Therapeutic focus - Avastin approved for brain cancer but late-stage pipeline is thin

Analysis

It is illustrative of the severe lack of treatment options available to treat glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer, that the FDA was willing to grant approval to Roche’s Avastin on the basis of results from a phase II trial in only 85 patients.

Once chemotherapy, radiotherapy and surgery fail to stem the disease’s progress, no treatment options remain. In this patient population Avastin managed to produce some credible results, including shrinking tumours to half their size in 28% of those treated. The antibody therefore becomes the first new treatment for GBM in more than a decade. Unfortunately, the late stage pipeline coming up behind is thin, so unless another compound can produce exceptional results and also win accelerated approval, options look set to remain limited for the foreseeable future (see table below).

On the market currently are the chemotherapy agents Temodar, sold by Schering-Plough, which is about to lose patent protection, and carmustine, which has been available generically for a number of years. A device called Gliadel Wafer, which is sold by several companies worldwide including Eisai, is used after surgery. Dime-sized wafers are implanted in the cavity created when a tumour is removed, which deliver carmustine, in an attempt to prevent or at least slow the return of the disease.

Avastin now joins this short list of available treatments.

Late-stage pipeline

The phase III pipeline contains a couple of hopeful candidates. Recentin from AstraZeneca is a once-daily, orally available, highly potent and selective VEGF signalling inhibitor that inhibits all three VEGF receptors, which are involved in the formation of new blood vessels. Although a phase III trial in recurrent glioma is underway, Astra’s main research focus is colorectal cancer, where it is pitting Recentin head-to-head against Avastin. Brain cancer data should be available early next year.

Cilengitide from Merck KGaA is a bit further behind, and is the first in a new class of investigational anti-cancer therapies called integrin inhibitors to reach phase III development. Integrin inhibitors target integrins, specific cell surface receptors that are improperly regulated in many tumour types and involved in cancer growth, specifically preventing the formation of new blood vessels to the tumour. The phase III Centric trial, which started in October last year, should report some time mid-2012.

Long shot

The other two candidates in phase III are far more uncertain. Pfizer’s CDX-110 is an immunotherapy vaccine that targets tumour specific EGFR mutant EGFRvIII, which may be expressed in up to 50% of GBM. However, the ongoing ACT III trial last year reverted to a single arm phase II trial because too many patients withdrew from the control arm, meaning the product is likely to be many years away from the market.

Pfizer licensed the vaccine from Celldex last year for $40m upfront and an equity investment of $10m, in a deal worth up to $390m.

Meanwhile, the way forward for NeoPharm’s candidate is very unclear, after permission from Indian regulators to conduct a confirmatory phase III trial of Il-13 was revoked late last year. Permission was dependent on concurrent enrolment of patients in a trial in the US. At the end of 2006 the company announced that a phase III trial had failed to prove the treatment was any more effective than Gliadel Wafer. However, the drug is being studied under a co-operative research agreement with the US National Institute of Neurological Diseases and Stroke, in various brain cancers.

The drug is a recombinant protein, cintredekin besudotox, consisting of a single molecule composed of two parts: a tumour-targeting molecule (IL13) and a cytotoxic agent (PE38). IL13 receptors are found on malignant glioma cells, but rarely on healthy brain cells.

Further back

The phase II pipeline contains many drugs also in development or on the market for other cancers, such as Tarceva and Zactima.

Candidates of note include Bristol-Myers Squibb’s Angiocept, which it acquired via its purchase of private biotech Adnexus in 2007. The compound is a highly potent VEGFR-2 pathway antagonist, acting on all protein activators in the pathway. Developing drugs to target tumours in the brain is especially hard because the compound has to be very small to cross the blood brain barrier, and Angiocept’s very small size could make it highly effective in acting on GBM.

Although few details have been given in the last year on its progress, entries on www.clinicaltrials.gov suggests data could be available in the first half of next year.

Lastly, Myriad’s Azixa is a small molecule with a dual mode of action, both a vascular disruption agent and a tubulin inhibitor, able to cross the blood brain barrier. Phase II trials to assess safety and efficacy are ongoing, with data on survival due in 2011.


