This article summarizes and reviews some of the more significant and interesting antiviral therapeutics-related news and developments reported in 1994 issues (Volume 7) of the Antiviral Agents Bulletin. Various indexes (Organization, Agent, Virus/Disease and Keyword) of 1994 articles are also included in this issue. Indexes of 1994 U.S. patents will be presented in an upcoming issue of the Bulletin.
In 1994, the Bulletin presented over 270 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 public and private sector resources devoted to antiviral therapeutics-related research and development. A growing number of articles involved clinical trials, with most of these articles reporting significant milestones, such as agents entering trials and results from clinical trials.
Opportunities may actually be increasing for those companies active in antiviral therapeutics development. Commercial antiviral therapeutics development continues to be very active, although industry consolidations, company restructuring and downsizing, and the financial difficulties that continue to plague smaller biotechnology companies apparently have resulted in a decrease in industry antiviral research and development. However, the opportunities and need for antiviral drugs and vaccines remain high--new antiviral therapeutics with substantial efficacy can readily attain worldwide markets exceeding $100 million or even $1 billion. Even partially effective therapeutics are needed and will find substantial markets. The need for drugs and vaccines may be growing as viral diseases (e.g., HIV, HSV, hepatitis) continue to spread largely unchecked in both developed and lesser-developed countries. Prophylactic vaccines are still needed for many viral diseases; however, vaccine development remains more challenging, and fewer companies appear willing to make the long-term, highly speculative commitments required to bring vaccines to the market. Government-funded research and development remains relatively constant, but is slowly decreasing in real terms after considering inflation in the cost of biomedical research and development. In the U.S., the possibility of price controls and broad-based health care reform, perceived as a threat by industry, has abated with the recent Congressional election. Smaller biotechnology companies continue to suffer from depressed stock prices and difficulties in raising capital.
The near-term prospects for highly effective anti-HIV drugs, immunotherapeutics and prophylactic vaccines did not significantly increase in the last year, but a number of promising agents and approaches entered clinical trials, including gene therapies and antisense oligonucleotides. A number of very encouraging developments were reported in 1994, with most of these involving positive results from clinical trials for herpesvirus (e.g., herpes simplex virus, cytomegalovirus, varicella-zoster virus) and hepatitis B and C virus indications, with little substantive clinical progress for treatment of HIV-infection. The most promising HIV therapeutics-related developments reported last year were the high level of efficacy reported in several trials using 3TC in combination with AZT and confirmation of increased efficacy from the combination of acyclovir with AZT. However, HIV-infection remains a terminal disease which is not affected in the long-term by available therapeutics. With our increasing knowledge about HIV and the pathogenesis of HIV-infection comes the realization that HIV is a more formidable foe and very adaptable. Few (if any) of the anti-HIV drugs or immunotherapeutics for which clinical trial data have been reported appear to offer much hope to fully halt HIV-infection progression or significantly extend survival. The prospects for the near-term availability of prophylactic HIV vaccines are dimming, as current candidates for large-scale trials do not offer much likelihood of high levels of protective efficacy and large-scale trials continue to be delayed.
Antiviral therapeutics that were approved in the U.S. and other countries in 1994 included famciclovir for treatment of herpes zoster; D4T and DDC for second-line treatment of HIV-infection; and AZT for prevention of maternal transmission of HIV-infection. Oral ganciclovir for maintenance treatment of cytomegalovirus retinitis was approved in the first week of 1995. This approval and several minor news stories from late 1994, including the U.S. Patent and Trademark Office liberalizing requirements for proof of clinical efficacy to obtain a patent, will be discussed in next month's Bulletin.
Encouraging Developments
Product approvals, reviews and filings included:
- Famciclovir (Famvir) from SmithKline Beecham Corp. was approved by FDA for oral treatment of herpes zoster, becoming the first new anti-herpesvirus drug to be approved in over a decade and the first drug to compete with acyclovir (Zovirax) from Burroughs Wellcome Co. This initiated the first large-scale competition in the marketplace for antiviral drugs.
- D4T (ZERIT) from Bristol-Myers Squibb Co. (BMS) received accelerated approval from FDA for second-line treatment of HIV-infection. BMS is now the only company marketing two nucleoside analogs (D4T and DDI) for treatment of HIV-infection.
- DDC (HIVID) from Hoffmann-La Roche Inc. was approved by FDA for second-line monotherapy treatment of HIV-infection. Second-line combination DDC/AZT treatment has been available since June 1992 under an FDA accelerated approval.
- AZT was approved for a new indication--treatment of pregnant mothers to prevent maternal transmission of HIV-infection.
- VectorVax FP-N, a live recombinant fowlpox virus vector vaccine from Syntro Corp. was approved by the U.S. Department of Agriculture for prevention of Newcastle disease and fowlpox in poultry.
- The OraSure HIV Oral Specimen Collection Device from Epitope Corp. and associated Oral Vironostika HIV-1 Microelisa System from Organon Teknika Corp. were the first non-blood (saliva)-based HIV diagnostics approved by FDA.
- Adatomed Silicone Oil produced by Adatomed GmbH, a subsidiary of Chiron Vision Corp., was approved by the FDA for second-line treatment of retinal detachment, usually associated with progression of cytomegalovirus retinitis in AIDS patients.
- An FDA advisory committee recommended approval in January 1994 of Havrix, a formalin-inactivated hepatitis A virus vaccine, from SmithKline Beecham Corp. Havrix is available in over 25 countries worldwide, but the vaccine has yet to receive FDA approval.
