Antiviral and HIV Drug and Vaccine Development - Annual Review

Published in the Antiviral Agents Bulletin, January 1996.

This large, multi-section article comprehensively reviews important developments and trends reported in 1995.

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Introduction

This article summarizes and reviews some of the more significant and interesting antiviral therapeutics-related news and developments reported in 1995 issues (Volume 8) of the Antiviral Agents Bulletin. Various indexes (Organization, Agent, Virus/Disease and Keyword) of 1995 news articles are also included in this issue. Indexes of 1995 U.S. patents will be presented in an upcoming issue of the Bulletin.

In 1995, the Bulletin presented over 300 news articles and over 380 pages of news, patents, literature abstracts and other information concerning antiviral drug and vaccine development. HIV-infection remains the predominant target for antiviral therapeutics development activities, receiving the largest portion of both industry and government resources devoted to antiviral therapeutics-related research and development. Development of antiviral drugs and vaccines for other viral diseases, such as cytomegalovirus (CMV), hepatitis and herpes simplex viruses is picking up and new therapeutics for CMV and herpes were approved in 1995.

Although it is difficult to quantify decreases in private sector therapeutics research and development, a general decrease in anti-HIV drug and vaccine research and development is starting to become evident as large and small companies consolidate, disappear, leave or deemphasize this field. Companies still active in anti-HIV therapeutics R&D appear to be putting less resources into this area. However, to their credit, many of these and other companies are undertaking long-term projects involving gene therapy and novel technologies that may provide effective means for treatment and prevention of viral diseases. The federal government's AIDS therapeutics-related efforts are either being scaled back or are shifting emphasis to more fundamental research rather than drug and vaccine development and assisting industry. Yet, the opportunities and need for antiviral drugs and vaccines remain high. Even partially effective therapeutics are needed and will find substantial markets. To its credit, the FDA has made considerable progress in accelerating drug approvals, particularly drugs for AIDS-related and life-threatening diseases.

Despite new drug approvals, HIV-infection remains a terminal disease with a long-term course that is largely unaffected by available therapeutics. With our increasing knowledge about HIV and the pathogenesis of HIV-infection comes the realization that HIV is a formidable foe and very adaptable. The available anti-HIV drugs, including the newer HIV protease inhibitors, do not yet appear to offer much hope to fully halt HIV-infection progression or add many years to patient survival. The prospects for availability of prophylactic HIV vaccines are dim as progress and vaccine clinical trials move at a glacial pace, and there remains no concensus on methods for validating these vaccines. Many believe that the current candidates for large-scale HIV vaccine trials do not offer much likelihood of high levels of protective efficacy and large-scale trials continue to be delayed.

Saquinavir was the first HIV protease inhibitor to receive approval and other protease inhibitors with potentially higher efficacy are not far behind. 3TC in combination with AZT was approved as a first-line treatment for HIV-infection, and other nucleoside analogs and combinations were shown to have improved efficacy relative to AZT monotherapy. However, it remains to be proven whether HIV protease inhibitors in combination with nucleoside analogs or combinations of nucleosides can demonstrate significant clinical efficacy or whether significant problems with drug resistance will arise. With the approval of oral and implant formulations of ganciclovir for treatment of cytogmegalovirus retinitis, more choices became available for AIDS patients facing blindness. Other approvals included the first hepatitis A virus vaccine; a varicella-zoster virus (chickenpox) vaccine; and two drugs for treatment of genital herpes, increasing the choice of available drugs from one to three.

Encouraging Developments

Product approvals and filings included:

• Invirase (saquinavir mesylate) from Hoffmann-La Roche Inc. was approved for use in combination with one or more nucleoside analogs for treatment of advanced HIV-infection. This was the first HIV protease inhibitor to be approved by FDA.

• 3TC (Epivir) from Glaxo Wellcome PLC in combination with AZT (Retrovir) received accelerated approval from FDA for first-line treatment of HIV-infection.

