http://biz.yahoo.com/bw/060123/20060123006007.html?.v=1

Drew,

What your takes on this news? It seems to me that DNA is responsible for the topical technology ( ..on the extent to which the active compound in the drug candidate as formulated is penetrating the patients' skin..). I am probably being to optimistic but I keep thinking CRIS would not have elected the 50/50 if the probably was not high that they can make this work.

Thanks,
Peter

Hi Peter,

Sort of surprising news. Well the simple answer is that they are not seeing results that they “anticipated.” My guess is that they will redo the topical formulation or maybe do a injection of Hh antagonist to the cancer area (i think this is how the BCC trial was designed in 01 when curis was bringing it into the clinic?) There seems to be no signs of toxicity, so up the dose, frequency, and make it more permeable to reach the basal area. I doubt they will change the drug candidate unless the structure is causing it not to reach the proper skin depth.

“Possible scenarios include, but are not limited to the following: extending the duration of the treatment regimen of the existing drug candidate, developing a new topical formulation of the existing drug candidate, selection of a new drug candidate, negotiation of the return of the compounds to Curis for Curis' further development, or termination of the basal cell carcinoma drug program.”

I would like to see what type of patients they treated. This might give some info about possible scenarios of changing the regimen. My thoughts regarding this, is because people with multiple BCC usually have gorlin syndrome, which have a ptch gene mutation. (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109400) These people inherit this syndrome and often have multiple BCC. IF some of these 7 patients as stated in the press release had gorlin syndrome and they did not respond as “anticipated” then there is definitely a problem with the formulation of the cream.

Mutationally speaking all people who have somatic mutations either caused by UV or some other environmental factors have about 70% mutations in ptch or smo. Based on the known mechanism of the Hh pathway, this says that they SHOULD be able to treat/cure about that percentage (70). The other 30% show Hh activation and is more up in the air if these can be treated.

As you can see it is hard to say what really went wrong, my guess is that it is on genentechs formulation, frequency, and concentration. There is another thing that they are probably doing. This would be after treating the BCC with the Hh antagonist, they are removing it to see if the Hh antag eradicated the tumor. because they are removing these tumors it would be very easy to subject them to the same Hh antag as in the BCC trial and see if it could treat the tumors in vitro. So there are lots of things that they could be doing to see why the anticipated results are lower then what they expected.

I might know more in about a week what the real problem is/was. If anybody calls curis please post what you find.

HH,

Looking at the PR and the list of possibilities, I think that CRIS/DNA will be heading in another direction with this program.

It will take me some time to sort through it but I am thinking that this will either be a longer time in the making and/or the outcome of this early stage will be used to formulate an alternative CRIS/DNA project.

Hh,

If they go back to injection for BCC that will be 5 years lost. As mentioned previous on this board they did not proceed with original IND to partner and go the Topical route. From what Dan said, they selected DNA (as much as DNA picked) them due to their expertise in topical formulation. With that in mind the news may be worst than we are thiking.

Hh,

I am also surprised by the lack of press support from DNA. Usually CRIS related news doesn't show under their ticker. They generally do not issue seperate statements, I do not know if that is part of the arrangement, so when good news CRIS hardly reacts, when seemingly bad news,the problem appears to be CRIS' alone and it gets creamed. I posted on DNA board last year and many had never heard of CRIS or hedgehog.

I wonder why dna changed it from a local injection to a topical formulation.

" I wonder why dna changed it from a local injection to a topical formulation. "

I believe they were trying to hit another target market. The idea of having a topical vs injection is/will be a more appealing product and have many more advantages.

Know:
• Current BCC Hh antagonist can overcome mutations in ptch and smo genes.
• Current BBC studies have put between 60-70% of all BCC patients have a mutation in one of those genes.
• All BCC’s have abnormal Hh expression compared to surrounding tissue.
• Hh antagonist seem to work great on tumors that have Hh pathway activation but don’t have mutations in Ptch and Smo. Most of these studies are oral doses of the Hh antagonist.

Don’t Know:
•What formula they used
•What patients they treated. For example there is a syndrome called Gorlin’s.
“Gorlin syndrome: The nevoid basal cell carcinoma syndrome, a genetic disorder inherited in an autosomal dominant manner and characterized by a broad face, rib malformations, and an extraordinary predisposition to basal cell carcinoma, a type of skin cancer.

The gene for Gorlin syndrome has been mapped to chromosome 9 and has been identified as PTCH, the human homolog of the Drosophila "patched" gene PTC.”
Let me try to explain this. Ptch is a gene in the Hh pathway, if ptch does not work properly then the Hh pathway is turned on. People with Gorlin syndorme almost always develop BCC and often have multiple BCC. In the European trial they treated a patient who had Gorlin’s syndrome, and it worked very well. So my question will be to DNA or Cris if they treated any patients with Gorlin’s syndrome. If they did and did not see eradication of tumor or significant decrease in tumor volume then there is definitely a problem with their topical formulation. On the flip side, if they only saw eradication in gorlin syndrome patients then BCC might not last much longer. So if they can answer this question it would yield a lot of insight into how bad the PR really was. If you have questions please ask.

Here is some info about topical formula in the BCC human trial in Europe:


The mouse models all use DMSO with the Hh antag which would definitely penetrate the basal area, and work great with. The animal model is just like a gorlin patient and it used the same Hh antag as the one that is current in the clinic.

