Since not many antisense oligonucleotides have made it to regulatory approval, some say the biggest challenge has been recognition of their potential. [© lily - Fotolia.com]
Isis remains the only company to date to gain FDA approval of an antisense oligonucleotide drug and bring it to market. Fomivirsin was approved by the FDA in 1998 for cytomegalovirus (CMV) retinitis but discontinued in 2004 due to a shrinking market.
Isis’ second success may be forthcoming. On May 29, Genzyme and Isis reported that FDA accepted their NDA for Kynamro for the treatment of homozygous familial hypercholesterolemia (HoFH). The filing triggers a $25 million milestone payment from Genzyme to Isis. The application has a PDUFA date of January 29, 2013.
Kynamro has been evaluated in four Phase III studies, all of which met all their primary, secondary, and teritiary endpoints. It is designed to reduce LDL cholesterol by inhibiting the production of apo-B, a protein that provides the structural core for all atherogenic lipids.
Isis continues to work with partners to bring new antisense drugs to market, as the company remains the major force to be reckoned with in the oligonucleotide universe. Its roughly 1,600 issued patents give the company ownership of and the licensing power for one of the largest antisense and RNA patent estates in the pharmaceutical industry. The patents cover antisense mechanisms, biology, and chemistry, inhibitors of gene expression, and manufacturing of antisense drugs.
Companies remain enthusiastic about oligonucleotide-based antisense drugs. In January Biogen Idec paid $29 million up front for an option to Isis’ ISIS-SMNRx program to treat spinal muscular atrophy (SMA). Biogen also agreed to up to $45 million in milestone-based fees that would come before it had to exercise its license option. If Biogen Idec takes up its option, Isis could earn another $255 million in license fees and regulatory milestone payments plus double-digit sales royalties.
Spinal muscular atrophy results from a loss of or defect in the survival motor neuron 1 (SMN1) gene. This leads to a decrease in the SMN protein, which is required for the health and survival of nerve cells in the spinal cord that support neuromuscular growth and function. ISIS-SMNRx is designed to treat all types of childhood SMA by altering the splicing of a closely related gene SMN2 that leads to the increased production of fully functional SMN protein, according to Isis. The firm initiated a Phase I study testing the intrathecally administered drug in 24 children with the disease in January.
Isis’ other early-stage drugs in development include its ISIS-TTRRx for transthyretin (TTR) amyloidosis, which results from a mutant gene that produces a misfolded form of TTR that progressively accumulates in tissues. Isis will develop the drug through Phase II proof-of-concept, at which time GSK has the option to license ISIS-TTRRx from the company. Last January Isis announced results of a Phase I study with the drug candidate showing that it produced dose-dependent statistically significant reductions of greater than 80% in TTR protein.
Isis’ first-generation antisense drug alicaforsen, which was being tested in Phase III for Crohn disease, was suspended in that indication last December. Isis’ generation two antisense chemistry, using 2’-methoxyethyl (MOE) nucleosides, improves the profile of antisense drugs relative to first-generation chemistry, Isis’ Eric Swayze, vp, chemistry explained to GEN. Kynamro is a generation two oligo.
Generation two chemistry improves the potency of antisense drugs by enhancing their stability in animals, allowing them to more efficiently reach their target RNA without any formulation or complex delivery vehicles. It also improves the safety of these molecules by hindering their nonspecific interactions with proteins, which, for example, reduces the pro-inflammatory profile relative to the previous first-generation oligonucleotide chemistries. Moreover, Isis noted, generation 2.5 chemistry provides an additional 5–10-fold improvement in potency via a further increase in binding affinity for target RNA and provides an improvement in therapeutic index, as the safety profile is similar to the generation two drugs.
