Status: approved; marketed

Organizations involved:

Isis Pharmaceuticals, Inc. – Manuf.; R&D; Tech.

Ciba Vision – World mark.

Novartis Pharmaceutical Corp. – Parent

National Cancer Institute (NCI), NIH – R&D; Tech.

National Institutes of Health (NIH) – Parent

University of Massachusetts – Patent dispute

Massachusetts (State) – Parent org.

Worcester Found. for Experimental Biology – Tech.

Mount Sinai School of Medicine – Tech.

Cross ref.: See the the Antisense Drugs entry above.

Description: Fomivirsen is a formulation of a synthetic 21-mer (21 nucleotide) phosphorothioate (first generation type linkage) antisense DNA oligonucleotide with a nucleotide sequence complementary to and binding specificity for sequences present in human cytomegalovirus (CMV) major immediate early region 2 (IE2) mRNA (encoding 55 and 86 kDa polypeptides). The sequence of fomivirsen corresponds to nucleotide coordinates 170,120-170,140 of the human CMV strain AD169 genome. By binding the viral mRNA (from transcription of CMV IE2), fomivirsen specifically and selectively inhibits expression of IE2 proteins critical to CMV replication.

Vitravene is approved for local (intravitreal or into the fluid of the eye) injection for second-line treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Fomivirsen was the first and remains the only antisense -oligonucleotide drug approved in the U.S., Europe and many other countries worldwide.

Nomenclature: CMV Antisense Drug [BIO]; fomivirsen sodium [FDA]; Vitravene [TR reg. to Novartis]; ISIS 2922 [SY]

Companies.: Vitravene was developed by and is manufactured by Isis Pharmaceuticals, Inc.. Vitravene is marketed in the U.S. by CIBA Vision Corp., a subsidiary of Novartis AG. CIBA Vision licensed exclusive worldwide marketing rights to fomivirsen for treatment of CMV retinitis from Isis.

Manufacture: The product is manufactured by chemical synthesis, not recombinant or other biological methods.

FDA class: Drug NDA

Approvals: Date =19980827; first approval, NDA

Indications: [first paragraph of the "Indications and Usage” section of product insert/labeling]:

Vitravene is indicated for the local treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), who are intolerant of or have a contraindication to other treatment(s) for CMV retinitis or who were insufficiently responsive to previous treatment(s) for CMV retinitis.

Status: Filing of the New Drug Application (NDA) for approval of fomivirsen was completed on April 9, 1998, was granted priority review status, and the NDA was approved on August 27, 1998 (approval time = ~5.5 months).

In Jan. 2003, Novartis Ophthalmics Europe voluntarily withdrew its European Union (EU) approval for marketing of Vitravene, where it had been approved for treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Novartis reported that demand for Vitravene in Europe was less than 1,000 units/year, and that its withdrawal was solely for business reasons.

Tech. transfer: Isis, through its own pioneering research in antisense oligonucleotides and licensing of related inventions has developed the dominant patent portfolio in the field. This includes fundamental antisense phosphorothioate (1st generation-type antisense technology) licensed from the National Cancer Institute (NCI), National Institutes of Health (NIH). This includes U.S. 5,276,019, “Inhibitors for replication of retroviruses and for the expression of oncogene products,” Jan. 4, 1994, assigned to NIH, with claims broadly describing antisense phosphorothioates targeted to specific gene sequences and their use to halt expression of targeted genes for therapeutic and other purposes. Related NIH patents include 5,264,423 and 5,286,717. Previous antisense oligo-deoxy-ribo-nucle-otides had limited utility, because they were readily degraded in vivo by nucleases or required excessively high concentrations to elicit therapeutic antiviral effects. Phosphorothioate-linked oligonucleotides are more effective, resistant to degradation and hybridize with complementary sequences much more efficiently.

Based on time in clinical trials and during FDA regulatory review (under 35 USC §156), the expiration date of 4,689,320, by A. Kaji, now assigned to Worcester Foundation for Experimental Biology and the Mt. Sinai School of Medicine, was extended 939 days to May 12, 2007. This patent, apparently licensed by Isis, describes antisense oligonucleotides with activity against herpesviruses, with cytomegalovirus a member of the herpesvirus family.

