The FDA has approved interferon alfacon-1 (Infergen; consensus interferon) from Amgen Corp. (Thousand Oaks, CA) for treatment of chronic hepatitis C virus (HCV) infection in adults (officially "for the treatment of chronic hepatitis C infection in patients 18 years of age or older with compensated liver disease who have anti-HCV serum antibodies and/or the presence of HCV RNA"). This is the first approval of Infergen in any country. Interferon alfacon-1 has demonstrated efficacy in interferon treatment-naive patients generally comparable to that of currently approved interferon-alpha products. Also, patients who have not responded to or who have relapsed after prior interferon treatment may benefit from subsequent retreatment with Infergen. As discussed in the June 1996 Bulletin (p. 141), Amgen has licensed worldwide rights (except for the U.S. and Canada) for development and marketing of Infergen for all potential indications to Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan), which has granted Amgen's Japanese subsidiary, Amgen K.K., certain co-development and co-promotion/co-marketing rights in Japan, and Amgen's subsidiary in Hong Kong certain co-development and co-promotion rights in China, Hong Kong and Taiwan.
Interferon alfacon-1 is a non-naturally occurring, recombinant, "consensus" type I form of interferon-alpha. Its 166 amino acid sequence was constructed by taking the most common amino acid occurring at each position within multiple subtypes of interferon-alpha. Four additional amino acid substitutions were made to facilitate the molecular construction. Infergen differs in sequence from interferon alpha-2 at 20 of its 166 amino acids (has 88% homology) and has over 30% homology with interferon-beta, a greater similarity than any natural interferon-alpha subtype. Infergen is expressed in E. coli bacteria, allowed to oxidize to its native state and is purified using a series of chromatography columns. Since it is expressed in a bacterial system, it lacks the glycosylation patterns of human interferon.
Other forms of interferon-alpha previously approved in the U.S. for treatment of hepatitis C, Intron A (E. coli-expressed interferon-alfa-2b) from Schering-Plough and Roferon A (E. coli-expressed interferon-alfa-2a) from Hoffmann-La Roche, are recombinant forms of single interferon-alpha subtypes. Interferon alfacon-1 displays five times greater in vitro antiviral activity compared to naturally occurring interferon-alpha subtypes. However, as shown by clinical trials, this did not translate into significantly higher efficacy for interferon alfacon-1 compared to the pure recombinant interferon-alpha subtypes. The recommended dosage of Infergen is 9 µg three times weekly administered subcutaneously for 24 weeks. Patients who have tolerated prior interferon treatment and failed to respond to this or relapsed may be treated with 15 µg three times weekly for six months. The drug is supplied in single-dosage vials containing 9 and 15 µg of Infergen at a concentration of 0.03 mg/ml.
Clinical trials with Infergen included a dose-escalation study using 3, 6, 9, 12 or 15 µg three times per week (tiw) in patients with compensated liver disease due to hepatitis C. The 15 µg dosage was the maximal tolerated dosage and all doses had an acceptable safety profile with indications of efficacy. A randomized, double-blind Phase III trial tested the efficacy of 3 and 9 µg tiw dosages in 704 adults with compensated liver disease previously untreated with interferon-alpha. Patients were positive for hepatitis C virus RNA and had serum alanine aminotransferase (ALT) levels 1.5 or more times the upper limit of normal. Infergen was administered for 24 weeks followed by a 24-week observation period. Efficacy was assessed on an intent-to-treat basis and determined by serum ALT levels at the end of 24 weeks of treatment and the additional 24-week observation period. Serum HCV RNA was assessed using a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay with a lower limit of 100 copies/ml. Liver histology was assessed by comparing pretreatment biopsy specimens with specimens taken at the end of the observation period. Patients received either subcutaneous 3 µg tiw (n=232) or 9 µg tiw (n=232) of Infergen or conventional subcutaneous treatment with 3 million International Units (about 15 µg) of Intron A (n=240). At the end of 24 weeks of treatment, among those receiving 9 µg tiw Infergen, 39% showed normalization of ALT levels and 33% became HCV RNA negative (below the limit of detection); while among those receiving Intron A, 35% showed normalization of ALT and 25% become HCV negative. At the end of the observation period, among those receiving 9 µg tiw Infergen, 17% showed normalization of ALT and 9% remained HCV negative, while among those receiving Intron A, 17% showed normalization of ALT and 8% remained HCV RNA negative.
The official labeling for Infergen states, "Among the Infergen treatment groups in this study, the 9 µg dosage arm demonstrated a similar efficacy profile when compared to the IFN a-2b [Intron A] dosage arm. The 3 µg Infergen dosage arm had lesser efficacy." Similar improvements in liver histology, assessed by histology activity index (HAI) scores in the range of 63%-68% were observed in all three trial arms. Serum antibody levels were measured in all patients using an Infergen- or Intron A-binding ELISA. Positive binding antibody responses were 11% in the 9 µg Infergen group and 15% in the Intron A group, with the ALT response rates in patients with Infergen antibodies similar to those in patients without antibodies. The safety profile observed with Infergen was similar to that of other interferon-alpha regimens, including flu-like symptoms. Overall, 7% of patients treated with 9 µg Infergen withdrew due to adverse events, including 4% due to psychiatric events. Subsequent treatment with 15 µg tiw Infergen was evaluated in an open-label trial in 107 patients having failed initial therapy with either 9 µg Infergen or Intron A. Patients received Infergen for 24 weeks and were observed for another 24 weeks. Overall, 16 patients (15%) had a sustained normalization of ALT levels and 10 patients (9%) remained HCV negative. Results of clinical trials using subsequent therapy with 15 µg tiw Infergen for 48 weeks have not been reported and are under review by FDA.
Infergen will be Amgen's third marketed product. However, unlike its other products, recombinant erythropoietin (Epogen) and granulocyte colony stimulating factor (G-CSF; Neupogen), which each have worldwide annual sales over $1 billion, Infergen may only attain a market on the order of $100 million or less and it will have to battle other current interferon products and new drugs (e.g., lamivudine, famciclovir) that may receive approval for hepatitis C indications in coming years. Schering-Plough reported $524 million in 1996 sales of Intron A worldwide with $160 million in sales in the U.S. About one half of Intron A sales or over $250 million worldwide are for hepatitis treatment. Infergen will compete directly with Intron A and Roche's Roferon A, more recently approved for treatment of hepatitis C. Intron A is well established in the marketplace, particularly for first-line treatment, and Amgen will have to fight to capture sales and market share from Intron A. Amgen researchers originally designed interferon alfacon-1 in 1982 and clinical trials began in 1991, shortly after the hepatitis C virus was cloned and linked to chronic hepatitis C. Patents covering Infergen and it use include U.S. 4,695,523; 5,372,808 and 5,541,293. As reported in the August Bulletin (p. 239), Biogen Inc. (which has licensed technology for Intron A to Schering-Plough) has filed a suit charging Amgen with violating patents covering use of E. coli expression systems. As discussed in the December 1996 Bulletin (p. 335), a separate suit by Schering-Plough alleges that Infergen infringes U.S. patent no. 4,530,901 concerning the production of recombinant interferon.
The wholesale cost for Infergen is $29.39 per 9 µg vial ($2,116 for a six-month course of treatment) and $48.98 per 15 µg vial ($3,527 for a six-month course of retreatment). Amgen has established the COMPASS program to provide patients and health care professionals with information about hepatitis C and facilitate access to Infergen. Amgen will use its own dedicated sales force to market Infergen to hepatologists and hepatitis-treating physicians. The current cost for an initial course of treatment with Infergen is lower than for Intron A, but the two are not directly comparable since Infergen has only been tested and approved for a six-month course of initial treatment, while Intron A is used for a minimum of a year for initial treatment (with many patients now treated with recently approved and more effective 18-24 month regimens). The average wholesale cost for Intron A comes to about $5,134/year. A full-year course of treatment with Infergen (initial six-months treatment plus six-months retreatment) costs about $5,643. Longer-term initial treatment with Infergen (9 µg tiw) may eventually be found to lead to improved efficacy, perhaps providing Infergen with a cost advantage.
