Experimental Treatments and New Areas of Research for Hepatitis C Virus (HCV) Infection
July 9-14, 2000
As has been true in the search for the best therapy for HIV infection, it will be a daunting challenge to develop the most effective and least costly combination therapies for HCV infection.
The prospects for future treatments for HCV, including targeted HCV antivirals such as protease, helicase, and ribozyme inhibitors, are scientifically rich and exciting. However (and unfortunately), the word "future" must be emphasized because only one of these, a ribozyme inhibitor, has begun clinical trials. Until novel targeted antivirals are available, it is imperative that we improve our standard of care by optimizing the use of our available arsenal.
Daily dosing of IFN has been suggested as a way of preventing the rebound of HCV viral production. Numerous clinical trials around the world are looking at both daily and higher initial doses of IFN (so-called induction therapy), either alone or in combination with RBV. Gonzales and colleagues recently presented results of a study comparing a four-week high- dose IFN induction regimen to a standard IFN regimen (Gonzales 2000). In this 48-week study, 135 untreated patients were randomized to receive 5 MU of IFN alfa-2b daily for four weeks followed by 5 MU tiw or 5 MU of IFN alfa-2b tiw. Seventy-six percent of the patients had HCV genotype 1, and 23% had stage 3-4 fibrosis. A virologic SR rate was observed in 14 of 67 (21%) patients in the induction group and 13 of 68(19%) controls (P = NS). Virologic SR rates were higher in the non-1 genotype group, yet no significant differences were noted between the treatment arms in the respective genotype groups. A trend toward more adverse events requiring IFN discontinuation was documented in the induction group compared to the standard group (34% vs. 20%; P = 0.08).
Recently presented results from an Austrian study using IFN induction therapy in combination with RBV did not show an improvement in virologic SR rates over what has previously been reported in the literature (Ferenci 2000). In tests of several induction regimens (5 MU, 10 MU, QD or Q2D) no statistically significant differences were documented among the three arms, which averaged a 37% virologic SR rate.
HCV treatment studies have also tested the strategy of using four-week high-dose IFN induction therapy before adding RBV. Two recently presented studies observed no significant differences in virologic ETR between patients who started with IFN monotherapy induction regimens and those who received standard dosing of IFN/RBV (Cheng 2000; Flamm 2000).
While based on elegant kinetics data, studies reveal that using IFN in higher doses and more often than tiw does not achieve any additional clinical antiviral benefit. Nonetheless, research on HCV viral kinetics -- and the impact of IFN -- is still a new field, and work in this area is considered by many to be crucial for understanding the virus.
Another question yet to be answered is: What is the optimal dose of RBV? Schering has refused to conduct large randomized controlled trials to ascertain if lower doses of RBV -- 600 or 800 mg -- are less toxic than, and as effective as, standard doses. Some researchers contend that Schering has this data (and has even commissioned studies), but will not release the results.
The 180 mcg dose was chosen for use in the three registrational PEG-IFN studies. The first of these studies was conducted in HCV patients with cirrhosis. Standard dose IFN monotherapy in cirrhotics has been shown to be relatively ineffective in producing sustained virologic suppression (~10%), and its ability to prevent hepatocellular carcinoma (HCC) and improve survival is debatable (Schalm 1997). In light of these data, U.S. and European HCV treatment guidelines do not universally recommend that cirrhotics receive therapy, yet say they "can" or "may" be treated (NIDDK 2000, EASL 1999). Roche was bold and conducted study NV15495, a 271-patient phase II/III trial comparing two doses of PEG-IFN (90 and 180 mcg) with standard IFN therapy for 48 weeks (Heathcote 1999; Ballart 2000). This is the largest prospective randomized study in cirrhotics ever conducted. The baseline demographics and disease characteristics and study results are listed below:
Never before had a prospective, randomized HCV clinical trial in cirrhotics documented a 30% virologic SR or 54% histologic improvement. Likewise, ~34% of PEG-IFN patients who did not achieve a virologic SR had documented histologic improvement. In many patients with cirrhosis, any decrease in histologic activity is needed and welcome. Response rates were not inflated by the 22% of patients with transition to cirrhosis. In fact, in the 180-mcg arm, the cirrhotics achieved a 32% virologic SR compared to 22% in the transition-to-cirrhosis patients.
