Current Advances

Isis Reacquires eIF-4E and Adds Two New Drugs to Its Development Pipeline

ISIS-EIF4E_Rx

In December 2009, Isis announced the reacquisition of its eIF-4E drug, ISIS-EIF4E_Rx, from Eli Lilly and Company. ISIS-EIF4E_Rx was discovered by Isis and licensed to Eli Lilly and Company in 2004 for the treatment of cancer. Eli Lilly and Company completed a Phase 1 study of ISIS-EIF4E_Rx in patients with cancer that showed that the drug was well tolerated at doses up to 1200 mg. With the reacquisition of this asset, Isis will independently develop ISIS-EIF4E_Rx through Phase 2 proof-of-concept for the treatment of multiple types of cancer, potentially including, breast, lung, prostate, bladder and colon cancers. Eli Lilly and Company has the right to reacquire ISIS-EIF4E_Rx on predefined terms prior to the initiation of Phase 3 development.

ISIS-EIF4E_Rx targets eukaryotic initiation factor-4E (eIF-4E), a protein involved in the translation of key growth and survival factors that contribute to tumor progression and the spread of cancer. In 2006, Isis and collaborators published data that provided the first in vivo evidence that cancers may be more susceptible to eIF-4E inhibition than normal tissues.¹

ISIS-EIF4E_Rx will be the first drug in development under Isis’ new initiative to build an internal cancer program. Isis’ new initiative is part of Isis’ business strategy to use its capital to invest in its core therapeutic areas. These investments ensure that antisense drugs within these areas have adequate resources to advance in clinical development and to reach greater value inflection points. Isis plans to partner these drugs after Phase 2 proof-of-concept.

ISIS-FXI_Rx

ISIS-FXI_Rx is the newest drug to enter Isis’ cardiovascular disease franchise. It expands the therapeutic reach of the franchise into thrombosis, an area where Isis’ antisense drugs could offer improved safety and patient convenience compared to current approved therapies.

ISIS-FXI_Rx targets Factor XI, a clotting factor produced in the liver. High levels of Factor XI are linked to myocardial infarction, stroke and venous thrombosis. In preclinical studies, ISIS-FXI_Rx demonstrated potent antithrombotic activity and a superior safety profile (lower risk of bleeding) compared with standard anti-clotting agents, including low molecular weight heparin, warfarin and Factor Xa inhibitors. Isis plans to begin IND-enabling preclinical studies on ISIS-FXI_Rx in the first half of 2010.

ISIS-SMN_Rx

ISIS-SMN_Rx is designed to treat spinal muscular atrophy (SMA), a neuromuscular disorder and the leading genetic cause of infant mortality. Isis is developing ISIS-SMN_Rx as part of its strategy to discover and develop antisense drugs against severe neurodegenerative diseases, where there are few treatment options. ISIS-SMN_Rx is the first antisense drug to enter Isis’ development pipeline that modulates splicing, a novel antisense mechanism.

SMA is caused by a genetic deletion of a gene that produces a protein associated with normal motor neuron function. ISIS-SMN_Rx is designed to treat SMA by modulating the splicing of a closely related gene, which leads to the production of the protein, SMN, that is absent in the disease. By altering splicing to produce SMN, ISIS-SMN_Rx may be able to compensate for the underlying genetic defect. In 2008, Isis and researchers from Cold Spring Harbor published data that demonstrated the feasibility of using Isis’ antisense technology to control splicing in mice.² This early work led to the discovery of ISIS-SMN_Rx and showed, for the first time, that Isis’ antisense technology, which has been used to inhibit protein production for the treatment of many diseases, could be used to increase the production of a protein important for normal function. Isis' SMA program is part of its collaboration in neurodegenerative disease with Genzyme, pursuant to which Genzyme has an exclusive option to license ISIS-SMN_Rx from Isis. Isis plans to initiate IND-enabling studies on ISIS-SMN_Rx in 2010.

¹Therapeutic Suppression of Translation Initiation Factor eIF4E Expression Reduces Tumor Growth without Toxicity. The Journal of Clinical Investigation. 117(9) 2638-2648. 2007.

²Antisense Masking of an hnRNP A1/A2 Intronic Splicing Silencer Corrects SMN2 Splicing in Transgenic Mice. The American Journal of Human Genetics. 82(4) 834:46. 2008.