With the approval of Infergen, three recombinant E. coli-expressed type I interferon products are now available in the U.S. for treatment of chronic hepatitis C. Each has roughly comparable efficacy and safety profiles, with these products leaving much room for improvement. Generally, fewer than half of all treated patients respond to initial therapy and of those who do, more than half eventually relapse. Only about 15%-25% of patients achieve normalization of ALT and HCV RNA below detectable levels at six months posttreatment. In some cases, longer terms of treatment may increase response rates. Infergen will likely be readily accepted as a treatment for those either failing to respond to or relapsing from treatment with other interferon products. Whether it will be able to capture a significant portion of the market for first-line therapy will largely depend on the medical community's experience and response and Amgen's ability to capture market share from well-established products, particularly Intron A.
Valacyclovir Approved for Suppression of Genital Herpes
Oral valacyclovir hydrochloride (Valtrex; caplet formulation) from Glaxo Wellcome Inc. (Research Triangle Park, NC) has received supplemental FDA approval for a major new indication, suppression (prophylaxis) of recurrent genital herpes in immune competent adults. This is the first once-a-day drug treatment available for suppression of genital herpes outbreaks. The recommended dosage of valacyclovir for suppression of genital herpes is one gram once daily (one 1,000 mg caplet or two 500 mg caplets). Patients experiencing nine or fewer recurrences annually may use an alternative regimen of one 500 mg caplet daily. Valacyclovir HCl (L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride) is a prodrug of (metabolized to) and the L-valyl ester of acyclovir, the first drug available for treatment and suppression of genital herpes, marketed as Zovirax by Glaxo Wellcome (and by generic drug manufacturers in the U.S. and other countries where acyclovir's patent protection has lapsed or was never granted). Valacyclovir has three to five times greater bioavailability than acyclovir, enabling once-a-day dosing convenience. Valacyclovir received its initial U.S. approval in mid-1995 for treatment of herpes zoster (shingles) in immune competent adults as reported in the August 1995 Bulletin (p. 225). Valacyclovir was approved for treatment of recurrent genital herpes in immune competent adults in late 1995 as discussed in the December 1995 Bulletin (p. 356). The drug received approval for treatment of initial outbreaks of genital herpes in October 1996. As reported in last month's Bulletin (p. 257), famciclovir (Famvir) from SmithKline Beecham Corp. has also similarly received supplemental approval for suppression of genital herpes.
In one Phase III trial involving 1,479 immune competent patients with a history of six or more recurrences annually, 55% of patients receiving once-daily therapy with valacyclovir (1,000 mg) were recurrence free after six months compared to 54% of patients receiving conventional twice-daily acyclovir (Zovirax) and 7% of patients receiving placebo. After one year of therapy, 34% of valacyclovir and acyclovir patients were recurrence free compared to 4% of placebo patients. Patients with nine or fewer recurrences annually showed comparable results when using a lower (500 mg) daily dosage. Valacyclovir was generally well-tolerated with the most commonly observed adverse events consisting of headache (35% vs. 34% for placebo), nausea (11% vs. 8% for placebo) and abdominal pain (11% vs. 6% for placebo). Valacyclovir showed efficacy comparable to acyclovir; otherwise, a major advantage of valacyclovir over acyclovir includes easier compliance (only once-daily dosing). Valacyclovir has also shown indications of efficacy for suppression of recurrent genital herpes in patients with HIV-infection and AIDS. However, the efficacy of valacyclovir for suppression of genital herpes in immune compromised (e.g., AIDS) patients has not been established.
Glaxo Wellcome Inc. reports, "As of August, 1997, Valtrex became the most widely used branded antiherpetic medication (Source Prescription Audit - August, '97)." However, as discussed in an article below, recent studies are indicating that famciclovir (Famvir) from SmithKline Beecham, marketed for genital herpes treatment and also recently approved for suppression of genital herpes, unlike valacyclovir, also significantly reduces herpes simplex virus type 2 latency and shedding. This may give famciclovir an advantage, particularly if FDA approves labeling changes and marketing claims along these lines. For those with fewer than nine recurrences annually, suppression treatment with valacyclovir costs less than suppression treatment with acyclovir (Zovirax), also from Glaxo Wellcome. The wholesale price for valacyclovir is $2.30/500 mg tablet taken daily ($2.30/day or about $69/month), while the wholesale price of Zovirax (two 400 mg tablets daily) is about $3.51/day or $105/month. However, a number of generic drug companies are now offering acyclovir at substantially reduced prices.
Indinavir/AZT/3TC Combination Continues to Show Efficacy at Two Years
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), investigators presented results at 100 weeks from a trial (Study 035) testing indinavir sulfate (Crixivan), an HIV protease inhibitor from Merck & Co., in combination with two nucleoside analogs--AZT (Retrovir) and lamivudine (3TC; Epivir), both drugs from Glaxo Wellcome Inc. HIV plasma viral load was maintained below the limit of detection (500 copies/ml) in 79% of triple-combination recipients. The median decrease in viral load from baseline at 100 weeks was 2.12 log (from a baseline of 43,190 copies/ml) and the median increase in CD4+ T-cell count was 230 (from a baseline of 144). Patients in this study had previously taken AZT for a median of 2.4 years, with no prior use of 3TC or protease inhibitors. Eighty-one percent of patients had AZT-resistant HIV upon entry. Further analysis of Study 035 has shown that adding indinavir to an existing two-drug regimen, AZT plus 3TC, was not as effective as starting triple therapy with indinavir, AZT and at least one other antiretroviral drug not previously taken, 3TC.
Dr. R. Gulick, New York Univ. School of Medicine, remarked, "This study suggests the need to begin with triple therapy including a potent protease inhibitor because adding one protease inhibitor to a failing two-drug regimen of nucleoside analogues appeared suboptimal." Preliminary results from another study presented at ICAAC showed that twice daily dosing with indinavir (1,200 mg every 12 hours) in combination with AZT plus 3TC suppressed viral load below detectable limits in 75% (12/16) of patients after 20 weeks of treatment, suggesting that this twice daily indinavir regimen may provide results comparable to the currently approved three-times daily (800 mg every 8 hours) regimen. This is currently being studied in a larger trial comparing the regimens in over 400 patients. Indinavir's accelerated approval by FDA was based on viral load and CD4+ T-cell count data from studies up to 24 weeks. Merck will still probably have to provide clinical efficacy data, e.g., improved survival, to obtain full approval for indinavir. Indinavir is currently the most popular HIV protease inhibitor with over 160,000 patients receiving the drug worldwide. The drug has now received approval in 65 countries, and Merck continues to market the drug (in the U.S.) at wholesale prices about 22%-36% lower than prices for other approved protease inhibitors (about $12/day or $4,380/year at wholesale).
Combivir, AZT/3TC Combination Tablet, Approved
The FDA has approved Combivir from Glaxo Wellcome Inc. (Research Triangle Park, NC), a tablet combining the two most commonly prescribed nucleoside reverse transcriptase inhibitors, AZT (Retrovir) and 3TC (lamivudine; Epivir), both also marketed separately by Glaxo Wellcome. Each Combivir tablet (to be taken twice daily) contains 300 mg of AZT and 150 mg of 3TC, half of the daily dosage for each drug when used separately. This is the first product approved by FDA to combine two antiretroviral drugs into a single orally administered formulation. By significantly reducing the "pill burden" for patients receiving combination therapy, it is hoped that patient compliance will be increased. Failure to take antiretroviral drugs on schedule is a major reason for development of resistant virus and treatment failure. One tablet can be taken twice daily, eliminating the need for patients on AZT/3TC regimens to take up to eight tablets daily.