• Oral ganciclovir (Cytovene) from Hoffmann-La Roche Inc. was approved by FDA for prevention of cytomegalovirus (CMV) disease, primarily retinitis, in patients with advanced HIV-infection. This was the first therapeutic approved for prevention of CMV disease in HIV-infected patients. It was also approved for treatment of CMV retinitis, becoming the first alternative to intravenous therapy for CMV retinitis maintenance.

• Hepatitis A Vaccine, Inactivated (Havrix) from SmithKline Beecham Biologicals was approved by FDA for prevention of hepatitis A virus infections. This is the world's first hepatitis A vaccine.

• Varivax, a live attenuated varicella-zoster virus (VZV) vaccine, from Merck & Co. was approved by FDA for prevention of chickenpox due to VZV infection.

• Valacyclovir hydrochloride (Valtrex Caplets), a prodrug of acyclovir, from Glaxo Wellcome Co. was approved by FDA for treatment of herpes zoster (shingles) due to varicella-zoster virus (VZV) infection and recurrent genital herpes simplex virus type 2 (HSV-2) infections in immune competent adults.

• Famvir (famciclovir) from SmithKline Beecham Corp. was approved for a new indication, treatment of recurrent genital herpes simplex virus type 2 (HSV-2) infections in immune competent adults.

• Intravenous Foscavir (foscarnet sodium) from Astra USA, Inc. was approved for a new indication, treatment of monocutaneous acyclovir-resistant herpes simplex virus (HSV) type 1 and 2 infections in immune compromised patients. This was the first therapy approved for treatment of acyclovir-resistant HSV in immune compromised (e.g., AIDS) patients.

• AZT from Barr Labs. was approved by FDA as a generic equivalent of Retrovir (AZT), but Barr will not be able to market generic AZT in the U.S. until Glaxo Wellcome's patents covering AZT expire in 2005.

• Merck & Co. filed for approval of Vaqta, a prophylactic highly purified, formalin-inactivated, alum-adjuvanted hepatitis A virus (HAV) vaccine.

• MedImmune, Inc. filed for approval of RSVIG-IV (respiratory syncytial virus immune globulin intravenous) for prevention of serious RSV disease in high-risk infants.

• Lotteries for expanded access to HIV protease inhibitors met with considerable demand. Hoffmann-La Roche Inc. successfully concluded a lottery for expanded access free distribution of saquinavir. Others lotteries included: Glaxo Wellcome for 3TC; Merck & Co. for indinavir sulfate; and Abbott Labs. for ritonavir.

• Matrix Pharmaceutical, Inc. filed for approval of AccuSite injectable gel containing 5-fluorouracil for treatment of genital warts.

• Gilead Sciences, Inc. filed for approval of intravenous cidofovir (Vistide; GS 504) for treatment of CMV retinitis, and the drug received a Treatment IND.

• TRAx CD4 Test Kit, a method for counting CD4+ T-cells, from T Cell Diagnostics Inc. was approved by FDA.

• HTLV-I (rp21e enhanced) immunodiagnostic assay from Cambridge Biotech Corp. was approved by FDA.

Encouraging clinical trial reports included:

• Interleukin-2 (IL-2; Proleukin) from Chiron Corp. showed efficacy for treatment of HIV-infection, with immune improvements sustained for two years. IL-2 also showed efficacy in combination with indinavir sulfate, a HIV protease inhibitor, from Merck & Co.

• Final results from Phase III trials confirmed the efficacy of D4T (stavudine; Zerit) and DDI (Videx) from Bristol-Myers Squibb Co. for treatment of HIV-infection.

• A large trial found DDI and DDI/AZT and DDC/AZT combinations more effective than AZT monotherapy.

• The Delta trial found that AZT plus either DDI or DDC offers improved clinical efficacy compared to AZT alone.

• Lamivudine (3TC) from Glaxo Wellcome PLC and BioChem Pharma showed significant indications of efficacy for treatment of chronic hepatitis B infection.

• A recombinant CMV glycoprotein B (gB) vaccine from Chiron Corp. induced potent antibody responses in a clinical trial and will be used by North American Biologicals to develop CMV immune globulin for treatment of CMV.