- Varivax, a live attenuated varicella-zoster virus vaccine, from Merck & Co. was recommended for approval, but a number of questions regarding efficacy and safety were cited as needing to be resolved.
- An FDA advisory committee recommended approval of oral ganciclovir from Syntex Corp. (now Hoffmann-La Roche Inc.) for maintenance treatment of cytomegalovirus retinitis in patients with compromised immune systems, including AIDS patients.
- Gamimune N (intravenous immune globulin) from Cutter Labs., Miles Pharmaceutical, was approved for use in HIV-infected children to prevent bacterial and other infections and for prevention of graft-versus-host disease in bone marrow transplant recipients less than 20-years old.
- Burroughs Wellcome Co. applied for over-the-counter status in the U.S. for oral Zovirax (acyclovir) for treatment of recurrent genital herpes, but this proposal encountered considerable resistance.
- Viratek Inc., a subsidiary of ICN Pharmaceuticals Inc., submitted a New Drug Application to FDA for use of ribavirin capsules for treatment of chronic hepatitis C virus infection.
- Burroughs Wellcome Co. filed for approval of valaciclovir for treatment of herpes zoster in the U.S. and over 19 other countries.
- T Cell Diagnostics filed with FDA for approval of its TRAx CD4 test kit for enumerating CD4-expressing (CD4+) T-cells.
Encouraging clinical trial reports included:
- ACTG 076, a clinical trial of AZT for prevention of maternal transmission of HIV, demonstrated significant efficacy for AZT treatment of pregnant mothers to prevent transmission of HIV to their newborn babies. This was the first major instance of any drug showing efficacy for prevention of HIV-infection. Another clinical trial confirmed these findings.
- The best clinical trial results so far for any HIV-infection drug therapy were reported from two clinical trials testing 3TC from BioChem Pharma Inc. and Glaxo Holdings PLC in combination with AZT (Retrovir) from Burroughs Wellcome Co.
- The first clinical trial showing efficacy with an antisense drug was reported. ISIS 2922 from Isis Pharmaceuticals, Inc. demonstrated indications of efficacy for treatment of cytomegalovirus retinitis in AIDS patients.
- A third clinical trial confirmed that concurrent administration of oral acyclovir, the primary drug used for treatment of herpes simplex and other herpesvirus infections, in combination with AZT (both from Burroughs Wellcome Co.) extends survival in HIV-infected patients compared to AZT alone.
- A Phase I clinical trial with HIV-IT (V), a retrovirus gene therapy vector containing HIV-1 env and rev genes, from Viagene, Inc. demonstrated induction of targeted antigen-specific cytotoxic T lymphocytes. This was the first report of induction of immunity in humans from direct intramuscular injection of a gene therapy vector.
- Sylka Managing Co. Inc. reported significant preliminary indications of efficacy with a live bovine immunodeficiency virus (BIV) for treatment of HIV-infection.
- AccuSite Injectable Gel, a controlled release formulation of 5-fluorouracil, from Matrix Pharmaceutical, Inc. demonstrated significant efficacy in a Phase III clinical trial for treatment of human papillomavirus-associated genital warts.
- Acyclovir was shown to significantly reduce shedding of herpes simplex virus type 2 during asymptomatic periods in women being treated for genital herpes, indicating that acyclovir or other antiviral therapeutics may be able to reduce infection of sexual partners.
- LIDAKOL or n-docosanol from LIDAK Pharmaceuticals demonstrated significant indications of efficacy for treatment of herpes labialis and genital herpes. Phase III trials for herpes labialis started.
- Lamivudine (3TC when used for hepatitis indications) from BioChem Pharma Inc. and Glaxo Holdings PLC demonstrated indications of efficacy for treatment of chronic hepatitis B in Phase II trials.
- Intraocular ganciclovir-releasing implant from Chiron Vision Corp. demonstrated significant indications of efficacy for treatment of cytomegalovirus retinitis in AIDS patients.
- Alum-adjuvanted recombinant herpes simplex virus type 2 glycoprotein D vaccine from Chiron Corp. demonstrated efficacy in a Phase II clinical trial, providing "the first evidence, in a carefully controlled clinical trial, that a vaccine used as a therapy can modify the course of a chronic viral infection."
- A herpes simplex virus type 2 glycoprotein D (HSV-2 gD2t) subunit vaccine from SmithKline Beecham Corp. demonstrated potential prophylactic efficacy for genital herpes in a Phase II clinical trial. Addition of monophosphoryl lipid A (MPL) adjuvant from Ribi ImmunoChem Research, Inc. to the alum-adjuvanted vaccine significantly increased cellular and humoral immune responses.
- A trial comparing seven different adjuvant formulations in combination with the Chiron Corp. recombinant HIVSF gp120 vaccine demonstrated that monophosphoryl lipid A (MPL) from Ribi ImmunoChem Research, Inc. plus alum formulated in liposomes was the best adjuvant, along with SAF/2 adjuvant from Syntex U.S.A. Corp. (now part of Hoffmann-La Roche Inc.).
- Thymosin alpha 1 from Alpha 1 Biomedicals, Inc. (now primarily belonging to SciClone Pharmaceuticals) demonstrated indications of efficacy for treatment of HIV-infection in combination with AZT and alpha-interferon.