In the U.S., AZT/3TC combination treatment generally involves taking either one 150 mg tablet of 3TC twice daily and two 100 mg capsules of AZT three times daily (for a total of eight tablets daily), or one 150 mg tablet of 3TC twice daily plus one 300 mg tablet of AZT twice daily (for a total of four tablets daily). Combivir does not require refrigeration and can be taken with or without food. The bioequivalence of Combivir to AZT plus 3TC therapy was demonstrated in a clinical trial, but the safety of Combivir has not been formally assessed. Both AZT (Retrovir) and 3TC (Epivir) tablets will continue to be available separately and in oral solutions primarily for pediatric use. Glaxo Wellcome has priced Combivir (at the wholesale level) to be equivalent to the two drugs purchased separately with Combivir costing $7.18/tablet to wholesalers and distributors or about $5,240/year. Combivir should already be available in U.S. pharmacies. Combivir is expected to simplify and improve patient compliance with combination drug regimens including AZT/3TC. Glaxo Wellcome has also filed for regulatory approval of Combivir in other countries worldwide.
Zanamivir Shows Efficacy for Treatment of Influenza
Dr. F.G. Hayden, University of Virginia, and collaborators in the GG167 Influenza Study Group reported in the September 25 issue of the New England Journal of Medicine the results of two clinical trials showing that zanamivir (GG167; 4-guanidino-Neu5Ac2en; 4-gaunidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) from Glaxo Wellcome Inc. (Research Triangle Park, NC) has some efficacy for treatment of influenza A virus infection in adults. Zanamivir is a sialic acid analog originally developed by Biota Holdings Ltd. (Glen Iris, Victoria, Australia) and licensed by Glaxo Wellcome. Two randomized, double-blind, placebo-controlled studies enrolling 417 adults with influenza-like illness for less than 48 hours were conducted at multiple centers in the U.S. and Europe during the influenza seasons of 1994-1995. Patients randomly received either 8.4 mg of zanamivir in solution administered by intranasal spray plus 10 mg of powder by intranasal inhalation; 10 mg of zanamivir powder by inhalation plus placebo spray; or placebo by both routes. Treatments were self-administered twice daily for five days.
The investigators report, "Of 262 patients with confirmed influenzavirus infection (63 percent of all patients), the median length of time to the alleviation of all major symptoms was one day shorter (four days vs. five days) in the 88 patients given inhaled and intranasal zanamivir (p = 0.02) and the 85 patients given inhaled zanamivir alone (p = 0.05) than in the 89 patients given placebo. Among the infected patients who were febrile at enrollment and among those who began treatment within 30 hours after the onset of symptoms, the median time to the alleviation of major symptoms was four days in both zanamivir groups and seven days in the placebo group (p < 0.01). Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those of the placebo group. The topically administered zanamivir was well tolerated." Direct nasal mucosal and respiratory tract administration of zanamivir was shown to significantly (statistically) reduce influenza symptoms in adults where treatment was started early in the course of infection. There was no difference in zanamivir's efficacy between influenza A and B infections or by location (U.S. vs. Europe). Treated patients with febrile illness were able to resume their normal work or other activities one day sooner than placebo-treated patients with febrile illness. The median duration of viral shedding was reduced among zanamivir recipients (four days) compared to placebo recipients (six days). The greatest benefit was observed in those with the most pronounced illness (fever) upon enrollment and in those treated within 30 hours of onset of symptoms. Zanamivir and its topical administration were well tolerated and the frequency of local irritation was low. Addition of intranasal spray administration did not appear to significantly improve the efficacy of powder inhalation.
A market of perhaps $1 billion or more annually awaits an effective, safe, convenient and affordable drug for influenza treatment. Zanamivir has shown efficacy for treatment of influenza, reducing the time of symptomatic illness by one or more days with increased efficacy in patients treated early and with more extreme symptoms. However, this still leaves considerable room for improvement and other factors may limit zanamivir's market potential. Even though the investigators conclude, "The magnitude of the clinical benefit observed in this study appears to be at least as great as that in earlier trials of amantadine and rimantadine for acute febrile influenza A illness in adults," zanamivir may not be perceived as offering significant improvements over these currently available influenza drugs (which are used infrequently). Zanamivir is a selective neuraminidase (sialidase) inhibitor of diverse influenza virus A and B strains (properties shared with GS 4104 discussed in an article below). Neuraminidase encoded by the virus is required for cleavage of sialic acid residues from viral glycoconjugates to allow the release of influenza virus from infected cells, prevent aggregation of the virus and possibly reduce viral inactivation by respiratory mucus. Because of its activity against both influenza A and B, zanamivir has advantages over the two drugs currently approved in the U.S. for treatment of influenza which are only active against influenza A strains--oral amantadine (Symmetrel) from DuPont Merck Pharmaceuticals and oral rimantadine HCl (Flumadine) from Forest Laboratories. Rimantadine is approved for use in adults only and amantadine is approved for both adults and children. Much like zanamivir, both of these drugs are useful treatments to help reduce and shorten the fever and systemic symptoms of influenza A infection when taken within 48 hours of onset of symptoms.
However, the efficacy of rimantadine and amantadine for influenza A treatment appears to be roughly comparable to that demonstrated by zanamivir--capable of reducing symptomatic disease by one or a few days when treatment is started early. These available drugs are not heavily promoted and are infrequently prescribed for a number of reasons including misperceptions about influenza treatment (such as those discussed in the December 1994 Bulletin, p. 360), the slight risk for drug adverse effects, and the lack of rapid and cost-effective influenza diagnostics to allow early treatment. Direct comparison clinical trials showing zanamivir to offer improvements in efficacy and safety compared to rimantadine and amantadine may be required before zanamivir could become widely accepted by the medical establishment which has not fully adopted use of the available drugs. Influenza vaccines are still the preferred method for prevention of influenza A and B. Vaccines are highly effective for individual prophylaxis and reduction of epidemics, are cheaper and lend themselves better to large-scale use and public health campaigns. Improved vaccines are on the horizon, such as the live recombinant intranasal influenza virus vaccine developed by Aviron, Inc. which provided 93% protective efficacy in a large pediatric trial (see July Bulletin, p. 193).
Zanamivir, because of its novel inhalation administration, will also be at a disadvantage in terms of marketing and consumer acceptance. The general public has little experience with inhaled intranasal topical administration of drugs in powdered form. However, if found sufficiently safe and effective, zanamivir could conceivably someday become an over-the-counter (nonprescription) drug. The lack of rapid and inexpensive diagnostics for influenza is another factor that may restrict the market for zanamivir. Note that in the trial described above, over one-third of treated patients did not have influenza. Availability of rapid, simple and inexpensive diagnostics would likely facilitate regulatory approval of widespread use of zanamivir and other new influenza drugs. Biota is working with several U.S. companies, BioStar, Inc. (Boulder, CO) and Binax, Inc. (Portland, ME), for the development of point-of-care (on-the-spot) influenza diagnostics. Biota is developing tests based on zanamivir and related compounds (having reporter molecules attached) with high affinity and specificity for influenza neuraminidase. Glaxo Wellcome is also developing rapid diagnostics, including collaborating with Quidel Corp. (San Diego, CA) for development of influenza diagnostics. Results from a Phase III clinical trial with zanamivir in Australia conducted this summer (winter in the Southern Hemisphere) have not yet been reported. Glaxo Wellcome will be conducting trials this flu season. Biota expects filing for approval of zanamivir to occur in the second half of 1998. Zanamivir may have to compete with other drugs which are showing considerable promise, such as GS 4104 (discussed below). Biota will receive a royalty of 6% based on sales of zanamivir.
GS 4104 Shows Efficacy for Treatment and Prevention of Influenza
Investigators from Gilead Sciences, Inc. (Foster City, CA) and F. Hoffmann-La Roche Ltd. (Basel, Switzerland) presented results from two randomized, double-blind, placebo-controlled Phase II clinical studies with GS 4104 (Ro 64-0796) at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). In one trial, oral administration of this potent influenza neuraminidase inhibitor "significantly decreased influenza viral replication and the duration of influenza symptoms when given as treatment." In another study for prophylaxis, GS 4104 "prevented illness and evidence of detectable virus." The companies are initiating Phase II/III clinical trials during this winter's flu season at over 100 sites in the U.S., Canada and Europe, enrolling patients with influenza and those at risk for contracting influenza.