• AG1343 from Agouron, VX-478 from Vertex Pharmaceuticals Inc. and Glaxo Wellcome Co., ritonavir from Abbott Labs. and other second generation HIV protease inhibitors exhibited improved bioavailability and indications of anti-HIV efficacy in clinical trials, particularly in combination with anti-HIV nucleoside analogs.

• CMV retinitis prophylaxis using oral ganciclovir from Hoffmann-La Roche Inc. was reported to rarely result in viral resistance.

• Intravitreal ISIS 2922, a CMV antisense oligonucleotide, from Isis Pharmaceuticals, Inc., demonstrated efficacy for treatment of CMV retinitis.

• Two live attenuated oral rotavirus vaccines from American Home Products Corp. and NIAID demonstrated protective efficacy in large-scale trials.

• A Phase III clinical trial of topical 10% Lidakol cream from LIDAK Pharmaceuticals, Inc. demonstrated efficacy for treatment of recurrent oral herpes.

• Passive immunization with HIV immune globulin continued to show promise for treatment of HIV-infection.

• Cidofovir (Vistide) from Gilead Sciences showed efficacy for treatment of CMV retinitis in a Phase II/III trial.

• Infergen, recombinant alpha-interferon, from Amgen Corp. demonstrated efficacy in a Phase III trial for treatment of chronic hepatitis C, and the company decided to go ahead and seek marketing approval.

• Immuno AG reported positive interim trial results with its recombinant HIV gp160 immunotherapeutic vaccines.

• Interferon-beta from Biogen Corp. showed promise for treatment of chronic hepatitis B and C.

• Hydroxyurea in combination with DDI demonstrated indications of efficacy for treatment of HIV-infection.

• HIV-IT (V), a retrovirus vector HIV-1 envelope and rev protein gene therapy, from Viagene/Chiron demonstrated indications of efficacy for treatment of HIV-infection.

• Natural Alpha Interferon from Interferon Sciences Inc. showed promise for treatment of chronic hepatitis C.

• Oral famciclovir demonstrated efficacy for treatment of experimentally-induced herpes labialis.

• A recombinant influenza A subunit vaccine from MicroGeneSys, Inc. demonstrateed prophylactic efficacy.

• An epidemiological study found no linkage between AZT usage and increased non-Hodgkin's lymphoma (NHL).

• Human immune globulin from survivors of Ebola virus infection showed indications of efficacy for treatment of Ebola fever.

• An autogenous vaccine prepared from genital warts was reported effective for treatment of perianal genital warts.

New and ongoing clinical trials included:

• AR177 from Aronex Pharmaceuticals, Inc. became the first HIV integrase enzyme inhibitor to enter trials.

• MedImmune, Inc. started clinical trials with MEDI-491, the first parvovirus vaccine to enter human testing.

• Human Anti-Cytomegalovirus Antibody (MSL-109) from Protein Design Labs. Inc. entered trials for CMV infection indications.

• GENEVAX-HIV, a gene therapy immunotherapeutic HIV vaccine, from Apollon, Inc. entered clinical trials.

• HIV p17/p24:Ty-VLP, a recombinant HIV p17/p24 virus-like particle vaccine, from British Biotech Pharmaceuticals entered clinical trials in the U.S.

• VX-478, an oral HIV protease inhibitor, from Vertex Pharmaceuticals and Glaxo Wellcome entered trials.

• Genta Inc. started clinical trials with a controlled-release formulation of AZT.

• Interleukin-12 from Genetics Inst. entered trials as an immune stimulant for treatment of HIV-infection and shows promise as a vaccine adjuvant.

• HNK20, a respiratory syncytial virus (RSV) antibody, nose drops from OraVax, Inc. demonstrated potential efficacy for prevention of RSV infections in infants.

• PRO 2000, a naphthalene sulfonate polymer, from Procept, Inc. entered clinical trials for HIV-infection.

• Viral Technologies, Inc. restarted clinical trials with HGP-30, the only HIV p17 vaccine in clinical trials.