- Famciclovir (Famvir) from SmithKline Beecham Corp. demonstrated efficacy for treatment of herpes zoster roughly comparable to that of acyclovir (and was approved for herpes zoster treatment last year). Several clinical trials of oral famciclovir demonstrated that the drug has potential efficacy for treatment of recurrent genital herpes.
- Valaciclovir, a prodrug of acyclovir, from Burroughs Wellcome Co. has demonstrated efficacy for treatment of herpes simplex and varicella-zoster virus infections and may eventually replace acyclovir, the world's and Wellcome's largest selling antiviral drug.
- Sorivudine (BV-araU) from Bristol-Myers Squibb Co. demonstrated efficacy comparable to acyclovir for treatment of herpes zoster (shingles) in HIV-infected patients.
- L-735,524, a HIV protease inhibitor, from DuPont Merck showed indications of efficacy in an early trial.
- D4T from Bristol-Myers Squibb Co. demonstrated advantages over continuation of AZT treatment in patients with over six months of prior AZT treatment.
- HIV gp160 vaccine from Immuno AG demonstrated indications of immunotherapeutic efficacy, including restoration of T-cell immunity, in patients with early HIV-infection.
- A controlled-release oral formulation of acyclovir from Genta Jago Technologies B.V., a joint venture of Genta Inc. and Jagotec AG, demonstrated the bioavailability and safety of this formulation.
- Nevirapine, a non-nucleoside inhibitor of HIV reverse transcriptase, from Boehringer Ingelheim Pharmaceuticals, Inc. in combination with AZT and DDI showed significant indications of efficacy in a Phase II trial.
- Thymosin alpha 1 from SciClone Pharmaceuticals, Inc. in combination with alpha-2b-interferon demonstrated significant efficacy in a Phase III trial for treatment of chronic hepatitis C virus infection. A smaller, uncontrolled trial demonstrated that it has significant efficacy in combination with natural interferon for treatment of chronic hepatitis B infection.
- An Italian clinical trial corroborated prior clinical trials showing that early initiation of treatment (when CD4+ T-cell counts fall below 500) of asymptomatic HIV-infected patients with AZT can significantly delay the progression of the infection to clinical AIDS.
- ALX40-4C, an inhibitor of HIV Tat transactivation, from Allelix Biopharmaceuticals Inc. was reported safe in Phase I trials.
- AZT and DDI combinations were shown to be safe and effective in children.
- Results were finally published from a clinical trial (CPCRA 002) comparing DDI and DDC as second-line monotherapy for treatment of advanced HIV-infection, with DDC showing a slight advantage.
- Several studies demonstrated a strong relationship between HIV viral load in pregnant mothers and the risk for transmission of HIV to their newborn infants, further supporting use of viral load as a surrogate marker.
New clinical trials included:
- Saquinavir (Ro 31-8959), an orally administered inhibitor of HIV proteinase (HIV protease), from Hoffmann-La Roche Inc. entered Phase III trials for treatment of HIV-infection.
- HIV-activated cytotoxic CD8+ T-cells, genetically modified by insertion of activation genes, from Cell Genesys, Inc. entered clinical trials for treatment of HIV-infection.
- TBC-3B, a multivalent live vaccinia virus vector-based HIV vaccine, from Therion Biologics Corp. has entered clinical trials for prevention of HIV-infection.
- The Inter-Company Collaboration for AIDS Drug Development began four clinical trials for treatment of HIV-infection with combinations of three anti-HIV drugs from different companies.
- AG1343, an oral HIV inhibitor, from Agouron Pharmaceuticals Inc. entered clinical trials for treatment of HIV-infection.
- The WHO Global Programme on AIDS, World Health Organization (Geneva, Switzerland), decided to proceed with large-scale Phase III clinical trials with HIV prophylactic vaccines, although the actual start of large-scale trials is years off. The first products to be tested will likely be two recombinant mammalian cell expressed HIV vaccines from Genentech Corp. and Chiron Corp.
- A synthetic monovalent HIV peptide vaccine from United Biomedical, Inc. entered clinical trials in Thailand in preparation for large-scale prophylactic efficacy trials. A pentavalent synthetic peptide HIV vaccine entered trials in the U.S.
- The first oral HIV vaccine from United Biomedical, Inc. entered clinical trials.
- Bucast (6-O-butanoylcastanospermine), an inhibitor of HIV glycosidase, from Marion Merrell Dow Inc. entered clinical trials.
- A "Bispecific" HIV monoclonal antibody for treatment of HIV-infection from Medarex, Inc. entered clinical trials.
- Lamivudine from BioChem Pharma Inc. and Glaxo Holdings PLC entered further Phase II clinical trials in numerous countries for treatment of chronic hepatitis B.
- RespiGam, respiratory syncytial virus (RSV) immune globulin, from MedImmune Inc. entered another Phase III trial for prevention of RSV infections in high-risk infants. RespiGam is on track for potential approval this year.
- RBC-CD4, erythrocytes (red blood cells) impregnated by electroinsertion with recombinant CD4, from Sheffield Medical Technologies Inc. entered clinical trials for treatment of HIV-infection.
- Vesnarinone, an oral cardiotonic drug on the market in Japan, entered clinical trials in the U.S. sponsored by Otsuka America Pharmaceutical, Inc. for treatment of HIV-infection.
- A prodrug of PMEA (GS 840; bis(POM)PMEA) from Gilead Sciences entered clinical trials for treatment of HIV-infection.
- Tetrachlorodecaoxygen (oxoferin) from Oxo Chemie GmbH entered clinical trials for treatment of HIV-infection.
