For a special limited time:

         Save 30%!

 Get all 3:

           currinBiotech.com
 
            currinTechnology
  
                       and
  
              rick'sResearch

       
  
  for one low price.

                Learn more

Biotech Stock: Curis and the Swiss Army Knife

publication date: Dec 8, 2010
Print

Perhaps this is timely with an ‘unexplained' 9% move today in the stock.  12/8/10

-Rick Currin

  

 

Curis and the Swiss Army Knife

12/7/2010

Rick Currin

 

We'll focus on the Swiss army knife in the second half of the report.  In the first half we'll recap some of the clinical trial activity of Curis.

The hedgehog in the clinic

There are two areas of clinical focus in the hedgehog drug GDC-0449.  The first is in mutation driven cancers like Basal Cell Carcinoma.  Early clinical response in this area was very encouraging and we view this program as right on track.  Roche (Genentech) has also started a trial in operable basal cell that has much higher market potential than the metastatic basal cell condition that is the focus of the initial trial.

The second area of focus is on non mutation driven cancers.  In these cancers there is no direct mutation of the target hedgehog gene the molecule seeks to block.  However there are varying degrees of research evidence suggesting that hedgehog signaling is critical for cancer survival and metastasis even without the direct involvement of a pathway mutation.    

Troubles in focus area 2

Curis has had setbacks in its hedgehog drug clinical trials that are being executed in partnership with Roche (Genentech) in the second focus area.  In a colorectal cancer trial the drug failed to improve survival when combined with current standards of care.  In another trial as a maintenance therapy for ovarian cancer, the drug was investigated as a means to delay the recurrence of the disease. 

While some positive signs of activity occurred in the ovarian trial, the results were not robust enough to pass the statistical scrutiny needed in the trial.

In the case of the failed colorectal trial we were not too surprised that the drug couldn't provide a meaningful benefit though we were certainly disappointed it failed to show any improvement.   The reason we were not too surprised, despite some previous optimism flowing from a study that showed the hedgehog inhibitor could show a benefit, was because the fundamental nature of most colon cancer is not dependent on hedgehog signaling but on another pathway called the Wnt pathway.  While Curis has a license with Roche (Genentech) for developing small molecule drugs for the Wnt pathway as well, finding a good candidate has been elusive.  The Wnt program appears completely stalled as a small molecule approach though activity in this pathway is being pursued with antibodies.

In the ovarian trial we were more surprised that a positive result at least warranting some optimism to head to the next Phase did not occur.  That's because research in ovarian cancer does indicate a better rationale for hedgehog signaling impacting metastatic potential in this disease.  Still the actual hard evidence heading into the ovarian trial was rather scant. 

One has to wonder why Genentech chose two of the harshest trials for the drug.  One perhaps slightly cynical answer is that Genentech was trying to solidify the market position it has in colorectal cancer with the marginally effective Avastin.  The colorectal cancer trial used the hedgehog inhibitor with Avastin and another drug.  Another rationale would be that if the inhibitor showed promise in these tangential hedgehog indications it would be more obvious to show a result in diseases more directly associated with the hedgehog pathway. 

From our review of the research, several much more promising areas for hedgehog inhibition are small cell lung cancer, prostate cancer, pancreatic cancer, and breast cancer.  

Of all these more promising indications, all of which have some trial associated with them, pancreatic cancer is drawing the most attention clinically.

The Deadliest Cancer

Pancreatic cancer is known as the deadliest of cancers.  Survivability is very low and the drugs used for treating it have been only marginally effective at extending life.  The standard chemotherapy is a drug called gemcitabine (Gemzar).  This drug at least improved survivability to the current state. 

Some promising results were seen in a phase II trial combining Gemzar and Abraxane.  The investigator of this study was also the investigator of the Phase I hedgehog trials, Dr. Von Hoff. 

Dr. Von Hoff believes that adding a hedgehog inhibitor to the Gemzar + Abraxane regimen could bring us close to a cure for the disease.  Of course cure and cancer should always be taken with a real measure of caution by investors.  However, unlike with the colorectal trial there are good reasons to be more optimistic about the role of hedgehog signaling in pancreatic cancer.  Perhaps most importantly is the pre-clinical trial work of combining a hedgehog inhibitor with Gemzar or Abraxane.