• AD-439 and AD-519, HIV monoclonal antibodies, from Tanox Biosystems entered combination clinical trials.

• The Inter-Company Collaboration (ICC) began two trials with triple combination treatments for HIV-infection.

• Intravitreal injection of cidofovir (Vistide) from Gilead Sciences entered trials for CMV retinitis, and topical cidofovir showed promise in clinical trials for treatment of genital herpes.

• A synthetic HIV-1 gp120 C4-V3 peptide vaccine from American Home Products Corp. entered trials.

• Injectable and oral liposomal HIV envelope vaccines from United Biomedical Inc. entered clinical trials.

• RBC-CD4, red blood cells impregnated with CD4, from Sheffield Medical Technologies Inc. entered trials.

• CytoDyn, Inc. began trials with cytolin, a monoclonal antibody to LFA-1 on the surface of CD8+ lymphocytes, for treatment of HIV-infection.

• A live canarypox virus vector prophylactic HIV vaccine, ALVAC-HIV (vCP205), from Pasteur-Merieux/Connaught Labs. entered clinical trials in the U.S.

• Columbia Laboratories, Inc. started Phase II/III clinical trials with SPC3, an anti-HIV gp120 peptide.

• Gilead Sciences Inc. started trials with oral GS 840, a PMEA prodrug, for treatment of chronic hepatitis B.

• An aerosolized intranasal live influenza vaccine from Aviron, Inc. entered clinical trials.

• Alferon N Gel, a topical formulation of natural interferon, from Interferon Sciences, Inc. entered trials for treatment of HPV-associated cervical dysplasia in HIV-infected women.

• Hypericin from VIMRx Pharmaceuticals Inc. entered clinical trials in Thailand for treatment of HIV-infection.

• Lidakol from LIDAK Pharmaceuticals entered a third Phase III trial for treatment of oral herpes (herpes labialis).

• The HIV Immunotherapeutic vaccine from Immune Response Corp. entered Phase III trials.

Encouraging research and preclinical results included:

• Endogenous immune modulatory proteins, chemokines and a cytokine, released by CD8+ lymphocytes that suppress HIV replication were identified. These proteins may play a role in the lack of progression of HIV-infection observed in long-term survivors.

• PMPA from Gilead Sciences, Inc. demonstrated protection against SIV infection, the first time a drug has shown complete protection against SIV-infection in primates.

• Epidemiological studies showed that HIV-2 infection provides some protection against infection with HIV-1, suggesting that live HIV vaccines may be effective.

• Genelabs Technologies, Inc. reported a new blood-transmissible human hepatitis virus, formerly called the hepatitis X virus, now called the hepatitis G virus (HGV).

• Abbott Labs. reported the discovery of several new blood-borne hepatitis viruses, designated GB viruses.

• Intracellular adhesion molecule-1 (ICAM-1) demonstrated efficacy for prevention of rhinovirus infections in chimpanzees, suggesting it may be possible to prevent the Òcommon coldÓ in humans.

• MedImmune, Inc. reported complete protection from mucosal infection in dogs with a papillomavirus vaccine.

• PathoGenesis Corp. reported a link between human herpesvirus-6 and multiple sclerosis (MS), suggesting that antiviral therapy may be useful for MS.

• Kaposi's sarcoma herpesvirus or human herpesvirus-8 was further linked as causing Kaposi's sarcoma.

• Human papillomavirus (HPV) was finally concluded to be the main etiological factor for cervical cancer.

• Intravaginal Lidakol from LIDAK Pharmaceuticals prevented transmission of SIV in female rhesus monkeys.

• The first well-documented case of an infant having cleared HIV-infection was reported.

• The National Inst. of Dental Research and Synergen, Inc. identified a protein, secretory leukocyte protease inhibitor (SLPI), in human saliva that inhibits HIV-1.

• Progenics Pharmaceuticals, Inc. is developing PRO 542, recombinant CD4-IgG2 for HIV-infection.

• A direct injected naked DNA ÒGene TherapeuticsÓ vaccine from Merck & Co./Vical Inc., showed efficacy in animals for prevention of influenza A virus infection.

