Therapeutic focus - Hedgehog targets given boost with phase II skin cancer data

Analysis

Roche and Curis appear to have taken a step closer to the market with a novel drug for the most common form of skin cancer that analysts believe could establish a new standard of care for the disease. GDC-0449, a hedgehog inhibitor, significantly shrank tumours in patients with basal cell carcinoma (BCC) in a potentially pivotal phase II study, the companies announced today.

Roche will now talk to regulators about filing for approval this year - significant progress for a drug that has suffered a number of clinical failures. GDC-0449 is still leading the pack in this class of drug but a number of other agents are also making progress; further mid-stage data from other candidates working on the hedgehog signalling pathway could emerge in the coming months (see table below).

Shrinking tumours

Curis announced today that the open-label study, which recruited 104 patients with inoperable BCC, met its primary endpoint of achieving a target overall response rate. The drug, now generically known as vismodegib, shrank advanced BCC tumours in a pre-defined percentage of people in the study.

Adverse events occurred as expected although there were deaths in the study – these are being investigated and are not thought to be related to the drug.

BCC rarely or causes death, but it can aggressively invade surrounding tissue and in some cases recurs regularly. Sometimes the tumours can be removed with surgery, but this is not always possible, and in those cases there is no alternative therapy. As such, these inoperable cases represent the biggest market opportunity, although Roche did start a phase II trial in operable cases last year. Results are due next year.

Hopes for success in this trial were raised earlier this year after the companies revealed positive data in patients with Gorlin's syndrome, a more severe form of BCC where people are genetically predisposed to developing these tumours. Patients given the drug developed fewer BCCs than those given a placebo pill while the size of existing lesions was reduced. Several patients had near remissions while no resistance emerged.

Still, in this trial 20% of patients dropped out due to tolerability issues, which could ultimately limit the market potential of the drug, some analysts believe. When full results of the trial announced today are detailed, possibly at the cancer conference ASCO later this year, the side effect profile will be closely scrutinised. For a cancer that is not fatal, an adverse side effect profile would feasibly only be acceptable in patients without the option of surgery.

Genetic mutations

Basal cell carcinoma is almost always caused by a mutation in an oncogene called Patch, which activates the hedgehog signalling pathway, stimulating tumour growth. Like another pipeline drug in this area, Novartis’ LDE225, vismodegib targets a protein implicated in the pathway called smoothened.

Gene mutations leading to activation of the hedgehog pathway are implicated in other cancer types such as medulloblastoma in children. Phase I data has been promising in this setting for vismodegib as well.

However in other cancers these agents have had less success – vismodegib failed in ovarian and colorectal studies last year (Curis drops on second hedgehog setback but could value be hibernating?, August 10, 2010). And studies of other drugs in the pipeline are restricted to a few cancer types, the table below shows.

In other news

News from the remainder of the hedgehog pipeline is on the horizon.

Novartis’ LDE225 is the closest competitor to vismodegib. A pivotal phase II is recruiting 36 patients with skin basal cell carcinomas associated with Gorlin's syndrome. Results should be announced by the end of the year and Novartis expects to file the drug in 2012. Phase I data from a follow-on SMO inhibitor, LEQ506, is also likely to read out next year.

Another phase II stage candidate is Infinity Pharmaceuticals’ IPI-926. Earlier this year the phase II portion of a PI/II trial was initiated in 120 patients with pancreatic cancer, in combination with gemcitabine; data from the phase Ib portion of the study should be available by the end of the year. Meanwhile a phase II trial recently started in 100 patients with chondrosarcoma, a rare but life-threatening form of bone cancer.

A phase I trial of Pfizer’s PF-04449913 is ongoing and is examining the compound’s effects in combination with dasatinib or bosutinib in chronic myeloid leukaemia; the trial will recruit 94 patients although data is unlikely before 2013.

And Exelixis’ XL139, already partnered with Bristol-Myers Squibb, is currently undergoing four phase I trials in a number of different tumour types.

A phase I trial of TAK-441 started at the end of last year in up to 46 patients with advanced non-haematologic malignancies, including basal cell carcinoma, with results not expected until 2013.

Further hurdles

Curis shares leapt 10% to $3.23 in early trade today, and the stock is now firmly back to the levels of June last year, before the two clinical set backs knocked confidence.

The compound still has several hurdles to vault before it reaches the market – full data still needs to be seen and regulators need convincing that accelerated approval is justifiable.

However the signs are certainly looking promising in BCC. Efficacy in other cancers types now needs to be seen, although it is looking unlikely that agents targeting hedgehog signalling will find a role in bigger oncology indications for now.

Still, early work on combinations of these agents with other targeted therapies is being explored by researchers, particularly in the field of overcoming drug resistance.

Hedgehog inhibitors could be emerging from hibernation.  

Hedgehog pathway antagonists in clinical development
Status Product Pharmacological Class Company Originator Lead Indications Launch WW annual sales in 2016 ($m)
Phase II Vismodegib (RG3616 / GDC-0449) Hedgehog protein antagonist Curis + Roche Curis Skin cancer, non-melanoma [Phase II]; Trial ID: NCT00833417
Colorectal cancer [Phase II]; Stomach cancer [Phase II]; Glioblastoma multiforme [Phase II]; Brain cancer [Phase II]; Small cell lung cancer (SCLC) [Phase II]
 2012  -
LDE225 Smoothened (SMO) inhibitor Novartis Novartis Skin cancer, non-melanoma [Phase II]  2013  47
IPI-926 Hedgehog protein antagonist Infinity Pharmaceuticals + Purdue Pharma Infinity Pharmaceuticals Pancreatic cancer [Phase II]; Chondrosarcoma [Phase II]  -  -
Phase I PF-04449913 Hedgehog inhibitor Pfizer Pfizer Leukaemia, chronic myeloid (CML) [Phase I]  -  -
XL139 Hedgehog protein antagonist Exelixis + Bristol-Myers Squibb Exelixis Small cell lung cancer (SCLC) [Phase I]; Multiple myeloma [Phase I]; Stomach cancer [Phase I]  -  -
TAK-441 Hedgehog protein antagonist Takeda Takeda Solid tumour indications [Phase I]  -  -
LEQ506 Smoothened (SMO) inhibitor Novartis Novartis Solid tumour indications [Phase I]  -  -

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