Other companies with late-stage antisense drugs have shown progress. Gene Signal is currently developing GS-101, administered as eye drops, for the treatment of excessive blood vessel growth in the eye. The company completed Phase I and Phase II studies in patients who have undergone corneal transplants and is currently completing enrollment of patients for a Phase III clinical trial. Corneal graft rejection occurs primarily through a T cell mediated immune response. Normal corneal immune privilege can be eroded, the company explained, by neovascularization, especially if accompanied by the sequelae of ocular inflammation and raised intraocular pressure.
“The aganirsen antisense oligo acts by blocking Insulin Receptor Substrate 1 (IRS-1), a protein over-expressed in pathological versus physiological angiogenesis,” Eric Viaud, Gene Signal’s CEO, told GEN. “Aganirsen is a single-strand fragment of DNA that binds IRS-1 mRNA to form a duplex. The formation of this duplex, or two-stranded molecule, prevents the mRNA from being translated into protein and producing the IRS-1 protein. Aganirsen therefore reduces IRS-1 expression upstream and concomitantly normalizes downstream vascular endothelial growth factor (VEGF) expression.” By blocking the expression of IRS-1 in pro-angiogenic conditions, aganirsen inhibits and regresses corneal and choroidal neovascularization without inhibiting healthy vessel turnover, he said.
Oligonucleotides that work via an RNAi mechanism continue to face developmental challenges. Big pharma started pulling back from its RNAi programs; Roche chose to chop RNAi from its budget in announcing plans to shut down its efforts in Kulmbach, Germany, Nutley, NJ, and Madison, WI. Alnylam cut its staff back in September 2010 after Novartis departed without picking up a $100 million option on Alnylam’s targets.
On May 30, Alnylam announced that its most advanced RNAi drug candidate, ALN-RSVO1, failed to meet the primary endpoint of a Phase IIb study. The drug was tested in RSV-infected lung transplant patients to determine whether, at 180 days post infection, it reduced the incidence of progressive brinciolitis obliterans syndrome (BOS).
While the study missed its primary endpoint in an “intent-to-treat” (ITTc) analysis of confirmed RSV infected patients, it achieved statistical significant reductions in two other prospectively defined analyses. In all analyses, ALN-RSV01 treatment was associated with a clinically meaningful treatment effect, with a reduction of over 50% in the incidence of day 180 BOS as compared with placebo.
But what Alnylam will do with the drug remains to be seen. “To be clear, we could decide to continue development of ALN-RSV01 toward regulatory approval or alternatively we could decide to terminate all further development efforts,” CEO John Maraganore said on a conference call following the May announcement. Analyst and blogger commentary suggests that having put “what must have been tens of millions” into the drug candidate and given a limited potential upside for the indication, the company may pass on further development.
But in what may signal a small but meaningful comeback for RNAi drugs, Alnylam reported results of an open-label extension study of its RNAi therapeutic ALN-VSP02 in liver cancer patients who had responded to therapy in a Phase I study on June 4, saying that it was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. ALN-VSP02, composed of lipid nanoparticle-formulated siRNAs, targets both VEGF-A and kinesin spindle protein (KSP). And although the oligo is an early-stage candidate, it has generated some excitement because it is the most advanced RNAi drug designed to circulate in the blood stream.
Citing the relative advantages of oligonucleotide molecules, Viaud remarked, “Intermediately sized bioactive molecules, peptides, small RNAs, and DNA oligonucleotides may offer the advantages of both small molecule-based drugs and biologicals while avoiding many of their shortcomings.” From the point of view of a drug developer, these molecules have multiple advantages including simplified rational drug design; simple, scalable, and inexpensive synthesis; and the possibility of extensive chemical modifications to enhance their properties, such as pharmacokinetic and clearance profiles, he added.
GEN asked Viaud what challenges remain for oligonucleotide development. “Since not many antisense oligonucleotides have made it to regulatory approval, our biggest challenge has been for our community to recognize the potential of an oligonucleotide.” But given the advantages of oligonucleotide drugs and some recent clinical successes, large pharma companies may reconsider their development pipeline options.