 "A paper published in Science last year by Cancer Research UK's Cambridge Research Institute in collaboration with Infinity reported that in a transgenic mouse model of chemotherapy-resistant pancreatic cancer, the administration of IPI-926 in combination with gemcitabine improved drug delivery, and resulted in induction of apoptosis in the tumor, decreased metastases, and a doubling of median survival as compared to control.

Further, Infinity presented new preclinical data at AACR building upon the rationale for combining IPI-926 with a variety of chemotherapies in pancreatic cancer. Data reported show that in a xenograft model of pancreatic cancer, the combination of IPI-926 and nab-paclitaxel resulted in 77% tumor growth inhibition compared to control (p=0.0048). These data, along with data showing an increase in tumor perfusion by IPI-926, demonstrated that IPI-926 may increase the activity of nab-paclitaxel through increased drug delivery."

Infinity Pharmaceutical Press Release announcing initiation of Pancreatic Cancer Trial with their Hedgehog Inhibitor IPI-926

While the Curis and Infinity drugs are different they both act as inhibitors of the same target.  Previous studies in mouse xenograft models using cyclopamine (the naturally occurring hedgehog inhibitor found in the corn lily plant that also hits the same target at GDC-0449 and IPI-926) also demonstrated promising results in combination with Gemzar.

From our review, we identified three major aspects of pancreatic cancer that could benefit from hedgehog inhibition.  While these obviously have to be verified in human clinical trials, we view it as promising that pancreatic cancer provides 3 different bites at the apple for a hedgehog pathway inhibitor to prove effective in combination with either Abraxane (nab-paclitaxel) or Gemzar (gemcitabine).

 

  • Pancreatic cancer cells impart hedgehog signaling on adjacent non cancerous cells.  This leads to providing growth support to the cancer.  It is believed that this growth support also helps to form the dense wall or cocoon around the pancreatic cancer cells that makes getting chemotherapy drugs like Gemzar and Abraxane to the cancer difficult. 

 

  • Hedgehog signaling promotes drug efflux.  Drug efflux is the ability for a cancer cell to "pump out" whatever drug is trying to be delivered to the cell.  This is especially problematic in pancreatic cancer as the fibrous wall around the cancer already makes getting enough Gemzar to the cancer cells a problem.

 

  • Hedgehog signaling promotes a target gene called N-myc that leads to proliferation of cancer.  The Myc gene promotes glucose and glutamine metabolism as necessary for cell proliferation of the pancreatic cancer cells.  Pancreatic cancer cells have been dubbed "addicted to glutamine" which may be the fundamental cellular reason why the cancer cells are sending hedgehog signaling activation requests to adjacent cells.  That is they want more glutamine and activating the hedgehog pathway in adjacent cells is the way they get it.

 

From a pure science standpoint these 3 areas provide 3 reasons, along with the promising pre-clinical evidence, to have substantially more reason to be optimistic about using a hedgehog inhibitor in combination with either Gemzar or Abraxane (or both) in pancreatic cancer.  Much of this is echoed in a very interesting news feature that appeared during a CBS News Stand up to Cancer series.  The profile features Dr. Von Hoff.

 

 

CBS News - The Cure for Pancreatic Cancer

Click the image to view the Stand up to Cancer Telecast on YouTube

 

The patient profiled in the piece has received the Gemzar/Abraxane combination.  The video also describes in easy to understand language the rationale for adding the Hedgehog inhibitor  GDC-0449 to that regimen.

One interesting thing about this trial from the standpoint of Rick's Research subscribers is that it combines all 3 of the companies originally selected as oncology stocks in the CurrinResearch portfolios.  Abraxis Biosciences (acquired by Celgene) developed nab- paclitaxel Abraxane. Genentech (in partnership with Curis developed the hedgehog inhibitor GDC-0449) and was acquired by Roche.  While this may just be an unusual coincidence of sorts it does highlight the approach to oncology stocks we are using in currinBIOTECH.  That is, using a baseball analogy sometimes used in biotech, a mixture of later stage and earlier stage biotech stocks provides the potential for near term success as doubles or triples and longer term success (albeit with a bit of patience) in the form of home runs and grand slams.

 

The Swiss Army Knife

In oncology there is increasing realization that molecules that attempt to block a single target may be initially effective only to ultimately suffer from resistance to the therapy.  This resistance can come from the activation of another pathway or from the backdoor activation of the same pathway via another cellular mechanism.