- Immupath, immune globulin containing polyclonal HIV antibodies obtained from pooled plasma donated by asymptomatic HIV-infected patients, from HemaCare Corp. entered Phase III trials.
- GEM 91, a HIV antisense oligonucleotide, from Hybridon, Inc. entered Phase I and then Phase II clinical trials in the U.S. for treatment of HIV-infection.
- The BioLogic-HT extracorporeal blood heating and electrolyte dialysis system for treatment of HIV-infection from Biocontrol Technology, Inc. and HemoCleanse, Inc. entered clinical trials in the U.S.
- GS 504 (HPMPC) from Gilead Sciences entered Phase II/III trials for treatment of cytomegalovirus (CMV) retinitis and genital herpes in AIDS patients. GS 504 in eye drop formulation entered clinical trials for CMV retinitis.
- Autolymphocyte therapy (ALT) from Cellcor, Inc. entered clinical trials for treatment of chronic hepatitis B virus infection. This was the first clinical trial with a cellular therapy for treatment of chronic hepatitis B.
- Curcumin, the substance in the spice tumeric that provides its yellow color and a HIV LTR inhibitor, entered clinical trials for treatment of HIV-infection.
- A Phase II/III trial began to compare the use of AZT monotherapy, AZT plus DDI and AZT/DDI/nevirapine triple combination for treatment of HIV-infection.
- A recombinant cytomegalovirus envelope glycoprotein B vaccine from Chiron Corp. entered clinical trials. This was the first recombinant cytomegalovirus subunit vaccine to enter trials.
- Thalidomide from Celgene Corp. entered clinical trials for treatment of AIDS-related cachexia (wasting) and HIV-infection.
- The Center for Special Immunology began trials with "cell-transfer immune reconstitution" in advanced AIDS patients, involving monthly intravenous infusions of immune globulin and peripheral blood lymphocytes obtained from a compatible HIV-seronegative donor, usually a close relative.
- Aspirin (acetylsalicylic acid) entered clinical trials for treatment of HIV-infection.
- Recombinant herpes simplex virus type 2 glycoprotein D (HSV-2 gD2t) subunit vaccine from SmithKline Beecham entered Phase III trials for prevention of genital herpes.
- PASSHIV-1, porcine-derived HIV immune globulin, from Verigen Inc. entered trials for treatment of HIV-infection.
- An oral formulation of hypericin from VIMRx Pharmaceuticals Inc. entered trials for treatment of HIV-infection.
- Delaveridine mesylate (BHAP-E), a non-nucleoside inhibitor of HIV-1 reverse transcriptase, from Upjohn Co. entered Phase II trials for treatment of HIV-infection.
- ISIS 2105, an antisense drug, from Isis Pharmaceuticals entered Phase II trials for surgical adjuvant treatment of genital warts.
Encouraging research results included:
- Interleukin-12 was reported to be "the most powerful immune response modulator" to date with potential for treating HIV-infection. Genetics Inst. and Hoffmann-La Roche are developing IL-12.
- Measurements of HIV in peripheral blood using quantitative polymerase chain reaction (from Hoffmann-La Roche Inc.) and measurements of branched-chain DNA (from Chiron Corp.) have shown a strong correlation between viral burden and clinical stages of disease. Viral burden measurements have already been adopted as de facto surrogate markers for use in clinical trials for treatment of HIV-infection.
- A high level of prophylactic efficacy in primates with a hepatitis E virus subunit vaccine was reported by NIH researchers.
- After testing over 20 million units of blood in the U.S., not a single case of HIV-2 infected donated blood was identified.
- Cytomegalovirus was reported to be associated with restenosis, a narrowing of blood vessels that commonly occurs after coronary angioplasty surgery, perhaps providing a new target for antiviral therapeutics development and a means to reduce the incidence of restenosis.
- Recombinant human respiratory syncytial virus (RSV) Fab single-chain monoclonal antibody fragments from Scripps Research Inst. and NIAID delivered directly into the lungs showed efficacy in RSV-infected mice.
- Virus-like particle "decoy" vaccines composed of HIV and other antigen-coated industrial diamond particles demonstrated efficacy in laboratory animals.
- Viral photoinactivation of blood and blood components was demonstrated by Cryopharm Corp. using brominated psoralen compounds that selectively bind to DNA/RNA.
- Baboons were successfully infected with HIV-2, perhaps providing an animal model for HIV-2 infection.
- Deuterium oxide (heavy water) used instead of water for the formulation of conventional inactivated poliovirus vaccine was shown to confer a significant level of heat stability, perhaps resolving heat instability problems which affect use of live polio vaccines in tropical and lesser-developed countries.
- The HIV genome was reported to apparently include several unreported genes and selenium-based drugs may be useful for treatment of HIV-infection.
- Hypericin demonstrated potential for photoinactivation of viruses in blood products.
- Cantab Pharmaceuticals PLC reported success from preclinical studies with its Disabled Infectious Single Cycle (DISC) herpes simplex virus type 2 (HSV-2) vaccine for prevention and treatment of genital herpes.
- Oxigene, Inc. reported preliminary results indicating that its serum thiols assay compares favorably with conventional b2-microglobulin assays as a prognostic indicator for advancement of HIV-infection.
- The Population Council is developing carrageenan-based and other antiviral and microbicidal vaginal gels to enable women to protect themselves from infection by HIV and other sexually transmitted diseases.
