ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT 8:v«-vüí (1998)Mary Ann Liebert, Ine.

Guest Editorial

Vitravene™—Another Piece in the Mosaic

STANLEY T. CROOKE

On July 22, 1998, the Ophthalmic Subcommittee of theDermatologie and Ophthalmic Drugs Advisory Commit¬

tee of the FDA recommended approval of the new drug applica¬tion for fomivirsen sodium (Vitravene™) for the treatment ofpatients with cytomegalovirus (CMV)-induced retinitis. CMVretinitis is a viral infection of the retina that occurs in AIDS pa¬tients and is uniformly progressive to blindness if untreated.The Committee concluded that Isis Pharmaceuticals presentedadequate evidence of the safety and efficacy of fomivirsen to

justify making the drug commercially available in the UnitedStates. The concerns expressed by the Committee focused on

the relatively limited number of patients studied (330 patients,433 eyes), but the Committee acknowledged the difficulty in re¬

cruiting patients with CMV retinitis into clinical trials and ap¬preciated the strenuous efforts of Isis Pharmaceuticals to com¬

plete the trials.Vitravene™ is injected intravitreally once weekly during in¬

duction and every 2 or 4 weeks during maintenance. The stud¬ies demonstrated safety and efficacy both in patients withnewly diagnosed disease and in those who have failed priortherapy with currently available drugs to treat CMV retinitis.There were no systemic side effects, and the ocular side effectswere limited and usually mild to moderate. Most adverse eventsresolved while patients continued therapy and were easily man¬

aged.Although the Committee's recommendation does not repre¬

sent final approval, we are optimistic that the FDA will acceptthe Committee's recommendation. As Vitravene™ was af¬forded priority review status, we expect a final decision by theFDA within the next few months.

We consider the recommendation for approval of Vitra-vene™ by the Committee to be important to patients with CMVretinitis, to Isis, and to antisense technology. As experiencewith Vitravene™ is gained, we believe it will become a corner¬stone of therapy for CMV retinitis. It provides effective localtherapy with no systemic side effects and very acceptable ocu¬lar safety. That the dose is given every 2 or 4 weeks during rou¬

tine visits to the ophthalmologist contributes to a higher qualityof life for these patients. Vitravene™ preserved visual acuity inpatients with CMV retinitis and reduced the retinal detachmentrate for untreated disease from 50%-60% to less than 10%, in 1year providing major benefits to patients.

The impact of the recommendation to approve Vitravene™on antisense technology must be considered in the context of all

the information we have generated about the technology. Thesuccess or failure of an individual drug can neither fully vali¬date nor invalidate a broadly enabling technology, such as anti-sense. Certainly, a drug that provides local therapeutic benefitsafter local treatment cannot provide answers to all of the ques¬tions that pertain to systemic therapy.

In vitro we have shown that Vitravene™, at low concentra¬tions, causes sequence-dependent reductions in target RNAlevels consistent with an RNase -dependent antisense mech¬anism. At higher concentrations, the drug also displays se¬

quence-independent effects. One mechanism to explain thenonantisense effects is direct binding to tjie viral coat proteins,preventing cell uptake of the virus. In in vitro systems, we mixhigh concentrations òf virus and cells (relative to the in vivo sit¬uation) with drugs. In human eyes, the virus is thought to bespread by cell-to-cell transfer, making it highly unlikely thatthis nonantisense mechanism plays any meaningful role in hu¬mans. Nor do the proinflammatory effects of the drug accountfor the therapeutic benefit. Vitravene™ causes only mild tomoderate transient inflammation in a fraction of the treated pa¬tients, which in no way correlates with the efficacy observed.Thus, we believe Vitravene™ provides evidence that a drugworking via an antisense mechanism can cause antiviral effectsin humans.

The data on Vitravene™, considered in the context of thevast database we have reported on pharmacologie, pharmacoki-netic, and toxicologie properties of these drugs in humans andanimals, do, in our opinion, provide compelling evidence thatantisense technology is delivering on its promise. Moreover,the recommendation to approve demonstrates that we havesolved the manufacturing, analytic, and formulation issues nec¬

essary for approval of a new drug. The preapprovai inspectionof our manufacturing facility and procedures went extremelywell, with only minor issues identified that were easily re¬

solved. This represents a substantial reduction in technologyrisk and a set of accomplishments that many, only a few yearsago, argued could not be done. At Isis, we believe that theprogress on Vitravene™ provides one more piece in the mosaicnecessary to prove the validity of antisense technology.

The discovery program for Vitravene™ was initiated lessthan 8 years ago. Simultaneously with the identification and de¬velopment of Vitravene™, we created the basic technologicbase, rigorously tested the technology, devised analytic andmanufacturing methods, and developed multiple additional an-

Vili CROOKE

tisense drugs. Moreover, we also created the basic medicinalchemistry for the next generations of antisense drugs. In thecontext of traditional drugs, taking 10-15 years in developmentafter 3-5 years of discovery efforts, we believe this represents a

meaningful accomplishment.It is, however, important to remember that at most we are at

the end of the beginning of the creation, testing, and exploita¬tion of this technology. Many more questions remain to be an¬

swered than those we have answered. Nevertheless, this mile¬

stone, in the context of all the other data, provides additionalsupport for continuing optimism about the technology. Cer¬tainly, antisense drug discovery and development merit contin¬ued investment and rigorous testing. We at Isis intend to con¬

tinue to play a major leadership role in the pursuit of thistechnology.

Dr. Stanley T. CrookeIsis Pharmaceuticals, Inc.

Carlsbad, CA 92008