In the Phase II treatment study, 80 healthy volunteers received either one of four dosage levels of GS 4104 or placebo once or twice daily for five days, with dosing initiated 28 hours after intranasal exposure to influenza A virus. Overall, GS 4104 decreased the median time to cessation of symptoms by about 50%, from 95 hours in the placebo group to 53 hours in treated subjects. Twenty-four hours after treatment was initiated, the influenza virus titers were reduced by over 100-fold in the treated group compared to placebo. These results were statistically significant. In the Phase II prophylaxis study, 37 healthy volunteers received either one of two dosages of GS 4104 or placebo once or twice daily for five days, with subjects exposed to influenza A virus 26 hours after treatment started. None of the treated patients had detectable influenza virus in their nasal passages compared to 50% in the placebo group. GS 4104 was well tolerated in both studies with no dosage limiting side effects observed.
Although GS 4104 was tested against experimental influenza A infection, it is active against both A and B strains of the virus. The target enzyme, neuraminidase, is essential and highly conserved among pathogenic influenza A and B strains, suggesting it should retain efficacy against the various strains that reach epidemic proportions each year. Animal studies show that orally administered GS 4104 persists in lung tissues, a primary site for influenza virus replication, for longer periods than in blood plasma, with drug levels in lung tissues 30-fold greater than plasma levels 24 hours after a single dose. As discussed in the September 1996 Bulletin (p. 231), GS 4104 has demonstrated potent activity against both A and B strains of influenza virus in preclinical testing and Roche has formed a worldwide collaboration with Gilead for development and marketing of GS 4104 for treatment and prevention of influenza virus infection. As discussed in an article above, zanamivir from Glaxo Wellcome administered by intranasal powder inhalation has also demonstrated some efficacy for treatment of acute influenza virus infection. GS 4104, which is administered orally, may have advantages in terms of consumer acceptance due to its more familiar oral route of administration.
Oral/Implant Ganciclovir Combination Shows Prophylactic Efficacy
In a late-breaker session at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), investigators reported results indicating that combining the slow-release ganciclovir intraocular implant (Vitrasert) with oral ganciclovir capsules reduces the incidence of cytomegalovirus (CMV) disease in other organs (extraocular disease), delays the onset of CMV retinitis in the unaffected eyes of AIDS patients and has other desirable effects. Dr. D. Martin, Emory Univ. School of Medicine, remarked, "This study is significant because it demonstrates the best way to treat patients with CMV retinitis is to combine intense local therapy (Vitrasert) with systemic treatment (Cytovene capsules)." Oral ganciclovir (Cytovene) capsules and intravenous ganciclovir are marketed by Hoffmann-La Roche Inc. (Nutley, NJ). Intravenous ganciclovir has long been available for treatment of CMV disease. Oral ganciclovir has been approved for CMV prophylaxis in advanced HIV patients as reported in the November 1995 Bulletin (p. 324). Vitrasert Implant from Chiron Vision Corp. (Claremont, CA) and co-promoted by Roche has been approved for treatment of CMV retinitis in AIDS patients (as discussed in the March 1996 Bulletin, p. 66). FDA has not specifically approved the use of the oral and implant forms in combination, but since both are approved there is nothing to stop their use in combination (except health insurer reticence to reimburse for more expensive and unapproved combination therapy).
Study GAN2304 was a randomized, controlled study in 377 patients with CMV retinitis in one eye who were either newly diagnosed or stable after treatment with intravenous ganciclovir. Patients randomly received either Vitrasert implant plus oral ganciclovir (1,500 mg tid; a dose higher than the 1,000 mg tid dose approved for maintenance therapy); Vitrasert plus placebo; or standard induction therapy (5 mg/kg every 12 hours for 14-21 days) with intravenous ganciclovir followed by maintenance therapy (5 mg/kg once daily, 7 days/week). The median survival times in the combination, intravenous monotherapy and implant monotherapy arms were, 568, 426 and 388 days, respectively, with the combination associated with improved survival. Both the combination and implant monotherapy groups had a longer time to disease progression than those in the intravenous ganciclovir arm. Progression of retinitis in the affected eye was significantly delayed in the combination arm compared to the implant arm. After six months, 22.4% of patients in the combination group experienced new CMV disease, compared to 37.8% of those with only the implant and 17.9% in the intravenous ganciclovir group. The incidence rates of Kaposi's sarcoma (now associated with human herpesvirus-8) in the combination group (2.7%) and intravenous group (1.5%) were reduced compared to the implant group (11%). Combination recipients also required significantly fewer hospitalizations, spent fewer days in the hospital and had a reduced incidence of new AIDS-associated conditions.
D4T Continues to Show Promise as Basis for HIV Drug Combinations
Results from several clinical trials presented at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) indicate, "Once-daily dosing of DDI, in combination with D4T, appears to be a safe and highly potent antiretroviral regimen and should be considered as the foundation of new standard triple or quadruple therapy for HIV disease." This suggests that D4T/DDI could replace AZT plus lamivudine (3TC) as the most commonly used combination of nucleoside reverse transcriptase inhibitors to which HIV protease inhibitors and/or other antiretroviral drugs are often added. This could include D4T/DDI replacing AZT/3TC as the basis for first-line treatment combination therapy. Already, sales of D4T are on track to surpass those of AZT. Both DDI (Videx; 2',3'-dideoxyinosine) and D4T (Zerit; stavudine; 2',3'-didehydro-2',3'-dideoxythymidine) are marketed by Bristol-Myers Squibb Co. (New York, NY).
Results were reported from a multicenter French clinical trial in 52 antiretroviral drug-naive patients who received D4T (40 mg twice daily) plus DDI (300 mg once daily) for 24 weeks. The median CD4+ T-cell count increased from 330 to 439 after eight weeks and to 469 at 24 weeks. HIV plasma viral load decreased from a baseline of 4.51 log copies/ml (Chiron bDNA assay) to 2.93 log copies/ml at week eight, a 1.58 log reduction (a 1.8 log reduction using Roche PCR assay). Seventy-five percent of patients achieved undetectable viral loads (below 500 copies/ml) at eight weeks, which was maintained in 62% at 24 weeks. The combination was generally safe and well tolerated.
Results from an open-label Phase II trial presented by the Swiss HIV Cohort Study group demonstrated that the triple combination of D4T and two protease inhibitors, ritonavir (Norvir) from Abbott Labs. and saquinavir (Invirase) from Hoffmann-La Roche, provides potent virologic and clinical responses in HIV-infected patients. Fifty-six patients received the triple combination D4T (30-40 mg twice daily), saquinavir (600 mg twice daily) and ritonavir (400-600 mg twice daily) for at least nine weeks. None of the patients had previously received either D4T or a protease inhibitor. Among the 49 patients for whom nine-week data were available, the median viral load decreased 2.5 log from a baseline of 5.2 log and fell below detectable levels (over 2 log reduction) in 86% of patients, and the median CD4+ T-cell count increased by 102. The addition of ritonavir to saquinavir increased the plasma concentrations of saquinavir by 10-100 times in all but one patient. The investigators concluded, "These data are very promising and justify further study of triple combination regimens that include two protease inhibitors and a nucleoside analog." Presently, most HIV combination regimens involve two nucleoside analogs plus one protease inhibitor. The dropout rate in both trials was low, below ten percent. In related news, a Phase I/II open-label clinical trial testing the combination of D4T plus lamivudine (3TC) is now underway for prevention of maternal transmission of HIV.
Famciclovir Reduces HSV-2 Shedding and Latency
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Dr. S.L. Sacks, Viridae Clinical Sciences, Inc. (Vancouver, BC, Canada), and collaborators reported results from the first clinical trial of its kind showing that famciclovir (Famvir) from SmithKline Beecham Corp. (SKB; Philadelphia, PA) is effective in suppressing asymptomatic viral shedding in patients receiving the drug for suppression of genital herpes recurrences (due to herpes simplex virus type 2 infection). This suggests that famciclovir may effectively reduce the risk of contracting genital herpes in non-infected sex partners. As discussed in last month's Bulletin (p. 257), famciclovir recently received supplementary approval for suppression (prophylaxis) of recurrent genital herpes outbreaks. Dr. Sacks reported, "This study shows that patients who have frequent genital herpes outbreaks and use Famvir on a daily basis experience a marked reduction in symptomatic and asymptomatic viral shedding." Studies have shown that transmission of genital herpes most often occurs during asymptomatic shedding--between recurrences when affected patients may not be taking adequate precautions. This randomized, double-blind, placebo-controlled, parallel-group study enrolled 177 women with frequently recurring genital herpes who received famciclovir or placebo treatment for four months. Patients swabbed their genital areas daily for viral testing and recorded lesions and other symptoms in a diary. "Patients treated with Famvir had approximately an 80-90 percent reduction in days with asymptomatic viral shedding and an 87-97 percent reduction in days with symptomatic viral shedding, compared with placebo."