• Mitotix Inc. reported two enzymes useful for screening drugs for treatment of HPV infections.

• Hypericin from VIMRx Pharmaceuticals Inc. showed activity against a surrogate for hepatitis C virus.

• Polycationic DNA analogs are a new class of antiviral drugs that strongly bind to DNA and RNA.

• Emisphere Technologies, Inc. reported oral microsphere delivery of alpha-interferon.

Discouraging Developments

Approvals denied, trials or development suspended, etc.:

• Approval of ribavirin (Virazole) from ICN Pharmaceuticals Inc. for treatment of chronic hepatitis C infection (Costa Mesa, CA) was rejected by FDA, and the company was accused of misleading investors.

• HemaCare Corp. halted development of HIV immune globulin (Immupath) for treatment of HIV-infection, largely due to problems with FDA concerning beta-propriolactone viral inactivation methods.

• Clinical trials with Reticulose from Advanced Viral Research Corp. for HIV-infection were suspended by FDA.

• The FDA rejected over-the-counter status for oral acyclovir for treatment of genital herpes.

• A clinical trial of aspirin for treatment for HIV-infection was halted after toxic effects were observed.

• Shaman Pharmaceuticals, Inc. encountered a problem with Provir for treatment of pediatric respiratory syncytial virus (RSV) infections with the drug unexpectedly becoming undetectable in stored biological samples.

Discouraging clinical trial reports included:

• A clinical trial comparing acyclovir vs. valacyclovir for prophylaxis of cytomegalovirus (CMV) retinitis in HIV-infected patients was halted after lower survival was noted in patients receiving valacyclovir.

• The AZT arm of a trial comparing initial therapy for HIV-infection with AZT, DDI and AZT/DDI combinations was halted when AZT monotherapy was associated with disease progression and higher incidence of side effects.

• Isis Pharmaceuticals, Inc. reported adverse retinal changes in a Phase III trial with ISIS 2922 for treatment of cytomegalovirus (CMV) retinitis, but the trial resumed.

• Peptide T from Advanced Peptides Inc. failed to show efficacy for treatment of neurological and cognitive impairment in AIDS patients.

• Russian claims that equine Ebola virus IgG was effective against Ebola fever were found to be premature.

• Autologous adoptive transfer of HIV-specific cytotoxic T-lymphocytes (CTLs) for treatment of HIV-infection failed in the one patient in which this procedure was tried.

• A long-term study of AZT demonstrated that early treatment slowed CD4+ T-cell decline but had no significant effects on survival or progression to AIDS.

• Influenza virus vaccination was shown to increase viral load in HIV-infected patients, suggesting that immune stimulation may increase HIV replication.

Other discouraging news and trends included:

• A live simian immunodeficiency virus (SIV) vaccine, a model for similar gene-deleted attenuated HIV vaccines, induced SIV infection, indicating that live attenuated HIV vaccines may not be safe for human prophylactic use.

• New models and understanding of HIV-infection show it to be a raging, rather than latent or low-level, infection with even more adaptability than previously thought.

• The Walter Reed Army Inst. of Research reported the first fully documented cases of patients simultaneously infected with two distinct strains of HIV-1.

• Early HIV protease inhibitors, such as those from Roche and Merck, remain very difficult and expensive to produce and have low bioavailability. Clinical trials often use suboptimal dosages. Second generation protease inhibitors may have advantages over first generation products in terms of efficacy, cost and convenience.

• Even vast excesses of HIV neutralizing antibodies fail to neutralize HIV trapped in the lymph nodes.

• Hepatitis E virus, previously considered only an enteric virus, may pose a threat in blood and blood products.

Corporate and Federal Activities

Corporate linkages and collaborations included:

• Pasteur Merieux and Connaught Labs. concluded an agreement with the Agence Nationale de Recherches sur de le Sida (ANRS), the French government's AIDS research effort, for development of HIV vaccines.

• Genelabs Technologies, Inc. concluded a cross-licensing and collaborative agreement with Chiron Corp. to develop products for hepatitis C and G virus infections.