Here is a long snippet from the curis paper.


Concluding remarks: Just based on the Hh pathway mechanism, animal models, and PR my guess is that it is a problem with the penetration of the skin. Remember curis was originally going to use an injection to the BCC area. As noted above by simple asking what type of patients they treated and a little info about how it worked with those patients would give us a lot of new info. My guess is that they will change the cream, and make it readily penetrate the skin, maybe up the dosage and frequency due to little to no toxicity.

They are not seeing very good results, they don’t really know why, but they are going to check the “clinical activity” which hints that the cream is not penetrating the skin to reach the basal area. Even if you up the dose it still probably won’t be able to penetrate the skin. Hence this is why they cancelled the highest dose. Because of penetration problems... They won’t know this for sure unless they finish the “clinical activity” part, however, as I have been saying if they treated a “gorlin syndrome” patient it up help clarify issues of penetration versus it just not working at all.

My best guess is going to be that they are going to have to redo the topical formulation, and I don’t know enough about the FDA to say how much that is going to set them back? Do you have any ideas?

A little more info about Presentation at bean murry.

The presentation said.

1) Completely cleared SOME BCC.
2) It was safe & well tolerated

What they are going to do next: (understanding the dynamics of what is happening)
1) Stop dosing patients at highest dose due to no tumor eradication in SOME pateints
2) Con’t with part three of trial to determine clinical activity
This will include how their current Hh inhibitor is working? Is it penetrating deep enough? It is only killing the cancer cells on the outside of the tumor, where is it clearing the lesion?

Future:
Depending on what they find in clinical activity these are some of their options:
1) If it starts clearing BCC cells then they might just increase the length of the Hh inhibitor.
2) If they think the problem is with the cream they could create new cream with or without the current Hh inhibitor.
3) If options 1 and 2 don’t seem logical then BCC will be stopped or return compound to curis .

Thoughts?

I also want to say that it was very stupid to make a cream with concentrations of the Hh inhibitor range from 0-4%. You would think that they would have made the range larger in case something like this happen. Or put a more potent inhibitor in the cream.

HH,

You stated:

" I also want to say that it was very stupid to make a cream with concentrations of the Hh inhibitor range from 0-4%. You would think that they would have made the range larger in case something like this happen. Or put a more potent inhibitor in the cream "

This is the first step of this trial.Based on their prior lab work/research they begin the testing based on the lowest dose compound possible. Rarely if ever is a trial run the other way around. The basis is always to get results with the lest amount of compound/drug.

Though it is frustrating to note this, the other side of the coin of using high concentrations could produce disasterous results . Ultimately, this would hinder further trials and/or be costly to defend a certain product safety going forward.

Think of all situations ,all outcomes . Beginning slowly, not having something work 100% vs. heavy hitting , toxic or bio damage occuring to patients, pending lawsuits by trial patients....etc.

Understand?

Yes I understand about the tox problems. However, don't you think they should have made the compound either more potent or a large range in concentrations? Unless they saw tox @ the 4% level in animal models, and in humans they haven’t seen it at that concentration.

Like you said which is a good point start slowly and work up to higher concentration or prolong the duration pending some clearance in ALL BCC’s. In the animal model they must have seen complete clearance at that dosage and duration. Here is another interesting thought... There is a large body of evidence that BCC arises from hair follicle stem cells. Mice hair or fur is greatly different then human hair. (this also goes for P&G hair program) This could be a little hick up in their model. They could have transplanted human BCC into the mice but I have not heard of anybody doing this due to difficulty in maintain BCC alive. In other words, BCC would be eradicated regardless of Hh inhibitor or nothing.

Anyways good post. Like your thoughts!

HH,

The key lies within the ramifications of using a higher dose concentration than necessary. They needed to begin at the level of the material that got the trial approved in the first place. There is no way that documents submitted showing XYZ pre clinical results (which then get approval to begin testing) would ever risk deviating from a certain protocol. It would be like a diet compound that was shown to have potential at certain pre clinical levels...then being upped to work with no regard to the cost of the patients health.

The legal cost of going before the FDA to try to undo a botched trial is not financially nor ethically wise. You are allowed certain parameters in which you must systematically work through the process. Overdosing patients, even if it has no long term toxicity , is not the goal of any drug/compound trial.

I dunno, it is hard to say it the delay is good or bad. IMO, it means there is no bad news as in they are not stopping the trail. My guess is that they are talking to the FDA and trying to see what they can do based on P1 and some of their clinical activity of their drug. For example, reformulate the compound. Genentech seems pretty confident about BCC at least from a mutation stand point. Their mutation analysis of BCC is 100% for two key genes (ptc/smo) which their current antagonist can over come. MY estimates were about 80% leaving about 20% unaccounted for. Which translates to 80% of patients clear the lesions and 20% may or may not, and Genentech’s estimates are 100% clearance. This is all based on mutations numbers.

If you listen the presentation of Genentech talking about BCC which is in the members only section (means you have to get a user account which takes about 2min), they didn’t really look at the tumor biology more of hair biology. Genentech also said that mouse/human skin is very different.


BCC is already treatable and no need for a drug for a cancer already essentially curable. Only reasons is for cosmetic effects and the chance of scarring.