The efficacy of famciclovir suppression therapy to reduce viral shedding, presumably directly associated with the risk for transmission of HSV-2, may give it an advantage over valacyclovir and acyclovir, both drugs from Glaxo Wellcome Inc., which are also approved for suppression of genital herpes episodes. SKB may pursue an additional indication for famciclovir, reduction of risk of sexual transmission. It remains to be seen whether FDA and other regulatory authorities would grant this based on surrogate marker-type data showing reduction in viral shedding. Famciclovir may offer other advantages, when compared with (val)acyclovir, including the ability to prevent further genital recurrences (perhaps essentially curing the disease) after treatment of initial outbreaks, as discussed in the October 1996 Bulletin (p. 264).
Along these lines, Dr. H.J. Field, Cambridge University Veterinary School, at ICAAC updated his preclinical findings in mice showing that famciclovir when administered during initial HSV infection is more effective than valacyclovir in reducing the number of cells containing latent HSV, even when treatment is delayed for several days. Famciclovir (but not valacyclovir) treatment during acute HSV infection was shown to prevent viral latency and/or subsequent reactivation. Latently infected cells were visualized using a new technique involving staining of LAT protein produced by dormant virus in latently infected cells. Mice were treated for 10 days with either famciclovir or valacyclovir starting within one or two days after infection. Compared to untreated controls, only a few cells in famciclovir-treated mice had latent HSV vs. 40% of cells in valacyclovir-treated mice.
Dr. Field concluded, "Famciclovir's high bioavailability combined with its ability to maintain high concentrations of its active form [penciclovir] inside infected cells for a long period of time may explain its benefits over other antivirals." Famciclovir significantly reduced latency even when treatment was started up to five days after infection of mice with either HSV-1 or HSV-2. Similar famciclovir-induced reduction of viral latency has been observed in murine neural tissues. These results were achieved using direct comparisons of oral famciclovir and valacyclovir in mice achieving drug levels comparable to those achieved in humans during therapy. Based on these results, an ongoing double-blind, randomized, parallel group clinical trial sponsored by SKB involving 300 patients at 50 sites worldwide (25 U.S. sites) is testing whether 10-day famciclovir treatment of initial outbreaks can eliminate further outbreaks.
Saquinavir Soft Gel Capsules Show Efficacy Comparable to Indinavir
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), investigators conducting the Dutch "Cheese" Study (M61003) reported 12-week data from "the first ever head-to-head trial comparing two HIV protease inhibitors show[ing] that Fortovase, an investigational soft gel formulation of saquinavir, has similar antiviral activity as the widely used Crixivan (indinavir) when either drug is taken in combination with AZT and 3TC," and Fortovase improved CD4+ T-cell counts better than indinavir. Early clinical trial reports with Fortovase from Hoffmann-La Roche Inc. (Nutley, NJ) have shown the drug to have significant anti-HIV activity and safety as reported in last month's Bulletin (p. 260). Indinavir, marketed by Merck & Co., is currently the leading HIV protease inhibitor in terms of sales.
Among 44 patients in the Cheese trial, both drug combinations reduced viral load by 2.3 log at 12 weeks, reducing HIV plasma RNA levels below the conventional limit of detection. Patients had CD4+ T-cell counts below 500 upon entry (median around 300 in both groups) and had a median viral load of 4.9 log (79,432 copies/ml). Fortovase increased the median CD4+ T-cell count by 124 compared to 49 for indinavir. Data from another trial (NV15355) also presented at ICAAC showed that among treatment-naive patients receiving Fortovase or indinavir in combination with two nucleoside analogs, 80% of those in the Fortovase arm at 16 weeks had viral load below the limit of detection compared to 43% in the indinavir arm. This is among the several studies that Roche has submitted to FDA to support approval of Fortovase. Fortovase is generally safe and well tolerated but, perhaps because more drug is delivered, Roche acknowledges, "In clinical trials comparing Invirase and Fortovase, the new formulation increased the risk of the following adverse events: diarrhea, nausea, abdominal discomfort, flatulence, vomiting, headaches, abdominal pain, insomnia and taste alteration."
Nevirapine, HIV NNRTI, Combinations Continue to Show Efficacy
In a late-breaker session at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Dr. S. Vella and collaborators reported 48-week data from an Italian Phase II clinical trial (ISS 047) in 71 previously untreated patients with advanced HIV-infection (CD4+ T-cell counts below 200) comparing the triple combination nevirapine (Viramune), a non-nucleoside reverse transcriptase inhibitor (NNRTI), from Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT) plus AZT (Retrovir from Glaxo Wellcome) and DDI (Videx from Bristol-Myers Squibb) vs. two-drug combination therapy with AZT and DDI. Patients had high viral loads (mean baseline of 500,000 copies/ml or 5.7 log in the triple combination arm and 300,000 copies/ml or 5.5 log in the double combination arm). At 48 weeks, the triple combination maintained "a significant reduction in plasma HIV RNA levels with a mean 99 percent reduction from baseline," which was significantly greater than the AZT/DDI arm. Plasma HIV RNA remained below the limit of detection in 60% of patients. CD4+ T-cell counts among triple combination recipients increased by an average of 130 from baseline compared to an increase of 40 among AZT/DDI recipients.
Also at ICAAC, follow-up results at one year, seven months from selected patients in the INCAS trial were updated. One-year results from this trial had showed that early treatment with nevirapine in combination with two nucleoside analogs reduced HIV plasma viral load below the limit of detection in over 50% of patients with no prior antiretroviral drug use (as reported in the December 1996 Bulletin, p. 326). Using an experimental assay with a lower detection limit of only 20 copies/ml, HIV plasma RNA was shown to be undetectable among patients who continued treatment with nevirapine plus two nucleosides (AZT plus DDI or 3TC) after the end of the one-year INCAS study. This demonstrates that nevirapine (and perhaps other potent NNRTIs) in combination with nucleoside analog reverse transcriptase inhibitors has the potential to maintain near zero levels or immeasurable HIV plasma RNA for over one year. In another study, INCAS investigators reported that viral load measured in the lymph nodes of 15 patients having completed one year of the triple-combination treatment remained suppressed at one year and correlated well with decreases in plasma viral load. The investigators concluded that antiretroviral regimens capable of maintaining suppression of plasma viral load can also result in reduction of HIV levels in the lymph nodes.
HIV Protease Inhibitor Treatment Failures May Be More Common Than Trials Indicate
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), researchers from the Univ. of California (San Francisco, CA) reported results from a retrospective study of patients treated with HIV protease inhibitors indicating treatment failure in 53%, a figure much higher than commonly reported from clinical trials with HIV protease inhibitor combinations. The medical charts of 450 HIV-infected patients were analyzed. Among the 200 patients treated with HIV protease inhibitor combinations, 53% showed evidence of treatment failure after at least six months of treatment. Generally, clinical trials with HIV protease inhibitors have been reporting similar treatment failures in about 10%-20% of patients. Patients in clinical trials are presumed to be healthier, more motivated and more likely to comply with complicated multi-drug combination regimens. The failing patients were generally more advanced and had one or more risk factors for disease advancement, such as starting therapy with a lower CD4+ T-cell count, higher plasma viral load, having received prior antiretroviral drug therapy, and had more difficulty with compliance. Rather than being an indictment of HIV protease inhibitors, these findings support starting treatment early with highly potent triple combinations including a protease inhibitor, rather than starting treatment with a double nucleoside analog combination, such as AZT and lamivudine (3TC), and later adding an HIV protease inhibitor. However, a significant portion of treated patients fail on HIV protease inhibitor combinations and, currently, there are few alternatives for these patients, except to try other protease inhibitors or non-nucleoside reverse transcriptase inhibitors in combination with nucleosides which they have not already taken.