Discouraging Developments
Discouraging clinical trial reports included:
- At least thirteen persons were reported to have become HIV-infected while participating in prophylactic HIV vaccine clinical trials. Besides this having a negative effect on recruitment of patients for HIV vaccine trials, this provided further support for those seeking to delay start of large-scale HIV vaccine efficacy trials.
- Monotherapy clinical trials with L-735,524, a HIV protease inhibitor, from Merck & Co. were put on hold after rapid development of viral resistance was noted.
- Results of the European Concorde clinical trial were finally published with the same results as reported preliminarily in 1993--that early AZT treatment does not significantly prolong the survival of HIV-infected patients.
- Yet another study (ACTG 019) demonstrated that the benefits of early AZT treatment may be outweighed by the adverse effects of chronic AZT usage--that AZT delays the onset of AIDS-related symptoms but at the expense of increased side effects which may reduce the patient's quality of life.
- G.D. Searle & Co., a subsidiary of Monsanto Corp., discontinued development of its HIV protease inhibitor, SC-52151, after completion of two Phase I/II clinical trials.
- Upjohn Co. halted development of CD4(178)-PE40, recombinant HIV-binding domains of CD4 linked to the A chain of Pseudomonas exotoxin, after insufficient indications of efficacy were observed in clinical trials.
- Genentech Inc. halted development of its HIVMN gp120 vaccine for immunotherapy of HIV-infection after observing insufficient indications of efficacy in clinical trials and is now focusing its efforts on development and clinical trials of HIV vaccines for prevention of HIV-infection.
- Burroughs Wellcome Co. discontinued development of Zonavir (882C87) which had been expected to enter Phase III clinical trials for treatment of herpes zoster.
- MedImmune Inc. discontinued development of RespiGam, respiratory syncytial virus (RSV) immune globulin, for treatment of infant RSV infections to concentrate on seeking approval for prophylactic indications.
- A clinical trial of thymosin alpha 1 for treatment of hepatitis B gave anomalous results (no efficacy seen), unlike other trials which show that it has considerable promise for this indication.
- The Japanese Ministry of Health and Welfare and local authorities began an investigation of Nippon Shoji Kaisha for alleged failure to report several deaths associated with clinical trials of BV-araU (Usevir; sorivudine) for treatment of herpes zoster.
- Results from a Phase II trial of GLQ223 (a-trichosanthin) from Genelabs Technologies for treatment of HIV-infection were not definitive.
Other discouraging news and trends included:
- NIAID decided to again delay start of large-scale prophylactic Phase III HIV vaccine trials in the U.S. after an advisory panel unanimously advised against start of these trials, largely basing their decision on insufficient likelihood that the candidate vaccines will demonstrate sufficient or dramatic efficacy. The reports of volunteers becoming HIV-infected while participating in HIV vaccine trials, lack of primate models and efficacy, costs, logistical problems and other factors contributed to this decision. While this decision was a major setback for companies with vaccines in more advanced development (i.e., Genentech and Biocine), this delay opens the field for more HIV vaccines to eventually be considered for initial large-scale NIAID-sponsored clinical trials.
- HIV was reported to be an oncogenic virus, perhaps being a direct cause of non B-cell lymphoma.
- A new, unidentified herpesvirus was reported to apparently be the cause of Kaposi's sarcoma.
- Human antibodies were shown to neutralize hepatitis C virus but the virus quickly mutates and evades the immune response, raising concerns about the possibility for developing effective hepatitis C prophylactic vaccines.
- A coalition of AIDS advocacy and service groups called for expanded or early access to saquinavir, Roche's HIV protease inhibitor. Activists also sought expanded access to other HIV protease inhibitors and drugs that have shown promise in clinical trials. However, supply and other problems, including the high cost of expanded access programs and apparent lack of relevance of expanded access to speeding approvals, will likely prevent expanded access to saquinavir and many other drugs for HIV-infection and other indications.
- Clinical researchers reported that fear, due to ignorance and mistrust, has been and will be major barriers to recruiting volunteers for prophylactic HIV vaccine clinical trials.
- A study showed that total health care costs among U.S. AIDS patients receiving AZT treatment were significantly higher compared to those not treated with AZT.
- The Japanese Ministry of Health and Welfare warned that severe depression and suicide may be associated with use of natural and recombinant alpha-interferon products.
- The Japanese Ministry of Health and Welfare mandated a 17.3% reduction in the price of Intron A (alpha-2b-interferon) used for treatment of chronic active hepatitis C virus infection.
- Human herpesvirus-6 (HHV-6) was further linked as a co-factor for the advancement of HIV-infection to AIDS.
- An official of the U.K. Herpes Association and critic of widespread promotion of acyclovir by Wellcome Ltd. was charged with extorting money from the company in exchange for promises to stop his organization's criticism of the drug.
- Medeva PLC elected not to exercise its option to license a candidate hepatitis A vaccine from American Biogenetic Sciences, Inc.
- The Centers for Disease Control and Prevention (CDC) proposed yet another name, Sim Hombre or no name virus, for the rodent-borne hantavirus that has caused outbreaks of deadly hantavirus pulmonary syndrome in the Southwest and other parts of the U.S.
- BioChem Pharma Inc. executives are being investigated for potential insider trading arising from large purchases of company stock before positive results were announced from a clinical trial of 3TC in combination with AZT for treatment of HIV-infection.