Late-stage glioblastoma multiforme pipeline
Product Generic Name Company Pharmacological Class Indication Summary
Phase III Recentin (AZD2171) cediranib AstraZeneca VEGFr kinase inhibitor Colorectal cancer [Phase III]; Glioblastoma multiforme [Phase III]; Renal cell carcinoma (RCC) [Phase II]; Leukaemia, acute myeloid (AML) [Phase II]; Gastro-intestinal stromal tumours (GIST) [Phase II]; Breast cancer [Phase II]; Non-small cell lung cancer (NSCLC) [Phase II]
Cilengitide cilengitide Merck KGaA Angiogenesis inhibitor Glioblastoma multiforme [Phase III]; Prostate cancer [Phase II]; Leukaemia, acute myeloid (AML) [Phase II]; Melanoma [Phase II]; Glioma [Phase II]; Head & neck cancers [Phase II]; Kaposi's sarcoma [Phase I]; Non-small cell lung cancer (NSCLC) [Abandoned - Unclassified]; Pancreatic cancer [Abandoned - Unclassified]; Breast cancer [Abandoned - Unclassified]
CDX-110 - Pfizer/Celldex Therapeutics EGFr cancer vaccine Glioblastoma multiforme [Phase III]; Prostate cancer [Phase I]; Ovarian cancer [Abandoned - Phase I]
IL13-PE38QQR cintredekin besudotox NeoPharm IL-13 & PE38 Glioblastoma multiforme [Phase III]; Pulmonary fibrosis, idiopathic [Pre-clinical]; Asthma [Pre-clinical]; Brain cancer [Research project]; Glioma [Suspended - Unclassified]; Renal cell carcinoma (RCC) [Abandoned - Unclassified]
Phase II Revlimid lenalidomide Celgene Immunomodulator Myelodysplastic syndrome [Marketed]; Multiple myeloma [Marketed]; Non-Hodgkin's lymphoma (NHL) [Phase III]; Leukaemia, chronic lymphocytic (CLL) [Phase III]; Solid tumour indications [Phase II]; Lymphoma [Phase II]; Myelofibrosis [Phase II]; Renal cell carcinoma (RCC) [Phase II]; Prostate cancer [Phase II]; Glioblastoma multiforme [Phase II]; Amyloidosis [Phase II]; Melanoma [Phase I]; Ovarian cancer [Abandoned - Phase II]; Non-small cell lung cancer (NSCLC) [Abandoned - Phase II]; General inflammatory disorders [Abandoned - Phase II]; Congestive heart failure (CHF) [Abandoned - Unclassified]
Tarceva erlotinib Roche EGFr antagonist Non-small cell lung cancer (NSCLC) [Marketed]; Pancreatic cancer [Marketed]; Head & neck cancers [Phase II]; Breast cancer [Phase II]; Glioblastoma multiforme [Phase II]; Hepatoma, liver cancer [Phase II]; Ovarian cancer [Abandoned - Phase III]; Colorectal cancer [Abandoned - Phase III]; Gastro-intestinal adenocarcinoma [Abandoned - Unclassified]; Renal cell carcinoma (RCC) [Abandoned - Unclassified]
Zactima vandetanib AstraZeneca EGFr & VEGFr inhibitor Non-small cell lung cancer (NSCLC) [Phase III]; Thyroid cancer [Phase III]; Breast cancer [Phase II]; Glioblastoma multiforme [Phase II]; Prostate cancer [Phase II]; Colorectal cancer [Phase I]; Head & neck cancers [Phase I]; Multiple myeloma [Abandoned - Unclassified]; Small cell lung cancer (SCLC) [Abandoned - Unclassified]
Enzastaurin enzastaurin Eli Lilly Protein kinase C (PKC) inhibitor Non-Hodgkin's lymphoma (NHL) [Phase III]; Leukaemia, chronic lymphocytic (CLL) [Phase III]; Non-small cell lung cancer (NSCLC) [Phase II]; Colorectal cancer [Phase II]; Lymphoma [Phase II]; Ovarian cancer [Phase II]; Prostate cancer [Phase II]; Breast cancer [Phase II]; Solid tumour indications [Phase II]; Glioblastoma multiforme [Phase II]
Zolinza vorinostat Merck & Co Histone deacetylase inhibitor Lymphoma [Marketed]; Non-Hodgkin's lymphoma (NHL) [Phase II]; Glioblastoma multiforme [Phase II]; Breast cancer [Phase II]; Prostate cancer [Phase II]; Renal cell carcinoma (RCC) [Phase II]; Leukaemia, acute myeloid (AML) [Phase II]; Non-small cell lung cancer (NSCLC) [Phase II]; Multiple myeloma [Phase II]; Mesothelioma [Phase II]; Myelodysplastic syndrome [Phase II]; Leukaemia, chronic lymphocytic (CLL) [Phase I]; Leukaemia, acute lymphocytic (ALL) [Phase I]; Leukaemia, chronic myeloid (CML) [Phase I]; Head & neck cancers [Suspended - Unclassified]; Colorectal cancer [Abandoned - Unclassified]