Four Drug Combination Shows Indications of Efficacy
At the recent 6th Conference on Clinical Aspects and Treatment of HIV-infection held in Hamburg, Germany, Dr. D. Ho, Aaron Diamond AIDS Research Center, Rockefeller Univ., presented preliminary results from a Phase II study using the twice-daily combination of 141W94 (1,200 mg), an HIV protease inhibitor from Glaxo Wellcome and Vertex Pharmaceuticals Inc.; AZT (300 mg; Retrovir) from Glaxo Wellcome; lamivudine (150 mg; 3TC; Epivir) from Glaxo Wellcome and BioChem Pharma Inc.; and 1592U89 (300 mg; abacavir; a carbovir compound), a nucleoside reverse transcriptase inhibitor from Glaxo Wellcome that is more potent and considered to be less toxic than AZT. Glaxo Wellcome has marketing rights for all of these drugs in most countries. Among 25 protease inhibitor- and 3TC-naive patients with chronic infection (n=12) and acute HIV-infection (n=13; infected for less than 90 days) taking the four-drug combination, at eight weeks there was a 2.27 log reduction in plasma HIV RNA in 10 chronically infected patients. Eight of these patients had plasma viral load below 100 copies/ml at week 12. Five of five acutely infected patients had plasma viral load below 100 copies/ml after week 16. Dr. Ho has been studying the potential for highly potent antiretroviral drug combinations to eradicate HIV-infection. From gastrointestinal lymph tissue biopsies, "5 of 6 patients evaluated had virus reduced to below detectable levels with the four drug treatment. In 6 patients, there is evidence of reduction in viral load." The combination was well tolerated with no grade three or four toxicities observed and no significant adverse events reported.
Dr. Ho also presented preliminary data at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) indicating that four-drug combinations including the protease inhibitors saquinavir (Invirase from Hoffman-La Roche Inc.) and ritonavir (Norvir from Abbott Labs.) have potent antiretroviral activity in advanced patients but the response is generally short-lived. In another ICAAC presentation, researchers from St. Vincent's Hospital (Darlinghurst, Australia) reported a high rate (41%) of resistance-related treatment failures after six months in advanced patients treated with saquinavir and ritonavir plus AZT and 3TC or D4T and 3TC.
New Phase III Trial for 141W94; Encouraging Phase II Results
Glaxo Wellcome Inc. (Research Triangle Park, NC) has initiated a third pivotal Phase III trial testing 141W94 (VX-478; 1,200 mg twice daily), an HIV protease inhibitor, in combination with a nucleoside reverse transcriptase inhibitor (NRTI) vs. indinavir (Crixivan from Merck & Co.; 800 mg three times daily) plus an NRTI. The open-label, randomized trial is enrolling 460 NRTI-experienced, protease inhibitor-naive HIV-infected adults at 65 centers in the U.S., Europe, Australia and Canada. This is the third pivotal Phase III trial with 141W94. The start of a pediatric trial was discussed in the July Bulletin (p. 202). Another adult Phase III trial started earlier this year. The new study's protocol has been amended so that after 16 weeks of treatment all patients will receive 141W94 plus AZT (Retrovir) plus lamivudine (3TC; Epivir). Patients will remain on 141W94/AZT/3TC for 48 weeks. Sixteen-week data from all three trials will be used to support regulatory filings for approval of 141W94 in the U.S. and other countries.
Vertex Pharmaceuticals Inc. (Cambridge, MA) and its partner, Kissei Pharmaceutical Co., Ltd., initially developed 141W94 which is being codeveloped internationally in collaboration with Glaxo Wellcome which holds clinical development and marketing rights in most countries. Vertex recently reported 12-week data from an ongoing Phase II trial (Vanguard) showing that 141W94 (900, 1,050 and 1,200 mg twice daily) in combination with AZT and lamivudine was generally well-tolerated and demonstrated potent anti-HIV activity at all three dosage levels, with about 70% of patients having undetectable viral loads (below 400 copies/ml). Patients taking the highest dose of 141W94 had a median reduction of 2.65 log in viral load from baseline compared to 1.33 log in the control arm (AZT/3TC). Additional data from trials involving other treatment regimens will be reported in coming months.
D4T Approved for First-Line Use in Europe
D4T (Zerit; stavudine) from Bristol-Myers Squibb Co. (New York, NY) had received approval in the European Union for first-line combination treatment of HIV-infection. The drug, which is replacing AZT as the most often used thymidine analog in many combination regimens, is approved in the U.S. only for use in patients having received prolonged prior AZT therapy.
Pediatric Filing for Interferon for Hepatitis B
Schering-Plough Corp. (Madison, NJ) has filed a supplemental Biologic License Application (BLA) with FDA for approval of recombinant interferon alfa-2b (Intron A) injection for treatment of chronic hepatitis B virus infection in pediatric patients one year of age or older. Intron A is currently approved in the U.S. for treatment of chronic hepatitis B in adults, and for other viral disease-related indications including chronic hepatitis C, Kaposi's sarcoma and genital warts.
HSV Vaccine Prophylactic Efficacy in Mice
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), researchers from CEL-SCI Corp. (Alexandria, VA) reported studies with herpes simplex virus heteroconjugate vaccines using the company's L.E.A.P.S. (Ligand Epitope Antigen Presentation System) technology. A synthetic heteroconjugate protein (JH1) composed of the 322-332 peptide (H1) of the ICP27 protein of herpes simplex virus type 1 (HSV-1) linked to a "J" (beta-2M 35-50) T-cell binding ligand elicited delayed-type hypersensitivity, TH1-like and protective responses against challenge with HSV-1 in immunized mice. CEL-SCI is also applying L.E.A.P.S. to improve the efficacy of its HGP-30 HIV vaccine as discussed in the February Bulletin (p. 43). L.E.A.P.S. technology was licensed from Cell Med Inc. (Columbia, MD). The Northeastern Ohio Universities College of Medicine is collaborating with CEL-SCI in the development of HSV vaccines. CEL-SCI recently entered into a Collaborative Research and Development Agreement (CRADA) with the National Cancer Institute for joint testing of L.E.A.P.S. heteroconjugates in animal models for prostate and mammary cancers.
ArQule and RiboGene Form Collaboration
ArQule, Inc. (Medford, MA) and RiboGene, Inc. (Hayward, CA) have formed a collaboration for the discovery of lead compounds for treatment of viral and bacterial infections. ArQule's Mapping Array library program will be used with RiboGene's assays to identify compounds that interfere with pathogen-specific translation mechanisms. The companies will share rights to compounds discovered and any resulting revenue.
Foscarnet Cream for Oral Herpes
Investigators sponsored by Astra USA, Inc. (Westborough, MA) have reported results of a clinical trial with 3% foscarnet (Foscavir) cream for treatment of oral herpes (herpes simplex virus type 1). Foscarnet sodium (phosphonoformic acid, sodium salt) has been marketed in the U.S. since 1991 for intravenous infusion treatment of cytomegalovirus disease indications. The topical cream was found to reduce the severity of ultraviolet radiation-induced herpes labialis lesions. The investigators concluded, "Foscarnet cream appeared to have clinical benefit, reducing the size and duration of delayed classic lesions. These data suggest that topical foscarnet can be efficacious and deserves further evaluation for the treatment of herpes labialis." Topical foscarnet has also shown indications of efficacy for treatment of genital herpes.
Milder Influenza Season Forecast in U.S.
The Centers for Disease Control and Prevention (CDC) has forecast that this winter's flu season will likely be milder than last year's, in the sense that fewer deaths are expected. About the same number of persons are expected to become sick. CDC forecasts that influenza type B infections will predominate with these less likely to cause death than influenza A strain infections which have predominated in recent years. Although influenza deaths from last year's season have not yet been officially reported, preliminary data indicate that mortality will be higher than normal. Typically, about 20,000 Americans die from influenza or its complications annually.
