What “should be” behind the jump in Curis (CRIS, $1.99)

Rick Currin

CurrinResearch.com

8/30//09

As you know, we just recently boosted our portfolio position in Curis by 25%.  So the 30% spike in shares this week is rather timely.  Our investment in Curis however is aimed at a long term gain of much more.  We believe Curis could be sitting on a goldmine.

With the spike in Curis shares this week based (according to market speculating pundits) on a revived rumor that Roche may have interest in acquiring Curis, portions of our report “Genentech…all about the Roche acquisition.  Or is it?” bears repeating.  But read on to find out why we are really excited about what “should be” behind the lift in Curis shares.

Pathway to other cancers
 
The hedgehog pathway is indicated in a wide range of cancers.  Success in basal cell would likely translate to other cancers where aberrant hedgehog pathway activity is indicated.  Just this past week Curis announced that Genentech and the National Cancer Institute would cooperate to investigate GDC-0449 in a variety of cancers.  While this news can be viewed as premature for evaluating any revenue potential, we believe it shows what Genentech believes they have in the hedgehog.  Already they are looking to speed along having the drug evaluated in many other indications beyond basal cell.  If the promise was not high, that is not something they would do.
 
The National Cancer Institute is already recruiting patients for two studies.  The first is for solid tumors and the second is for brain cancer.  The solid tumor category is a very expansive target of cancer.  Success in this area would create a blockbuster drug.
 … 
Genentech’s commitment to hedgehog is key for Curis.  We view holding on to Curis shares as a post DNA acquisition performer directly linked to DNA’s innovation pipeline.  With their previous setbacks and the impact that has had to cash burn, Curis is well under the radar.  The DNA milestone will help in that area.
 
Roche and Curis
 
Interestingly, Roche and Genentech already planned to collaborate on commercialization of GDC-0449.  Which means GDC-0449 was a Roche/Genentech and Curis project even before this acquisition attempt.  Could it be that Roche is just as excited about the potential for hedgehog?  We believe they very well could be.  The hedgehog is similar to Avastin in one critical respect.  If successful it will target mechanisms of cancer rather than a specific type of cancer and therefore have an immense market potential.

While Curis is a long range investment we remain optimistic about its chances especially with Genentech as a partner.  Notwithstanding the long range focus it was good to see the stock get a lift on the milestone payments and NCI collaboration news.
 
from our previous report:  (Genentech…all about the Roche acquisition.  Or is it?)

Takeover Rumors…Taking Over in theColon Cancer Treatment Market?

It’s certainly reasonable to think that if Curis’s hedgehog drug candidate (working its way through the pipeline with Roche holding Genentech as a partner) is a success in colorectal cancer, Roche will have interest in acquiring the company.  This is why we asked “Could it be Roche is just as excited about the potential for hedgehog?” while Roche was still trying to acquire Genentech. 

We believe “they very well could be” interested so the takeover chatter is certainly already part of our frame of reference for the Curis investment.  But the takeover chatter is not why we were excited about the movement in the stock last week.  It’s the real scientific news that has us excited.

Real News for Curis

What we found so interesting about the dramatic spike in shares for Curis was that the market couldn’t really identify a good reason for it.  So the standard takeover chatter rumors began to fly which likely led a few day traders or takeover speculators to the action as well. 

But while we were checking to find any takeover confirmation whatsoever (other than our own predisposition to recognize the logic of such an eventual acquisition), we were busier digesting some real news that the market failed to even mention. 

Targeting hedgehog has just been validated as a potent cancer killer for metastatic colorectal cancer. 

This news is far from the chatter of takeover speculation and indeed more obscure to market observers unfamiliar with Curis.  That’s what happens when a stock is under the radar.  But the news and its potential impact for Curis was plain as the eye can see for those following hedgehog research activity.

Perhaps instead of the takeover chatter headlines the following would really move Curis shares.

Curis’s Hedgehog drug candidate may help eradicate metastatic colon cancer.

(Or officially)

Human colon cancer epithelial cells harbor active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion

“Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced bCATENIN (bCAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases.  We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.”

Note: (bold and bold is our emphasis)

Source: (EMBO Molecular Medicine, released August 27th, Wiley-Blackwell )

OK so it’s a mouthful but actually understanding a biotech can be at times.  Perhaps talking about takeover chatter is just plain easier.

While Curis is not mentioned in the research of the Swiss scientists releasing the report, the implications of this research appearing in EMBO Molecular Magazine are large for the Curis drug candidate CDC-0449.  According to the scientists, targeting hedgehog and GLi1, as the Curis/Genentech/Roche drug candidate in phase II colorectal trials does, is predicted to decrease tumor bulk and eradicate colon cancer stem cells and metastases.    