Corporate Activities
New corporate linkages and collaborations included:
- Warner-Lambert Co. and Burroughs Wellcome Co. formed a joint venture, Warner Wellcome Consumer Health, combining the marketing of many of the major over-the-counter (OTC) drugs from these two large pharmaceutical companies. The first major drug Warner Wellcome hopes to market is OTC acyclovir (Zovirax).
- Merck & Co. and Pasteur Merieux Serums et Vaccins formed a collaboration to market vaccines and other products within the European Union.
- Tularik, Inc. and Merck & Co. concluded an agreement to collaborate on the discovery and development of small molecule inhibitors of viral transcription. Disease targets include HIV, herpes simplex virus, human papillomavirus, cytomegalovirus, respiratory syncytial virus and Epstein-Barr virus.
- Pasteur-Merieux, a subsidiary of Rhone-Poulenc Rorer, entered into an agreement with Vical Inc. for development of five naked DNA vaccines including vaccines for cytomegalovirus and respiratory syncytial virus.
- Medeva PLC and Proteus International formed a 50/50 joint venture, Beavermade Ltd., for development of synthetic vaccines, concentrating initially on oral hepatitis B and C virus vaccines.
- Connaught Labs. concluded an agreement with Merck Frosst Canada Inc. for production of Vaqta, a formalin-inactivated hepatitis A virus vaccine.
- Viagene, Inc. and Green Cross Corp. expanded their agreement for development of Viagene's HIV ImmunoTherapeutic, involving intramuscular injection of non-replicating murine retrovirus containing gene sequences for HIV-1 envelope and rev proteins.
- Ribozyme Pharmaceuticals, Inc. formed a collaboration with Chiron Corp. for research and development of ribozymes, with HIV being among their first targets.
- Gilead Sciences, Inc. concluded an agreement with Storz Instrument Co., a subsidiary of American Cyanamid Co., to develop ophthalmic eye-drop formulations of GS 504 for treatment of cytomegalovirus retinitis.
- Agracetus Inc., a subsidiary of W.R. Grace & Co., concluded an agreement with Bio-Rad Laboratories for the design and development of gene guns, including hand-held models.
- Isis Pharmaceuticals, Inc. concluded an agreement with Cambridge Research Biochemicals, a subsidiary of Zeneca Ltd., for production of ISIS 5320, a HIV gp120 V3 loop-binding phosphorothioate oligonucleotide being developed for treatment of HIV-infection.
- The Cleveland Clinic formed Cellect Therapeutics Inc. to develop antisense oligonucleotides conjugated with 2',5'-oligoadenylate for treatment of viral infections and other diseases.
- Hedral Therapeutics, Inc. is a new antiviral therapeutics development company linked with ICOS Corp. The company exclusively licensed technology from the Oregon Health Sciences Univ. and may pursue development of furin inhibitors for treatment of HIV-infection.
- HemaSure Inc. formed a collaboration with the German Red Cross Blood Transfusion Service for development and testing of the company's LeukoVir-MB Filter for viral inactivation of blood plasma.
- SmithKline Beecham Biologicals signed a letter of intent with the China National Biological Products Corp. and the Shanghai Institute of Biological Products for the manufacture and marketing of Havrix inactivated hepatitis A vaccine in the Peoples Republic of China.
- Procept, Inc. and Chiron Corp. concluded an agreement to apply Chiron's combinatorial chemistry capabilities to assist Procept in the discovery of small molecules active against certain immunomodulatory receptor targets.
- AMRAD Corp. concluded an agreement with the Western Australia government for research and conservation work connected with development of conocurvone isolated from Conospermun (Smokebush) shrubs, allowing development of conocurvone for treatment of HIV-infection.
Corporate disputes included:
- The Department of Defense (DOD) decided not to proceed with a Congressionally-mandated, large-scale Phase III clinical trial with VaxSyn HIV-1 vaccine from MicroGeneSys, Inc. American Home Products Corp. (Philadelphia, PA), MicroGeneSys' development and clinical trials collaborator/sponsor, subsequently announced it was terminating its sponsorship of VaxSyn. The $20 million appropriated to the U.S. Army is being used to fund the HIV Research Program, a new grants program which will follow strict peer review procedures.
- Alpha 1 Biomedicals lost binding arbitration of its disputes with SciClone Pharmaceuticals, Inc. concerning licensing matters and its failure to provide SciClone with sufficient supplies of thymosin alpha 1 for SciClone to begin marketing. Alpha 1 Biomedicals essentially lost most patent and marketing rights for thymosin alpha 1, a drug which it developed.
- The Immune Response Corp. and Rhone-Poulenc Rorer Inc. had to resort to binding arbitration to settle a dispute over control of the HIV immunotherapeutic envelope-depleted, inactivated, gamma-irradiated HIV (Salk) vaccine being developed by their joint venture, Immunization Products Ltd. Immune Response won and retained control of clinical trials and development of the vaccine.
- Epitec Ltd. and GA Investments SA, two Swiss companies which funded hepatitis B vaccine research, early clinical trials, and then licensed hepatitis B vaccines to Medeva PLC, alleged that Medeva violated their development agreement by delaying development of the vaccines.
Corporate acquisitions and restructuring included:
- American Home Products Corp. acquired the pharmaceutical and vaccine divisions of American Cyanamid Co. for about $8.5 billion, including Lederle Labs., Immunex Corp. and the Lederle Praxis Biologicals vaccine division. This will create the third largest pharmaceutical company after Merck & Co. and Glaxo.
