Breaking through the barrier

Geron licenses peptide from Angiochem to help get cancer therapeutics past the blood-brain barrier

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MENLO PARK, Calif.—Seeking to enable better treatment ofprimary brain cancers and cancers that have metastasized to the brain, GeronCorp. has entered into a worldwide exclusive license agreement with Montreal,Canada-based Angiochem Inc. for peptide technology to facilitate the transferof anti-cancer compounds across the blood-brain barrier (BBB).
In addition, the companies have entered into a research andcollaboration agreement to put these receptor-targeting peptides to worktransporting telomerase inhibitors into the central nervous system (CNS).
The license covers proprietary receptor-targeting peptidesconjugated to tubulin disassembly inhibitors, including GRN1005, which wasformerly known as ANG1005. GRN1005 is a novel taxane derivative that hascompleted two Phase I clinical trials in patients with primary brain tumors andin patients with brain metastases from breast and lung cancer.
Angiochem will receive an upfront license fee from Geron forthe exclusive license rights.
Angiochem is also entitled to receive milestonepayments, royalties on product sales and a share of sublicensing revenues.
Specific terms were not announced.
"This in-licensing augments our oncology clinical pipelineto address metastatic brain cancer, a large global unmet medical need," saysDr. Thomas B. Okarma, president and CEO of Geron. "With GRN1005, we now have anadditional compound tracked to provide Phase II human proof-of-concept in 2012.The results of the completed Phase I trial in brain metastases from commoncancers showed that GRN1005 is highly active as a single agent. If theseresults are confirmed in our Phase II study, we anticipate rapid marketingapproval."
He adds that he and the rest of his company also lookforward to collaborating with Angiochem in combining the CNS-targeting peptidetechnology with Geron's telomerase inhibitor technology "to enable clinicaldelivery of its demonstrated preclinical activity against brain cancer stemcells."
"Primary brain tumors and brain metastases present asignificant unmet medical need because drugs that might be effective againstthose tumors are not able to efficiently enter the brain," adds Dr. Stephen M.Kelsey, Geron's executive vice president and chief medical officer foroncology. "GRN1005 has a demonstrated ability to penetrate brain tissue and,more importantly, brain tumors in nonclinical models and in patients.Furthermore, patient data from the Phase I clinical study in brain metastasesshowed compelling preliminary evidence of anti-tumor activity."
The deal is important for Angiochem in part to demonstrateand facilitate its continued progress.
As Angiochem's chairman, president andCEO, Dr. Jean-Paul Castaigne, tells ddn,his company has already shown proof-of-concept for small-molecule formulations,and one of the next steps for Angiochem is to move into more work withpeptides, proteins, enzymes and the like.
In addition to its concern with developing therapeutics forbrain disorders and diseases that migrate to the brain, Castaigne notes thatAngiochem also has a promising peptide for pain management.
"Also, for obesity we have a modified leptin able to crossthe BBB," he says. "Leptin is produced by the fat cells and then is transportedto the brain by the leptin transporters at the surface of the blood-brainbarrier. Unfortunately in obese patients those transporters are impaired andthe more you are obese, the less leptin is transported to the brain."
Also on deck is a possible treatment for Parkinson'sdisease, and a desire to further develop the oncology platform, with plansalready forming to do more work with Geron on that front.
Castaigne says the two companies had not worked togetherbefore but found that they connected well after face-to-face meetings and foundthey had similar aims and outlooks.
"We are very pleased to enter into thelicense and the collaboration agreements with Geron, whose clinical oncologyteam is highly experienced in taking anti-cancer drugs through clinicaldevelopment," Castaigne noted in the news release about the deal. "We lookforward to further clinical development of ANG1005, now GRN1005, and tocollaborating on combining our proprietary BBB-penetrating peptides withGeron's telomerase inhibitor technology for clinical development."
Telomerase is a critical and broadly applicable tumortarget, the two companies note. The enzyme is expressed in a wide range of malignanttumors, and its activity is essential for the indefinite replicative capacityof cancer that enables malignant cell growth.
Telomerase has now also beenshown to be a target for cancer stem cells. 
The 'why' and 'how' of GRN1005

The blood-brain barrier (BBB) prevents foreign substances,including more than 95 percent of drugs, from entering the brain. This presentsa practical challenge to the treatment of brain cancer, including primary tumorsas well as brain metastases, which represent a substantial global unmet medicalneed.
The United States alone sees approximately 200,000 cases of metastaticcancers in the brain annually and as many as half of patients die as a directresult of intra-cerebral disease.
There are currently no drugs approved forbrain metastases.
GRN1005 is designed to exploit a natural mechanism by whichessential substances, such as lipids and hormones, successfully enter the brainthrough receptors in the BBB.
GRN1005 is comprised of three molecules ofpaclitaxel, a drug with proven anti-tumor activity outside of the brain, linkedto a proprietary peptide that targets the lipoprotein receptor-relatedprotein-1 (LRP-1), one of the most highly expressed receptors on the surface ofthe BBB.
Binding to LRP-1 facilitates receptor -mediated transcytosis acrossthe BBB into the brain tissue. Importantly, LRP-1 is also upregulated in manytumors, including malignant glioma and metastatic cancers both in the brain andvisceral organs, enabling efficient entry to tumor cells in the brain and inthe periphery using the same receptor-mediated pathway.
Geron's clinical development plan for GRN1005 includes a Phase IIclinical trial to be initiated in the second half of 2011 in patients withbrain metastases arising from non-small cell lung cancer and breast cancer.Geron also plans to initiate a Phase II clinical trial in patients withglioblastoma multiforme in the first half of 2012.
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