One big step forward one small step back for hedgehog inhibitors

What should be an exciting time for companies testing oncology candidates utilising hedgehog inhibition has to be tempered with some disappointment. The first US approval of a drug in the class, Roche and Curis’ Erivedge, followed closely the mid-stage failure of one of the most advanced products, Purdue Pharma and Infinity Pharmaceuticals’ IPI-926, in pancreatic cancer.

With two other products in the midst of phase II trials and the Infinity-Purdue compound active in other indications, the next two years will be pivotal in the development of the drug class (see table). With about a dozen phase II trials due to report by the end of 2013 if additional indications for Erivedge are included, pharma executives should soon have a much better idea of hedgehog inhibitors’ promise.

Highs and lows

The hedgehog signalling pathway has a role in embryonic cell development and differentiation. It is mostly inactive in adults, but when it misfires it can cause transcription of genes that are believed to lead to tumour growth.

Hedgehog inhibits a protein receptor called patched, which in turn inhibits a downstream signalling protein receptor that blocks key hedgehog transcription factors. In the presence of hedgehog the smoothened pathway is uninterrupted, allowing for the transcription of hedgehog target genes; thus, Erivedge and some other candidates in the class act as inhibitors of both hedgehog and smoothened.

Erivedge’s approval - coming an impressive month earlier than anticipated - followed a pivotal trial that showed it significantly shrank basal cell carcinomas. They are mostly non fatal-tumours treated with surgery, but can aggressively invade surrounding tissues and become inoperable. Non-surgical options are imiquimod and 5-fluorouracil topical creams, but they are effective only with early stage tumours; Erivedge is intended for patients with advanced disease.

It is not an insignificant indication – EvaluatePharma’s consensus forecasts $285m in 2016 sales. It is originator Curis’ only product on the market; its most advanced pipeline product is in phase I.

Infinity, on the other hand, tried in the notoriously difficult pancreatic cancer indication, which has known little but failure; thus it was a high-risk trial that if successful would have paid handsomely.

Investors had been expecting the trial in metastatic disease in combination with gemcitabine to read out in the second half of the year, and shares had mounted to a four year high of $10 last week. Instead, Massachusetts-based Infinity reported that the interim data analysis showed overall survival favouring gemcitabine plus placebo over the arm with IPI-926.

Phase II trials continue in chondrosarcoma, which may report in the latter half of 2012, and myelofibrosis, expected in 2013.

The rest of phase II

Novartis and Bristol-Myers Squibb both have entrants in the hedgehog game that are moving toward critical phase II validation. The Swiss company lists four trials of LDE225 in basal cell carcinoma and Gorlin’s syndrome, an inherited condition that results in such carcinomas – the largest, a 120 patient efficacy and safety trial, is not likely to report until late 2013.

Phase I/II trials are also planned in pancreatic cancer and adenocarcinoma in combination with gemcitabine; those trials are likely to report in the second half of 2013 or early 2014.

BMS and Exelixis’ XL139 is being tested with Sprycel in two leukaemia phase II trials. The larger of the two is a 271 patient test in the US not expected to report until 2014, so those trials will be anxiously awaited.

In phase I Pfizer, Eli Lilly and Takeda are also trying their hands at the hedgehog game. With Erivedge coming to the market, investigators in phase I and those preparing to move projects into the clinic must be heartened to know the class appears to have a future. Given the direction of later-stage trials, it will be interesting to see if hedgehog inhibitors can prove themselves outside of the skin, blood and connective tissue cancers toward which the current research is gravitating.

Hedgehog pathway inhibitors in clinical development
Phase (Current) Product Pharmacological Class Generic Name Company 2012 sales ($m) 2016 sales ($m) Indication Summary
Approved Erivedge Hedgehog pathway/smoothened (SMO) inhibitor vismodegib Roche/Curis 29 285 Skin cancer, non-melanoma [Approved]; Stomach cancer [Phase II]; Glioblastoma multiforme [Phase II]; Brain cancer [Phase II]; Small cell lung cancer (SCLC) [Phase II]; Pancreatic cancer [Phase II]; Solid tumour indications [Phase I]; Ovarian cancer [Abandoned - Phase II]; Colorectal cancer [Abandoned - Phase II]
Phase II LDE225 Hedgehog pathway/smoothened (SMO) inhibitor erismodegib Novartis - 13 Skin cancer, non-melanoma [Phase II]; Pancreatic cancer [Phase II]; Solid tumour indications [Phase I]; General cancer indications [Abandoned - Pre-clinical]
XL139 Hedgehog pathway/smoothened (SMO) inhibitor - Bristol-Myers Squibb/Exelixis - - Leukaemia, chronic myeloid (CML) [Phase II]; General cancer indications [Phase I]
IPI-926 Hedgehog pathway/smoothened (SMO) inhibitor saridegib Purdue Pharma/Infinity Pharmaceuticals - - Pancreatic cancer [Phase II]; Bone cancer [Phase II]; Myelofibrosis [Phase II]; Solid tumour indications [Phase II]; Head & neck cancers [Phase I]; Leukaemia, acute lymphocytic (ALL) [Pre-clinical]; Ovarian cancer [Pre-clinical]; Small cell lung cancer (SCLC) [Pre-clinical]
Phase I TAK-441 Hedgehog pathway inhibitor - Takeda - - Solid tumour indications [Phase I]
LY2940680 Hedgehog pathway/smoothened (SMO) inhibitor - Eli Lilly - - Solid tumour indications [Phase I]
LEQ506 Hedgehog pathway/smoothened (SMO) inhibitor - Novartis - - Solid tumour indications [Phase I]
PF-04449913 Hedgehog pathway/smoothened (SMO) inhibitor - Pfizer - - Leukaemia, chronic myeloid (CML) [Phase I]; Solid tumour indications [Phase I]

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