• Chiron Corp. and Hoffmann-La Roche Inc. formed a collaboration for marketing and co-promotion of Vitrasert, a ganciclovir intraocular implant, for treatment of cytomegalovirus (CMV) retinitis.

• CSL Ltd., UniQuest Ltd. and Merck & Co. joined to develop a vaccine for prevention of cervical cancer and genital warts due to human papillomavirus (HPV).

• Hoechst Marion Roussel linked with Cell Genesys, Inc. for development of HIV gene therapies.

• MedImmune, Inc. linked with Baxter Healthcare for development and commercialization of RSVIG (respiratory syncytial virus immune globulin) outside North America.

• American Home Products Corp. linked with Apollon, Inc. for development of GENEVAX facilitated DNA injection-based HIV, HSV and HPV vaccines.

• RiboGene, Inc. linked with Warner-Lambert Co. and Houghton Pharmaceuticals, Inc. for antiviral screening.

• BioCryst Pharmaceuticals, Inc. linked with the Univ. of Alabama at Birmingham for development of influenza virus neuraminidase enzyme inhibitors.

• Rhone-Poulenc Rorer Inc. withdrew from its collaboration with Immune Response Corp. for development of the HIV Immunotherapeutic inactivated HIV vaccine.

• BioChem Pharma Inc. linked with XTL Biopharmaceuticals for screening of drugs for hepatitis C and other viral infections.

• Pfizer Central Research moved into the gene therapy area, linking with four companies including Immusol Inc.

• Avid Therapeutics Inc. and Terrapin Technologies Inc. formed a collaboration for hepatitis B drug discovery.

• Aviron, Inc. formed a strategic alliance with Sang-A, a Korean pharmaceutical company.

• Pharma Mar S.A. is collaborating with the Institut Pasteur for the development of marine drugs for treatment of viral and HIV-infections.

• Paracelsian, Inc. linked with the National Cancer Institute and the National Institute of Child Health and Human Development for development and testing of HIV protein-tyrosine kinase inhibitor drugs.

• Emisphere Technologies, Inc. linked with Pasteur Merieux/Connaught to demonstrate oral delivery of influenza virus vaccines.

• Immune Response Corp. formed a collaboration with Trinity Medical Group for development of its HIV Immunotherapeutic inactivated HIV vaccine in Thailand.

• Cantab Pharmaceuticals PLC linked with Pfizer Inc. for development of veterinary viral vaccines.

• American Home Products Corp. and MedImmune, Inc. changed the terms of their strategic alliance.

• The American National Red Cross linked with HemaSure Inc. for development of viral inactivation methods.

• CEL-SCI Corp. and Alpha 1 Biomedicals, Inc. disputed funding development of HGP-30, an HIV p17 vaccine.

Corporate acquisitions and mergers included:

• Glaxo PLC completed its acquisition of Wellcome PLC. Glaxo Wellcome, became the world's largest pharmaceutical company and number one in antiviral drugs.

• Sandoz Ltd. acquired Genetic Therapy, Inc., a leader in development of ex vivo gene therapies.

• Hoechst AG acquired Marion Merrell Dow Inc. to form Hoechst Marion Roussel.

• Chiron Corp. acquired Viagene Inc.

• The Upjohn Co. merged with Pharmacia AB.

• North American Biologicals, Inc., the largest U.S. blood and specialty plasma processor, merged with Univax Biologics, Inc., a company developing vaccines and therapeutic immune globulin preparations.

• Argus Pharmaceuticals, Triplex Pharmaceutical and Oncologix, Inc. merged into Aronex Pharmaceuticals.

• CEL-SCI Corp. acquired the 50% interest owned by Alpha 1 Biomedicals, Inc. in the HGP-30 HIV vaccine.

• Sequel Therapeutics Inc., a joint venture of Cytel and The Scripps Research Inst., was fully acquired by Cytel.

• Warner-Lambert Co. acquired the Glaxo Wellcome PLC portion of their joint venture for over-the-counter sales of acyclovir and other drugs.