- Ciba-Geigy Ltd. purchased a 49.9% stake in Chiron Corp. for about $2.1 billion. As part of the deal, Chiron received Ciba-Geigy's half of their Biocine Corp. joint venture developing various vaccines; Ciba-Geigy's diagnostics business (Ciba Corning Diagnostics); and about $1.1 billion in cash.
- Roche Holding Ltd., the parent of Hoffmann-La Roche Inc., acquired Syntex Corp. for $5.3 billion. Roche became the fourth largest pharmaceutical company in the world and acquired an established antiviral drug, ganciclovir.
- Eli Lilly & Co. halted its in-house research and development of treatments for HIV-infection as part of the company's restructuring efforts.
- Repligen Corp. halted its HIV vaccine and drug development and clinical trials as part of the company's restructuring efforts.
- Shaman Pharmaceuticals, Inc. cut back its antiviral drug research and development efforts to a lower level as part of the company's restructuring efforts.
- As part of an agreement with the Federal Trade Commission regarding its acquisition of American Cyanamid's pharmaceutical operation, American Home Products Corp. must license out its rotavirus vaccine research and technology.
- Cambridge Biotech Corp., plagued by allegations of mismanagement, was forced into bankruptcy and to reorganize.
- ICN Pharmaceuticals merged its three main operating units--Viratek, SPI Pharmaceuticals and ICN Biomedicals.
Federal Activities
- The FDA proposed amendments to the requirements for clinical trial design and conduct and sponsor reporting requirements. The multiple deaths that occurred in the clinical trial of FIAU for treatment of hepatitis B were the primary impetus for these new regulations.
- The FDA conducted a reexamination of accelerated approval as a confluence of events, particularly progress in trials with HIV protease inhibitors, brought increasing attention and pressure for refining or redefining this early approval option. Some treatment activists made proposals that essentially would do away with accelerated approval, requiring further proof of clinical utility before approval.
- The National Task Force on AIDS Drug Development was formed, but has yet to make a major impact on AIDS-related therapeutics development.
- Criminal charges arising from allegations of misconduct from the HIV discovery patent dispute against Dr. R.C. Gallo, NCI, and his co-worker, Dr. M. Popovic, were dropped.
- The Orphan Drug Act was revised, maintaining many aspects of exclusivity but including provisions limiting an orphan drug's market size.
- The FDA issued official warning letters to Eli Lilly & Co., Oclassen Pharmaceuticals, Inc., the National Institutes of Health and several clinical researchers concerning the conduct of clinical trials with fialuridine (FIAU) for treatment of chronic hepatitis B. Several persons had died during or after the trial due to unforeseen liver mitochondrial toxicity.
- An official NIH investigation of the conduct of clinical trials with FIAU essentially cleared all of those involved of any wrongdoing related to the trials and resulting deaths.
- Dr. William E. Paul became the Director of the Office of AIDS Research, NIH, with considerable authority over all NIH AIDS-related research.
- The NIAID made its first awards under a new grant program, Strategic Program for Innovative Research on AIDS Treatment (SPIRAT).
- The National Library of Medicine (NLM) removed online charges for a number of AIDS-related databases (AIDSLINE, AIDSTRIALS, AIDSDRUGS and DIRLINE).
- A new service, HIV/AIDS Treatment Information Service (ATIS), provides federally approved treatment information and guidelines issued by various federal agencies.
- A full-text database of AIDS-related U.S. patents became available on Internet.
- In a controversial decision, the Canadian government awarded contracts for supply of influenza vaccine to two companies--BioVac, a subsidiary of BioChem Pharma Inc., which would make the vaccine in Canada, and Connaught Labs., a subsidiary of Rhone-Poulenc Rorer, which would provide vaccine produced in the U.S. but at a lower price.
Patents and Technology Transfer
Patent/product licensing activity included:
- Verex Laboratories Inc. concluded an agreement with Burroughs Wellcome Co. granting an option for an exclusive worldwide license for Aztec, a controlled release formulation of AZT now in Phase III trials. With Wellcome lacking any anti-HIV therapeutics in advanced stages of development and facing competition from new drugs and generic AZT when its patents expire, Aztec may provide the company an opportunity to extend its sales of AZT and its dominance in HIV and antiviral therapeutics marketing.
- Glaxo Holdings PLC granted Wellcome PLC an option to market 3TC, but later withdrew this offer, deciding to market the drug itself after very promising results were reported from several clinical trials for treatment of HIV-infection. An equally-owned joint venture between Glaxo Inc. and BioChem Pharma Inc. will market 3TC in North America.
- Agouron Pharmaceuticals, Inc. traded the three-dimensional structure of human rhinovirus type 14 3C protease with its former research partner, Eli Lilly & Co., for full rights to promising HIV protease inhibitors that the companies developed collaboratively.
- Merck & Co. exercised its option to exclusively license naked DNA vaccine technology developed by Vical Inc. for two additional viral diseases, hepatitis C and human papillomavirus, and Merck again extended its option to exclusively license naked DNA vaccine technology for herpes simplex virus and hepatitis B vaccines.
- U.S. Bioscience, Inc. licensed fluorine derivatives of DDI and DDA from NIH for treatment of HIV-infection.
- Avid Therapeutics Inc. licensed from ARCH Development Corp. the UL13 protein kinase enzyme of herpes simplex virus and related kinases of cytomegalovirus and varicella-zoster virus for use in its drug screening and discovery programs.