As impressive as these results appear, there continues to be a marked difference in response rates between those with genotype 1 and non-1. In the 180-mcg arm, the genotype-1 patients achieved a 13% virologic SR compared to 53% in patients with genotype non-1. The response rates, documented in the chart on the next page, are further splayed when analyzed according to good viral prognostic factors (genotype non-1 & HCV RNA <2 million copies/mL) vs. poor viral prognostic factors (genotype 1 & HCV RNA > million):
Roche next conducted U.S. and European phase III randomized controlled trials of PEG-IFN vs. IFN. Study NV15497, the 531-patient phase III European trial, was recently presented by Zeuzem and colleagues (Zeuzem 2000). This study compared PEG-IFN 180 mcg weekly vs. 6 MU tiw of IFN. Baseline demographics and disease characteristics, as well as study results, are detailed below:
When analyzing the results based on genotype and baseline HCV RNA, the sustained responses are markedly different. The chart below details the 72-week virologic SR rates according to patient's genotype and viral load:
A 28% SR on PEG-IFN is the highest response recorded for genotype-1 patients treated with monotherapy and coincidentally identical to the virologic SR in genotype-1 patients on the IFN/RBV arm of the U.S. phase III IFN/RBV registrational study (McHutchinson 1998).
Roche has not publicly released the results of its U.S. phase III trial (study 15496) and will not until the fall. Study 15496 is a three-arm trial of ~650 untreated HCV patients randomized to receive IFN 3 MU, or PEG-IFN at 135 mcg or 180 mcg. Roche submitted its PEG-IFN NDA to the FDA on 22 May 2000. In a press release Roche contends:
In rigorous intent-to-treat analyses of three pivotal clinical studies involving a total of more than 1,400 patients, those treated with 180 mcg. of PEGASYS had overall sustained virologic responses of 35 percent in patients without cirrhosis and 30 percent in patients with cirrhosis. (Roche Press Release, 5/22/00)
Because the press release reveals a 35% virologic SR in non-cirrhotics, it is obvious they are discussing the results of the 180 mcg arms in the two phase III trials. With a 39% virologic SR in the 180-mcg arm of the European study (15497), the SR in ~215 patients in the 180-mcg arm of the U.S. study must be between 28% and 30% to mathematically achieve an overall 35% virologic SR.
The data from the three studies presented demonstrate that PEG-IFN is significantly more effective than IFN (all P-values were < 0.001). For those in whom ribavirin is contraindicated and cannot initiate combination therapy, PEG-IFN is an excellent alternative and will likely be considered first-line for HCV monotherapy.