Federal Activities (other than product approvals):

• The National Institutes of Health abandoned use of the Òreasonable pricingÓ clause in exclusive licenses and Collaborative Research and Development Agreements (CRADAs).

• The U.S. Patent and Trademark Office (PTO) issued guidelines for the examination of patents that enable the acceptance of in vitro and animal data, rather than requiring demonstration of efficacy in clinical trials.

• The PTO also implemented expedited review of patent applications for AIDS-related therapeutic inventions.

• The FDA asserted its authority over xenotransplantation (transplanting of animal organs into humans) and approved a trial involving baboon bone marrow transplant into an advanced AIDS patient.

• The Centers for Disease Control and Prevention (CDC) has announced its support for voluntary HIV-1 p24 antibody status testing of all pregnant women.

• Congressional investigations finally ended concerning alleged misconduct by Dr. Gallo in the discovery of HIV.

• For the first time, CDC issued recommendations for the use of drugs for influenza prevention.

• NIAID is considering conducting Òintermediate sizeÓ rather than large-scale clinical trials with prophylactic HIV vaccines.

• The National Cancer Inst. is considering cutting back its intramural (internal) AIDS-related research programs.

Patents and Technology Transfer

Patent/product licensing activity included:

• ICN Pharmaceuticals Inc. concluded a licensing agreement with Schering-Plough Corp. under which Schering will develop ribavirin (Virazole) in combination with its recombinant alpha-2b-interferon (Intron A) for treatment of chronic hepatitis C virus infection.

• The National Institutes of Health licensed F-ddA and F-ddI, anti-HIV nucleoside analogs, to U.S. Bioscience, Inc.

• OncorPharm licensed patents covering triplex-forming antisense oligoncleotides from Princeton University.

• Viagene, Inc. obtained a license from Biogen Inc. for use of hepatitis B virus genes in gene therapies.

• Interferon Sciences, Inc. granted exclusive Japanese rights for human leukocyte-derived alpha-interferon (interferon alfa-n3) to Fujimoto Pharmaceutical Co. The company reacquired marketing rights for its Alferon N Injection (natural interferon) in North America.

• SmithKline Beecham Corp. exclusively licensed oral HIV immunodiagnostic assays from Epitope, Inc.

• The National Institutes of Health (NIH) received a U.S. patent broadly covering ex vivo gene therapy. An exclusive license had already been granted to Genetic Therapy, Inc.

• Aviron, Inc. licensed intranasal live influenza virus vaccines from the Univ. of Michigan and concluded a Collaborative Research and Development Agreement (CRADA) with NIAID for development and testing.

• Connaught Labs. took an option from Vaxcel, Inc./CytRx Corp. for evaluation of the Optivax System for vaccine adjuvancy/delivery.

• Glaxo Wellcome PLC let its option lapse to exclusively license Aztec, a sustained release formulation of AZT, from Verex Laboratories, Inc.

Patent disputes, new and continuing, included:

• Promega Corp. continued its challenge to the validity of patents now held by Hoffmann-La Roche Inc. concerning Taq DNA polymerase used extensively in polymerase chain reaction (PCR) procedures.

• A U.S. Bankruptcy Court ruled that Cambridge Biotech Corp. is infringing patents assigned to Institut Pasteur concerning HIV p18, p13 and p25 diagnostics.

• An interference was declared between claims made by Hoffmann-La Roche Inc. and Memorial Sloan Kettering Cancer Center concerning purified interleukin-2 (IL-2).

• OncoRx Inc. claimed that it holds U.S. rights to the use of lamivudine (3TC) for treatment of hepatitis B.

• Dr. D.W. Bradley, formerly with the Centers for Disease Control and Prevention, filed suit against Chiron Corp. challenging hepatitis C virus patents.

Patent disputes resolved included:

• Biogen won an arbitration ruling in its dispute with SmithKline Beecham Corp. over royalty rates for U.S. use of Biogen's hepatitis B virus patents.

• Organon Teknika won its U.K. hepatitis C virus diagnostics patent dispute with Chiron Corp. and Ortho Diagnostic Systems.

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