Angiocept - Bristol-Myers Squibb VEGF antagonist Glioblastoma multiforme [Phase II]; Solid tumour indications [Phase I]; Non-Hodgkin's lymphoma (NHL) [Phase I]
Azixa (MPC6827) - Myriad Genetics Apoptosis inducer Glioblastoma multiforme [Phase II]; Brain metastases [Phase II]; Solid tumour indications [Phase II]; Melanoma [Pre-clinical]
Banoxantrone (AQ4N) banoxantrone BTG DNA intercalator & topoisomerase II inhibitor Glioblastoma multiforme [Phase II]; Leukaemia, acute lymphocytic (ALL) [Suspended - Unclassified]; Oesophageal cancer [Suspended - Unclassified]; Bladder cancer [Suspended - Unclassified]; B-cell neoplasia [Suspended - Unclassified]
AMG 102 rilotumumab Amgen Anti-hepatocyte growth factor MAb Glioblastoma multiforme [Phase II]; Renal cell carcinoma (RCC) [Phase II]; Solid tumour indications [Phase II]; Gastro-intestinal adenocarcinoma [Phase II]; Renal cell carcinoma (RCC) [Phase II]; Small cell lung cancer (SCLC) [Phase II]; Colorectal cancer [Phase II]; Prostate cancer [Phase II]
OncoGel paclitaxel BTG Taxane Oesophageal cancer [Phase II]; Glioblastoma multiforme [Phase II]; Breast cancer [Phase II]; Pancreatic cancer [Abandoned - Unclassified]
CC-8490 - Celgene Benzopyran Glioblastoma multiforme [Phase II]; Breast cancer [Abandoned - Unclassified]
XL184 - Bristol-Myers Squibb/Exelixis VEGFr2, RET & Met tyrosine kinase inhibitor Thyroid cancer [Phase III]; Glioblastoma multiforme [Phase II]; Non-small cell lung cancer (NSCLC) [Phase II]; Solid tumour indications [Phase I]
XL765 - Exelixis PI3K & mTOR inhibitor Solid tumour indications [Phase II]; Non-small cell lung cancer (NSCLC) [Phase II]; Glioblastoma multiforme [Phase II]; Colorectal cancer [Phase I]; Renal cell carcinoma (RCC) [Phase I]; Mesothelioma [Phase I]
Talampanel talampanide Teva Pharmaceutical Industries AMPA antagonist Glioblastoma multiforme [Phase II]; Amyotrophic lateral sclerosis (ALS) [Phase II]; Epilepsy [Abandoned - Unclassified]; Parkinson's disease [Abandoned - Unclassified]; Multiple sclerosis (MS) [Abandoned - Unclassified]
Cervene (TP-38) - Teva Pharmaceutical Industries EGFr ligand-PE38 conjugate Glioblastoma multiforme [Phase II]
Angiocept - Nektar Therapeutics VEGF antagonist Glioblastoma multiforme [Phase II]; Solid tumour indications [Phase I]; Non-Hodgkin's lymphoma (NHL) [Phase I]
Cotara - Peregrine Pharmaceuticals Anti-cancer MAb-iodine 131 conjugate Glioblastoma multiforme [Phase II]; Colorectal cancer [Abandoned - Unclassified]; Pancreatic cancer [Abandoned - Unclassified]; Biliary cancer [Abandoned - Unclassified]; Prostate cancer [Abandoned - Unclassified]; Hepatoma, liver cancer [Abandoned - Unclassified]; Soft tissue sarcoma [Abandoned - Unclassified]
Karenitecin cositecan BioNumerik Pharmaceuticals Topoisomerase I inhibitor Ovarian cancer [Phase III]; Non-small cell lung cancer (NSCLC) [Phase II]; Melanoma [Phase II]; Glioblastoma multiforme [Phase II]; Glioma [Phase II]; Solid tumour indications [Phase I]
DCVax-Brain - Northwest Biotherapeutics Cancer vaccine Glioblastoma multiforme [Phase II]
ARC 100 - Archer Biosciences Microtubule inhibitor Prostate cancer [Phase II]; Pancreatic cancer [Phase II]; Glioblastoma multiforme [Phase II]; Solid tumour indications [Phase II]
MFL AS M01 - MagForce Nanotechnologies Anti-cancer agent Glioblastoma multiforme [Phase II]; Prostate cancer [Phase II]; Oesophageal cancer [Phase I]; Solid tumour indications [Phase I]; Pancreatic cancer [Phase I]
BSI-201 - BiPar Sciences Poly (ADP-ribose) polymerase (PARP) inhibitor Breast cancer [Phase II]; Glioblastoma multiforme [Phase II]; Ovarian cancer [Phase II]; Uterine cancer [Phase II]; Soft tissue sarcoma [Phase II]; Pancreatic cancer [Phase II]; Non-small cell lung cancer (NSCLC) [Phase II]

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