We liken the problem to that of a determined burglar unable to access the front door being pretty consistent about getting through either a window or back door.  Such is the nature of a cancer that seems determined to not only survive but proliferate.

Drugs companies are finding ways to deal with the problem.  The method being investigated in scores of clinical trials is to combine 2 or perhaps 3 drugs. 

Some examples will provide clarity.  Gleevec is a very effective drug at forcing remission of leukemia.  However the drug does not seem to kill the cancer stem cells that can ultimately lead to relapse.  For Gleevec, which is arguably one of the most effective targeted therapies on the market, the relapse might occur several years from treatment.  Of course it might occur sooner depending on the patient.

Studies indicate that combining Gleevec with a drug called an HDAC inhibitor can target not only the Gleevec target but also the leukemia cancer stem cells. This is viewed as very promising for eliminating the relapses seen with Gleevec used alone. 

Of course the use of two drugs presents special issues.  Are the drugs safe together?  Does the HDAC allow Gleevec to work optimally?  Do the drugs have interactions or clear the body at the same rate?

Curis has taken an approach we call the Swiss army knife.  Instead of using 2 or 3 drugs with the issues of assuring that they indeed work safely together, the company is combining the Gleevec target with HDAC in one molecule. 

With one drug to administer for two or more targets there is tigher control of safety and efficacy.  The overall Curis approach can potentially take advantage of all the experience gained with Gleevec and Gleevec/HDAC combination research.  As a Swiss army knife the HDAC is the red body of the knife as it is common to whichever drug target blade is pulled out in combination.

Thus Curis has a platform.  The platform is HDAC in combination with other proven drugs.  This has powerful potential for licensing as companies without a leukemia drug look to enter that market.  Similarly, combining HDAC with a known breast cancer drug like Herceptin led to Curis's first Swiss army knife drug in the clinic.  That drug is CUDC-101.  The beauty of the platform is that Curis has and is seeking further patent protection for the combination approach.  That potentially opens the entire cupboard of "proven candidates" to the company.  In terms of the Swiss army knife it is "proven candidate" - HDAC - "proven candidate".  We like the platform and view it as fully disregarded in determining Curis's current market cap.

The possibilities are mind boggling as far as what Curis could produce in the Swiss army knife platform. 

Much more intriguing than the promises and pitfalls of hedgehog clinical success in the shorter term is this multi targeting platform approach that is the true long range reason to own Curis.  The approach literally opens up virtually every successful drug that suffers from the backdoor resistance problem (and that's every one of the targeted therapies Herceptin, Tarceva, Gleevec, Nexavar, Erbitux, etc.) to being improved upon in a "single candidate combination therapy" that can be licensed to a competitor of those successful drugs.

Hedgehog and the Swiss Army Knife?

The hedgehog inhibitors that target the gene SMO have already been exposed as having a backdoor issue.  When mutations in the gene called RAS are present, hedgehog signaling can be activated regardless of the SMO blockade imparted by GDC-0449.  However, in order for the RAS mutation (kras) to proliferate it needs to reproduce from a cancer cell. 

HDAC helps prevent KRAS proliferation by way of blocking the DNA replication of the cells that have this mutation.  As the base of the Swiss army knife HDAC becomes a good choice as it works on the general DNA replication of the troublesome mutations that lead to drug resistance.

Of course blocking general DNA replication also has side effects of its own that we are watchful to access in early results.

So while hedgehog signaling may not have been effective in colorectal cancer or ovarian cancer harboring kras mutations it is feasible and perhaps even likely that adding a drug that helps block kras (a PI3K or HDAC inhibitor for example)  will be effective in a combination.  From our point of view Curis stands in a unique position to tackle combination therapies and attract licensees on its way to long term success. 

 

Editor's final note -12/8/10-  Shares of Curis are higher today by about 9%.  We view this as sort of a ‘putting the pieces together purchase' by someone following HDAC safety results as related to the hematology (i.e. leukemia) space. 

A company with an HDAC inhibitor (the foundation of the Curis platform) just released very good safety data and is moving to a Phase II trial seeking "combinations".  HDAC alone is not the drug needed...is it a Swiss army knife using HDAC?

In addition there were study results released today showing that a drug similar to one element of Curis's latest candidate CU-201 performed better than Gleevec.  This bodes well for finding a CU-201 partner. 

One thing about stocks under the radar is people sometimes don't even know what news happened today that is very relevant. 

Research is your edge in smaller names like this.