HIV Integrase Inhibitor Pharmacokinetic Trial
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), researchers from Aronex Pharmaceuticals, Inc. (The Woodlands, TX) reported the results of single and multiple dose Phase I pharmacokinetic studies with Zintevir, an HIV integrase inhibitor drug. Subjects received single doses of Zintevir at 0.75, 1.5, 3 or 6 mg/kg or multiple doses at 1.5 or 3 mg/kg administered by intravenous infusion over two hours every other day for 14 days. Among those receiving single doses, Zintevir plasma concentrations exceeded the in vitro HIV inhibitory concentration for up to 12 hours after the 6 mg/kg dosage. Among those receiving multiple doses, "Zintevir was detectable in the plasma for up to 122 hours at 3 mg/kg following the final dose. Zintevir was extremely well tolerated by patients in the Phase I clinical trials." Dr. J.M. Chubb, President, Aronex, stated, "The relatively long half life of Zintevir suggests the possibility of favorable dosing regimens." Zintevir is currently in a multiple dose-escalating clinical trial in HIV-infected patients expected to be completed in early 1998.
HIV Sequence-Based Genotyping Kits Available
Visible Genetics Inc. (Toronto, Ontario, Canada) has introduced HIV TruGene, a new line of sequenced-based HIV genotyping kits, useful for detecting drug resistant HIV mutations for both the reverse transcriptase and protease regions of HIV. The kits use the company's proprietary Clipper "genotyping engine" and CLIP, a single-tube DNA sequencing method. The HIV TruGene product line includes three kits--a low-cost, low-resolution, high-throughput screening kit that "identifies 93% of the known mutations"; a medium-resolution kit providing full DNA sequence data in the 3' direction; and a high-resolution kit providing full duplicate A, C, G and T sequence data in both the 3' and 5' directions. The product line includes the HIV Mutation Library that rapidly locates known mutations in a sample along with Gene Librarian software providing literature citations for each mutation found. The company claims, "With a single Clipper, users can carry out up to 64 low resolution genotypes per day, or 32 medium resolution genotypes per day or 16 high resolution genotypes per day," with each kit going from isolated DNA sample to final result in about 3 to 4 hours.
MKC-442, HIV NNRTI, Continues to Show Activity
At the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), researchers from Triangle Pharmaceuticals, Inc. (Durham, NC) presented data from an ongoing Phase I/II, double-blind, randomized, placebo-controlled trial testing repeated administration of increasing oral dosages of MKC-442, an HIV non-nucleoside reverse transcriptase inhibitor licensed from Mitsubishi Chemical Corp. (Tokyo, Japan). Forty asymptomatic HIV-infected patients received MKC-442 at dosages from 100-750 mg twice daily for up to two months. Among the patients receiving the highest dosage, all had at least a 90% decrease in HIV plasma RNA (median 96% or 1.5 log decrease) after one week of treatment. These decreases were followed by a gradual increase in viral load toward baseline levels over the next month. These results are typical of NNRTIs when tested in monotherapy trials. A mutation in HIV-1 reverse transcriptase at position 103, probably associated with resistance, was observed in virus recovered from several patients (also consistent with observations from other NNRTI monotherapy trials). Further dose escalation is ongoing to determine the optimal safe and effective dosage. MKC-442 was reported to be metabolized by the same cytochrome P450 enzymes responsible for metabolism of other NNRTIs and HIV protease inhibitors. To date, the drug has been well tolerated in over 300 patient-weeks of testing with the only clinically significant adverse reaction being moderate rash in two patients.
Viral "Biological Sabotage" in New Zealand
The government of New Zealand has confirmed an act of "biological sabotage" involving the purposeful introduction into New Zealand of a highly lethal rabbit calcivirus disease, apparently in an attempt to kill off or reduce the number of rabbits which are considered pests by many farmers. Authorities fear that the virus introduction could have unexpected environmental results, such as depriving ferrets, feral cats and other predators of their usual rabbit diet and forcing them to switch to preying on lizards, birds and endangered species for food during the winter. The virus originally escaped from a quarantine station in Geelong, Australia, last year and is expected to wipe out about 60% of Australia's 300 million rabbits. New Zealand farmers had been threatening to introduce the virus illegally to reduce the rabbit population which has been a problem in the country ever since they were first introduced in 1864. Several virus outbreaks hundreds of kilometers apart have been reported and authorities are taking steps including setting up roadblocks in affected areas and surveying farms by helicopter for dead rabbits.
Ritonavir/D4T Pediatric Efficacy
In a late-breaker session at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), results from a Pediatric AIDS Clinical Trial Group (PACTG) study were reported indicating that ritonavir (Norvir), an HIV protease inhibitor, from Abbott Laboratories (Abbott Park, IL) in combination with D4T (stavudine; Zerit) from Bristol-Myers Squibb Co. or AZT (Retrovir) plus 3TC (lamivudine; Epivir) has improved efficacy for treatment of pediatric HIV-infection compared to AZT plus 3TC (both from Glaxo Wellcome Inc.). Viral load data were available for 162 of the 298 children (median age 7.1 years) in the trial with a median follow-up of 3.4 months. In the ritonavir/D4T group at 12 weeks, 61% of the children had undetectable HIV RNA (below lower limit of 400 copies/ml), compared with 57% of those in the ritonavir/AZT/3TC group and 14% in the AZT/3TC group. Based on these results, the PACTG closed the AZT/3TC arm of the trial and is offering ritonavir to these children. Dr. E. Sun, Abbott Labs., remarked, "These findings, from an ongoing study, suggest that a protease inhibitor, such as Norvir, is critical in anti-retroviral management of children." The adverse event profile in children was similar to that observed in adults. Ritonavir was approved for pediatric use as reported in the March Bulletin (p. 67). See also several stories above discussing results from clinical trials including D4T or ritonavir in various combination regimens.
Australian RSV Drug Design Collaboration
Biota Holdings Ltd. (Glen Iris, Victoria, Australia) and the Biomolecular Research Institute (BRI; Melbourne, Australia), have formed a collaboration for the design of drugs for viral disease and cancer treatment. The first project will concentrate on respiratory syncytial virus (RSV). BRI will provide crystallography, microscopy, spectroscopy and drug design expertise and services to determine the structure of RSV surface proteins. Biota will provide BRI with an access fee and royalties on a project-by-project basis.
Quidel and Glaxo Wellcome Link for HSV-2 Diagnostics
Quidel Corp. (San Diego, CA) and Glaxo Group Ltd. (Middlesex, U.K.) have formed a collaboration for development of two point-of-care (e.g., in physician's office) diagnostics for genital herpes (herpes simplex virus type 2). Glaxo is funding development by Quidel of QuickVue Generation III one-step assays which Quidel will market with Glaxo receiving royalties based on sales. Glaxo retains options to market the assays in markets where Quidel does not have a sales presence, and will promote the need for improved diagnostics along with its drugs (valacyclovir and acyclovir) for treatment of genital herpes. This agreement follows a similar previous one between the companies for development of point-of-care diagnostics for influenza A and B virus.
First FDA Approval for HCV Viral Load Assay
The FDA has recognized Superquant HCV, a quantitative polymerase chain reaction (PCR) assay for hepatitis C virus (HCV), from National Genetics Institute (NGI; Culver City, CA) as an acceptable means to determine the antiviral efficacy of treatments for chronic HCV infection. This is the first time that FDA has allowed "product claims that include direct measurement of the antiviral effects of a treatment for chronic HCV infection." The assay uses proprietary robotic equipment developed by NGI to quantify HCV over a wide range of concentrations. This assay was used by Amgen Corp. to support recent approval of its consensus interferon (Infergen) for treatment of chronic hepatitis C (see lead story). The assay has been and is being used in several other clinical trials testing HCV therapeutics. The assay has been commercially available since April 1996 and over 3,000 U.S. clinicians are using it to monitor over 20,000 patients.
New Publications
HIV and the Pathogenesis of AIDS, 2nd edition, by J.A. Levy, American Society for Microbiology, Washington, DC, October 1997, 400 pages, $56.95 ($47.95 for members).
