclopamine?
My point was only that since cyclopamine is described is as being unacceptably toxic in this application, that the relative dosages between it and itraconazole (the dosages needed to achieve effective Hh pathway blocking) wouldn't appear to matter here. If cyclopamine is essentially unusable, what difference does relative potency mean? Fentanyl is about a hundred times more potent than morphine, but that wouldn't mean a thing if fentanyl were intolerably toxic.
With that in mind, if it took a higher dose of itraconazole to match the effects of GDC-0449, and if the adverse effects profile in each case were the same, then you'd have two very similar drugs. One of them would be a lot cheaper and have a great deal more safety data behind it. I still believe that's a very real possibility.
Other issues have been raised here, and good ones, IMO. While some very large institutions are involved in trials for itraconazole, the final push would be costly, and the question remains whether public or charitable funds could be found. For the sake of cancer patients I would hope so.
Then there's the issue of co-therapy. It has been rightly pointed out that Hh blockers aren't cytotoxins. They inhibit growth. And one would think that combining this effect with a direct attack on cancer cells may be more successful. So DDI becomes a big issue.
As to the argument that Roche/Genetech wouldn't have developed GDC-0449 if they didn't have a very good reason for believing it superior to itraconazole--that study from HHMI points out that a number of Hh pathway blockers were in development when this team decided to screen for existing drugs that might do the same trick. I'm pretty sure that GDC-0449 development was far along before anyone involved learned that a generic anti-fungal was also an effective SMO-blocker.
All in all, I think very good argument has been made here for the case that GDC-0449 can compete with an existing generic with nearly identical mechanism of action. Some of that argument rests on the sad fact that even if it proved effective, a cheap drug to which no one owns the rights could very well languish. But the drug-drug interaction question stands out in my mind as a legitimate one, and maybe even make-or-break.
I thank everyone here who contributed to an informed discussion of this issue. And again, I wish all investors in this promising technology the very best.
<<rul612 snip>>Someone correct me if I'm wrong. I'm by no means expert on this aspect of the drug business.<<snip>> Since this whole exercise is relative to financial implication (e.g. share price of CRIS), consider how vital that understanding of the business aspect really is.
Your assumption that the major cancer centers will underwrite trial costs is flawed. Kimmel, Memorial Sloan Kettering, MD Anderson, Johns Hopkins etc are not inclined to "fund" late stage trials. "Participate", yes. Underwrite the considerable data assimilation costs (double digit millions) of most regulatory submissions, uh-uh.
Suggest you add to your scientific skills by boning up on the economic aspects. (I think DeMasi at Tufts did some interesting calculations.)
Any way you slice it, it's mega bucks to bring any drug to market.
If I were you I'd start trying to ask better questions. For example try these. Are these two pathways really competitive or could they be complimentary? Do GDC0449 and itraconozole both have a similar atagonist mechanism of action on smoothened? Did you mention that the paper you cited shows cyclopamine at a lower concentration actually performed much better than itraconozole in vivo? How about the part in the paper where they combine itraconozole with cyclopamine? Be careful as edges can can be both a strength and a weakness.
Since cylcopamine, itraconazole, and GDC-0449 all bind to and inhibit the native form of SMO--as single agents they're all doing essentially the same thing. In combination, through binding to different sights, there could conceivably be some synergy. Perhaps a SMO molecule that's bound at two sights could be more efficiently blocked--that's beyond my understanding. Also using two drugs and binding the protein by more than one sight may make it harder for the cancer to mutate around the effects of a single agent. (this kind of mutational resistance was documented in a patient treated for medullablastom with GDC-0449). Again, this I'm not sure about. So there's possible complimentarity--though only direct experimentation could speak to that.
That cyclopamine effectively blocks SMO at lower concentrations than itraconazole is a moot point, since it's far too dangerous a drug for this application. It's a good research tool, and not much else. The etymology of the name itself comes from the fact that sheep grazing on the plant from which it's derived gave birth to offspring with just one eye!
For me the bottom line, regardless of whether using two different SMO blockers together works better than one, is that there's a drug out there that does essentially the same thing as GDC-0449, and it's safe enough to have been on the market for decades and it's generic. Also major institutions like Johns Hopkins have it in PII trials. I think they'll provide the means and turn out the data needed for approval (assuming efficacy). And the profits are there for the manufacturers who are already making the drug to expand its sales into the enormous market for cancer treatment
Curis will very likely develop some good data for GDC-0449. I'm betting on positive results against basal cell carcinoma. And the stock could soar on such news. In the long run, though, I think that itraconazole will be one of the first hedgehog pathway blockers in wide use, and that the competition in that arena will be stiff. That and the possibility that the market could take a very dim view of exciting results coming out of an intraconazole trial is enough of a concern for me to bow out. Call me way overcautious.
I wish everyone who stays with the stock the very best.