While our mock headline may be a premature, it’s logically supported by the research just released. 

Whether the takeover chatter is accurate or not as a cause of the move in the stock, the reason for the move “should be” the research report issued by the Swiss scientists.  Perhaps not coincidently the research was released the same day as the supposed takeover chatter causing the stock to advance.  Our guess is that someone else in the market understood the implications of the scientific report and that the takeover chatter was just that.   

GDC-0449 and the Trojan Horse (Hedgehog: The Mutants vs. The Ligands)

We would like to draw your attention to our statement when we increased the Curis share position several days ago.

“We are adding to the position in Curis as a long term biotech stock.  While Curis remains years away from seeing their Genentech collaboration produce a cancer drug, there is substantial buzz about the candidate being a breakthrough in oncology.  Its early ability in Basal Cell Carcinoma (BCC) has been quite impressive as it progresses through clinical trials.

The BCC work is simply a Trojan horse candidate for a potential breakthrough in the general solid tumor cancer market that is the golden vein of biotech.”

Despite our long term focus, given the stock’s recent action, the brief statement begs fleshing out.  The reason we consider BCC a Trojan horse is because the likely efficacy of blocking the hedgehog pathway for BCC was fairly well recognized before heading to clinical trials, as BCC is directly related to hedgehog mutation.  Indeed early evidence suggests that GDC-0449 will be effective in BCC.  Basic BCC however is typically treated with simple surgical excision of the site.  Metastatic BCC is quite rare, thus a big market is not in store for BCC.  As GDC-0449 passed Phase I and moved to Phase II, it did so without blockbuster potential. 

However, with a favorable safety profile in hand from the BCC Phase I trial, Genentech moved GDC-0449 to phase II in ovarian and colorectal cancer.  In colorectal cancer GDC-0449 is teamed up with Genentech’s Avastin.  Ovarian and colorectal cancer are much larger markets and more commonly occurring (and unfortunately recurring), metastatic diseases.  However these diseases are not identified with being hedgehog mutation driven.  They are driven by hedgehog ligand instead. 

Huh?

If the mutation vs. ligand distinction was not an important one to Curis investors perhaps we wouldn’t bother going into this. 

Cancers driven by hedgehog ligand include colorectal, lung, esophageal, prostate, liver, pancreatic, and breast among others.  Hedgehog ligand essentially leads to the mechanism for a cancer cell to propagate cancer to an adjacent cell through hedgehog pathway activation.  In other words the cancer cell clones itself (or “self renews” as the Swiss scientists put it) to adjacent healthy cells through hedgehog pathway activation.   The Swiss study validates hedgehog ligand as critical and required for colorectal cancer metastasis.

That brings us to even more reason to be excited about the hedgehog ligand driven news associated with the Swiss study.  As noted in Curis’s latest investor presentation:

Genentech indicated that data to support positive ‘proof of concept’ data in ligand-driven

cancers is estimated to occur in Q4 2010 and, if positive, will result in potential rapid

expansion in additional indications including in the following cancers:

Small cell lung cancer, Pancreatic, Upper GI, Prostate, Multiple myeloma, Non-small cell lung cancer, Glioma, Endometrial, Melanoma

Source: Curis

With GDC-0449 already in Phase II for colorectal cancer, the Swiss study suggests that that “proof of concept” will arrive.  As early as 2010 many more cancer indications could be pursued by (Genentech) Roche. 

It would seem plausible if Curis has the keys to a general indication cancer molecule for a wide variety of cancers in the Roche pipeline, Curis may be a target.  

A hedgehog a day to keep cancer away?

It’s important perhaps to consider what the eradication of metastases of different cancers driven by hedgehog ligand could mean commercially.  What it could mean is that a patient with cancer would get the latest standard of care plus GDC-0449.   This is especially so for notoriously difficult and notoriously recurring cancers such as pancreatic, ovarian, colorectal, and lung.  Given that GDC-0449 is a daily dose cancer pill with seemingly few side effects to date, usage could be mind boggling as a cancer recurrence preventer.

The market potential is so large that the term finding a blockbuster drug might be replaced with “finding a hedgehog” drug.

We are bullish on Curis.  As of this writing we still haven’t seen anyone comment on Curis as it relates to the Swiss study.  Armed with this we view a pullback as an opportunity and a continued surge as perhaps more likely as the “real news” gets out.

Thank you.