Knowledge, Action, Health--A Woman's Guide to HIV Treatments, "the first-ever women's comprehensive HIV treatment guide," Women Alive, Los Angeles, CA, September 1997. Available from Women Alive, 1566 Burnside Ave., Los Angeles, CA 90019; Phone: 213-965-1564; Fax: 213-965-9886.
Market Dynamics: HIV, an overview and market assessment, DATAMONITOR, New York, June 1997, $2,995.
Global Biotechnology Product Registration: EU, US, and Japan, edited by M. Struck, M. Mathieu and H. Okabe, Parexel, Waltham, MA, 1997, 392 pages, $395.
Biologics Development: A Regulatory Overview, edited by M. Mathieu, Parexel, Waltham, MA, 1997, 330 pages, $135.
Infectious Diseases in Immunocompromised Hosts, edited by V. St. Georgiev, CRC Press, Boca Raton, FL, December 1997, 1,200 pages, $149.95.
Designer Vaccines: Principles for Successful Prophylaxis, edited by H.P. Hughes and M. Campos, CRC Press, Boca Raton, FL, December 1997, 208 pages, $99.95.
Human Papillomavirus, an overview and market assessment, Decision Resources, Waltham, MA, September 1997. Contact: Frank Sama; Phone: 781-487-3753; Fax: 781-487-5750; E-mail: sama@dresources.com.
Topley and Wilson's Microbiology and Microbial Infections, 9th edition, Oxford University Press, New York, 1998, available as a 6 volume set and/or on CD-ROM, includes Volume I, Virology, various prices starting at $995 for 6 volume set with pre-publication (before end of year) discount up to $1,595 full list price for both books and CD-ROM.
New Meetings
Hepatitis, January 22-23, 1998, Washington, DC. Contact: IBC USA Conferences, Inc., 225 Turnpike Road, Southborough, MA 01772-1749; Phone: 508-481-6400; Fax: 508-481-7911; E-mail: reg@ibcusa.com; Web site: http://www.ibcusa.com/conf/hepatitis/.
Antisense DNA & RNA Based Therapeutics, February 2-3, 1998, Coronado, CA. Contact: IBC USA Conferences, Inc., 225 Turnpike Road, Southborough, MA 01772-1749; Phone: 508-481-6400; Fax: 508-481-7911; E-mail: reg@ibcusa.com; Web site: http://www.ibcusa.com/conf/antisense/.
Towards an HIV Vaccine: Immunopathogenesis of HIV Infection, March 5-8, 1998, Palm Springs, CA. Contact: Ms. Nita Driscoll, Cancer Research Center, Univ. of California, Irvine, Bio. Sci. II, Room 3221, Irvine, CA. 92697-3905; Phone: 714-824-5886; Fax: 714-824-4023; E-mail: nrdrisco@uci.edu.
International Conference on Emerging Infectious Diseases, March 8-11, 1998, Atlanta, GA. Contact: American Society for Microbiology; Phone: 202-942-9248; Web site: http: //www.asmusa.org/mtgsrc/mtgs.htm; E-mail: meetinginfo@ asmusa.org.
American Society for Virology, July 11-15, 1998, Vancouver, BC, Canada. Contact: ASV 98 Secretariat, UBC Conference Centre, 5961 Student Union Blvd., Vancouver, BC, Canada V6T 2C9; Phone: 604-822-1050; E-mail: registration@brock.housing.ubc.ca; Web site: http://www.conferences.ubc.ca.
OraVax Licenses Flavivirus Vaccine Technology and Rights to Yellow Fever Vaccine
OraVax, Inc. (Cambridge, MA) has acquired an exclusive license from St. Louis University (St. Louis, MO) for chimeric vaccine technology being used by OraVax to develop a series of ChimeriVax vaccines against Japanese encephalitis, dengue, hepatitis C and other viruses. Chimeric flavivirus vaccine technology developed by Dr. T. Chambers, St. Louis Univ., involves constructing a recombinant virus combining the genes required for replication of the yellow fever virus YF 17D vaccine strain with the genes for the viral coat antigens of the target virus. The resulting live yellow fever vector vaccine retains the safety and immunogenicity of the YF 17D vaccine but induces immune responses specific to the inserted target viral antigens. The yellow fever vaccine is considered "one of the safest live virus vaccines ever developed" with a single inoculation providing life-long immunity in nearly 100% of recipients. These properties are expected to apply to other YF 17D vaccine constructs. OraVax has already constructed a Japanese encephalitis vaccine using this approach which has demonstrated a high level of activity and protection in animal models.
OraVax, Inc. recently concluded an agreement with Evans Medical, a subsidiary of Medeva PLC (London, U.K.), to become the exclusive U.S. marketer and distributor of Evan's live-attenuated yellow fever virus vaccine (Arilvax). OraVax will also work with Evans to introduce the vaccine into other international markets. OraVax will conduct clinical trials and make regulatory filings for FDA approval of Arilvax, with Evans funding all costs. Evans anticipates filing a PLA for FDA approval in 1998. OraVax will distribute the vaccine to both civilian and military U.S. markets. Arilvax is currently marketed by Evans in European and selected Asian markets. Yellow fever virus vaccine (YF-VAX) from Pasteur-Merieux Connaught is currently the only yellow fever virus vaccine marketed in the U.S., costing about $48/dose and is recommended for all travelers to and from areas where yellow fever is endemic.
Company Seeks Partners for Prophylactic Herpes Vaccine Development
Henderson Morley Ltd. (Birmingham, U.K.) is seeking corporate partners for development of a herpes simplex virus (HSV) vaccine originally developed by Dr. G. Skinner, Univ. of Birmingham. The vaccine is an "intracellular subunit" HSV-1 vaccine involving a specific HSV-1 strain cultured in serum-depleted MRC5 human embryo lung cells with the cell cytoplasm processed by Nonidet detergent and formaldehyde extraction, ultracentrifugation and acetone precipitation to be particle-free and contain only the outer glycoprotein coat of HSV-1. The vaccine is commonly called the "Skinner Vaccine," or NFU.Ac.S-[MRC5] HSV, with this latter name derived from the sequence of processes used for its manufacture. This vaccine had previously been licensed by Porton International PLC which concentrated primarily on developing the vaccine as an immunotherapeutic for treatment of recurrent genital herpes.
As reported in the May 1990 Bulletin (p. 7), a Phase III trial found the vaccine not to provide statistically significant improvements over placebo for treatment indications. Various open-label trials in sex partners of patients with recurrent genital herpes have indicated that the vaccine has efficacy for prevention of genital herpes. In one trial in 347 partners of patients with recurrent genital herpes, only 2.4% of those having received two to four inoculations became infected over a two-year period and 11.1% of those receiving a single inoculation became infected--rates much lower than the 30% or higher infection rate that would normally be expected. However, development was terminated by Porton in the late 1980s, even though safety and indications of immunotherapeutic and prophylactic efficacy were observed in multiple trials. The difficulty and expense involved in conducting clinical trials to prove prophylactic efficacy and then trying to market a novel product were among the reasons for the company abandoning the vaccine. Over 2,000 patients have received the vaccine with no reports of significant adverse effects.
Henderson Morley has obtained exclusive worldwide rights to the vaccine from the Univ. of Birmingham, with product and process patent protection in the U.S. (including no. 5,219,567) until 2010. The company believes the vaccine has advantages over recombinant subunit vaccines cur- rently in development (and the one abandoned by Chiron Corp., discussed in the December 1996 Bulletin, p. 325) because the vaccine presents a number of epitopes, essentially all HSV-1 polypeptides (many of which cross-react with HSV-2) including gD2 and more closely simulates viral infection. Besides potential for prevention of genital herpes, the vaccine may also be useful for prevention of and treatment of herpes labialis (oral herpes) and herpes ocularis.
Highlights of U.S. Patents
Highlights of recently issued U.S. patents for which abstracts and/or exemplary claims are presented [in the next link] include:
Antiviral Agents
Other Inventions, Not Shown Below--Some recent patents for viral diagnostics and generic (non-antiviral or virus specific) technologies include:
Antimicrobial Agents