In late 2003, the U.S. Patent and Trademark Office (PTO) initiated an interference action between first generation phosphorothioate antisense oligonucleotide applications assigned to the University of Massachusetts (UMass), which have been exclusively licensed by Hybridon, Inc. (which has also licensed antisense technology from the Worcester Foundation), and three patents assigned to NIH. The PTO declared an interference between application 08/356,270 assigned to UMass and U.S. patents 5,276,019; 5,286,717; and 5,264,423. UMass was declared the senior party. PTO reported that all claims of all the involved applications/patents are at issue, indicating a dispute over who was the first to invent fundamental aspects of this antisense technology. Interferences are often settled with the first to invent the technology receiving patent protection with the competing applications/patents withdrawn, or the parties cross-license their technologies. Hybri-don is not currently developing any phosphorothioates, but had developed and conducted trials with phos-phorothioates, including GEM 132 for treatment of cytomegalovirus retinitis and systemic infection, and GEM91 for treatment of HIV-infection.

Trials: The pivotal Phase III trial (CS2) of fomivirsen for treatment of CMV retinitis was conducted in treatment-naive AIDS patients. Intravitreal injection of fomivirsen sodium demonstrated statistical significance (p = 0.0001) in delaying CMV disease progression, and was well tolerated with no serious side effects. An intent-to-treat analysis demonstrated that the mean time to disease progression for the immediate fomivirsen treatment group was 71 days vs. 13 days for a deferred treatment (control) group (p = 0.0001) having received formivirsen treatment only upon evidence of disease advancement. Baseline CD4+ T-cell counts (reflecting HIV/AIDS-related immune suppression) were an insignificant factor in treatment outcome. Results from another Phase III clinical trial (CS9) in advanced CMV retinitis patients having failed other therapies showed a median time to progression of 90 days. Another trial (CS7) in advanced patients having failed multiple previous treatments also supported the findings of these trials.

Medical: The recommended dosage consists of an induction dose on days 1 and 15 followed by monthly intravitreal injections (330 µg).

Market: The 2007 Average Wholesale Price (AWP) is not available (not in 2007 Red Book). The 2004 (AWP) was $1,000/vial (Red Book, 2004).

The incidence of CMV retinitis and use of drugs for treatment of CMV retinitis have been decreasing in recent years, particularly among HIV-infected patients receiving triple and other potent antiretroviral drug combination therapies which allow many patients to retain immune responses sufficient to prevent CMV disease (which is an opportunistic infection). Besides improved antiretroviral drug combination therapy resulting in fewer patients advancing to AIDS, other drugs for CMV retinitis, particularly more recently introduced oral valganciclovir from Hoffmann-La Roche Ltd., have significantly reduced the market for Vitravene.

Since most CMV retinitis patients eventually fail first-line therapy, and with improved anti-HIV and other drug therapy extending the life of HIV-infected patients, there may eventually be more patients needed treatment for CMV retinitis, as their antiretroviral drug regimens fail (due to development of drug resistant HIV).

Isis estimated (at time of approval) that there are 7,000 to 10,000 CMV retinitis patients in the U.S. The total U.S. market for CMV retinitis drug treatment is less than $100 million, with some analysts estimating the current market in the $40-$70 million range. First-line treatments include well-established oral and intravitreal ganciclovir (Cytovene) from Hoffmann-La Roche Inc. and phosphonoformic acid (Fos-carnet) from Astra Pharmaceuticals. However, more recently approved oral valgan-ciclovir (a ganciclovir prodrug) from Hoffmann-La Roche is rapidly replacing these drugs for first-line use and as the standard-of-care for CMV retinitis treatment. These other drugs are now used for second-line treatment, with Vitravene used more as a last resort or salvage treatment. The need to inject Vitravene intravitreally (into the fluid of the eye) is a factor discouraging its use.