- MediChem Research, Inc. licensed calanolide A from NIH for treatment of HIV-infection.
- Targeted Genetics Corp. nonexclusively licensed from Hoffmann-La Roche Inc. the interleukin-2 gene for gene therapy uses, with cytomegalovirus and HIV-infection as its first targets.
- Sheffield Medical Technologies Inc. exclusively licensed Liposome-CD4 technology, involving recombinant CD4 inserted into liposomes containing cytotoxic and/or antiviral drugs, from CBR Labs. The company also obtained an option to license b2-microglobulin-based HIV vaccines from INSERM, the French national medical research agency.
- Sandoz AG exclusively licensed from Johnson Matthey PLC a novel unspecified class of drugs active against HIV.
- North American Biologicals, Inc. acquired an exclusive license from the Univ. of Southern California (USC) School of Medicine for human autoimmune-related antibodies for treatment of HIV and other viral infections.
- Interferon Sciences, Inc. acquired full rights to ALFERON N Injection (leukocyte-derived interferon alfa-n3) in Europe and other major markets from Mundipharma Pharmaceutical Co., an affiliate of Purdue Frederick Co.
- Bioclones (Pty) Ltd. concluded a licensing and collaborative agreement with HEM Pharmaceuticals for Ampligen and other nucleic acid-based antiviral drugs.
- Pasteur Merieux Serums & Vaccins sought to retain U.S. marketing rights for its rabies vaccine, seeking to alter an agreement arising from its acquisition of Connaught Labs., citing the advent of competition (new entrants) for marketing of rabies vaccines in the U.S.
- TargeTech, Inc., a subsidiary of Immune Response Corp., licensed exclusive Far Eastern rights for its liver-targeted hepatitis B antisense therapeutic to Chugai Pharmaceutical Co., Ltd.
- Seragen, Inc. concluded an agreement with Ajinomoto Co., Inc. which provides Seragen with worldwide rights to interleukin-2 (IL-2) gene patents assigned to the Japanese Foundation for Cancer Research for use in its IL-2 Fusion Toxin, now in clinical trials for treatment of HIV-infection and other indications.
Patent disputes, new and continuing, included:
- Chiron Corp. and its business partner for hepatitis C diagnostic products, Ortho Diagnostic Systems Inc., vigorously defended Chiron's hepatitis C virus patents worldwide. In the U.S. and Europe, the companies filed a patent infringement suit against United Biomedical Inc. to halt the production and sale of its hepatitis C virus immunodiagnostic products. In Japan, the companies filed suit against Kyokuto Seiyaku Kogyo Inc.
- Burroughs Wellcome Co. filed suit against SmithKline Beecham Corp. alleging that newly approved famciclovir infringes two of Burroughs Wellcome's U.S. patents.
- A U.S. Patent and Trademark Office reexamination rejected a number of critical claims from a patent assigned to Hoffmann-La Roche Inc. covering leukocyte-derived interferon species (including alpha-interferon).
- Cell Genesys, Inc. and GenPharm International became involved in a dispute over ownership of transgenic mouse technology for production of human monoclonal antibodies.
- The Wellcome Foundation, the largest holder of Wellcome Co. stock, filed suit in Israel against Teva Pharmaceuticals charging infringement of patents covering acyclovir.
- NovaGene Inc. and the Baylor College of Medicine filed suit against Syntro Corp. alleging patent infringement concerning Syntro's PRV/Marker recombinant swine pseudorabies virus vaccines.
Patent disputes resolved included:
- Burroughs Wellcome Co. was upheld as the sole inventor and assignee for the main U.S. patents covering use of AZT (Retrovir) for treatment of HIV-infection and AIDS, winning a challenge by generic drug companies.
- The U.S. government and NIH decided to increase the royalty income provided to Institut Pasteur from the main HIV patents co-assigned jointly to NIH and the Institut Pasteur. Royalty rates were adjusted to enable the French to receive an equal amount of royalties based on sales of HIV immunodiagnostic products over the life of the patent. This settlement largely resolved the long-standing international feuds between Dr. R. Gallo, NIH, and the U.S. government and Dr. L. Montagnier, Institut Pasteur, and the French government concerning HIV discovery and patent royalties, although arguments over misconduct by Dr. Gallo and NIH continue.
- The European Patent Office upheld the Biogen Corp. patent concerning production of recombinant hepatitis B virus surface antigen. Biogen retains patent protection for hepatitis B surface antigen in most countries.
- Medeva PLC won its dispute with Biogen Corp. over issuance of a U.K. patent to Medeva concerning recombinant hepatitis B surface antigen and hepatitis B vaccines.
- Genetics Inst. and Hoffmann-La Roche Inc. cross-licensed patents concerning interleukin-12, avoiding a major patent dispute.
- Abbott Labs. and Hoffmann-La Roche Inc. cross-licensed patents concerning gene amplification technologies for diagnostic applications, avoiding a major patent dispute. This includes Roche's patents covering polymerase chain reaction (PCR) technology and Abbott's ligase chain reaction (LCR) and repair chain reaction (RCR) technologies.
- Chiron Corp. was granted a permanent injunction in the U.K. barring Murex Diagnostics Ltd. and Organon Teknika Ltd. from manufacture and sale of hepatitis C virus immunodiagnostic products.
- IDEXX Corp. and the Univ. of California settled a patent infringement suit with Synbiotics Corp. (San Diego, CA) concerning feline immunodeficiency virus diagnostics.
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