When FDA approved, PEG-IFN is expected to be used in combination with RBV. Roche only needs to demonstrate superiority over standard IFN in order for initial FDA approval. In expectation of promising results as combination therapy, and out of the desire to compete with Schering for its share of the HCV market, Roche is conducting a series of studies testing PEG- IFN with RBV. Sulkowski and colleagues recently presented 24-week follow-up data on a small, 20-patient open-label study of PEG-IFN plus RBV (Sulkowski 2000). Study NV15800 administered 180 mcg of PEG-IFN plus RBV (1,000-1,200 mg) to 16 genotype-1 patients for 48 weeks and to 4 genotype-2 patients for 24 weeks. Study results are listed below:
Safety Profile of PEG-IFN
While not a PEG-Intron registrational study, Schering conducted a small-to-medium-sized multi-armed pharmacokinetics (PK), safety, and "efficacy" (Schering's term) study of three doses of PEG-Intron in combination with three doses of RBV compared to PEG-Intron monotherapy (Glue 1999). In this 72-patient study, it appears that patients received at least six different doses of two treatments: PEG-Intron 0.35 mcg/kg, 0.7 mcg/kg, or 1.4 mcg/kg; alone or in combination with RBV 600 mg, 800 mg, or 1,000-1,200 mg. There were 35 men and 37 women ranging from 20 to 68 years of age, and ~50% were infected with genotype 1. PK results demonstrated that "RBV did not alter the PK profile of PEG-Intron," and "PEG-Intron dose-dependently augmented the antiviral activity of RBV." It is difficult to make anything out of the "efficacy" results, and Schering's Paul Glue, during his presentation, said that there was no difference observed in RBV doses, so results were collapsed. The virologic SR rates listed in the chart below are as Schering presented them:
Schering's PEG-Intron development plan was mediocre in demonstrating the efficacy of the 1.0- mcg/kg dose over IFN. The 1.0-mcg/kg dose, which is planned for marketing, was studied in 297 patients and found to be superior to IFN in its only phase II/III dose-ranging study. In contrast, Roche's PEG-IFN 180-mcg dose was used in ~600 patients and found to be superior to IFN in four separate studies. Nonetheless, on 31 May 2000, the European Union granted approval to Schering's PEG-Intron for treatment of patients with HCV. The PEG-Intron NDA was submitted to the FDA on 23 December 2000, approximately five months ahead of Roche's PEG-IFN. It is expected that both will be eventually approved by FDA, which has 12 months to review the applications. Whether the FDA will approve both pegylated interferon NDAs in the order they were received or at the same time (so as to not show favoritism) is anybody's guess. Nonetheless, PEG-IFN has the distinct advantage (at least in the scientific community) of better-documented efficacy and safety data in HCV patients with and without cirrhosis.
All PEG-Intron arms were found to be significantly more effective at achieving sustained viral suppression than IFN monotherapy. When stratifying by genotype, SR rates decreased by ~40% in genotype-1 patients and doubled for those with non-1. Likewise, the patients with high baseline viral loads (HCV RNA >2 million copies/mL) did significantly worse than those with low viral loads. The chart below documents the virologic SR rates for all arms according to genotype. PEG-Intron 1 mcg/kg is the dose Schering has submitted in its NDA to the FDA.
The NIH's NIDDK recently gave a thumbs-up to Roche when it chose PEG-IFN as the pegylated interferon it will use in the randomized monotherapy phase of its HALT-C trial. The HALT-C trial (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) is a planned eight-year, 28-million-dollar study of 1,350 IFN or IFN/RBV relapsers with stage 3 fibrosis. At nine selected sites, all will be retreated with IFN/RBV for five months. Those patients not achieving a virologic response will be randomized to receive PEG-Intron or no treatment for another ~3 years to determine if continuing antiviral therapy will decrease the incidence of HCC and increase survival.
Recombinant IL-2 has been studied in patients with chronic HBV and HCV in the hope that IL-2 can shift T-cell responses towards a predominantly TH1-like phenotype and thus facilitate clearing of virus without being necroinflammatory. In a 1993 pilot study, recombinant IL-2 (rIL- 2) demonstrated immunomodulatory and antiviral activity in HBV patients (Tilg 1993). RIL-2 was tested a few years later by Pardo and colleagues in 33 IFN-naive HCV patients (Pardo 1997). The 33 patients were randomized to receive three different doses of IL-2 (0.9, 1.8, and 3.6 MU) five times a week for 12 weeks. At 12 weeks, those who responded stopped treatment while non-responders continued with a higher dose of 5.4 MU. Approximately 24% of patients had normalization of their ALT levels at the end of treatment, yet only 8% had an SR on follow-up. No patient's HCV RNA became undetectable, and no histologic improvement was found. Some 24% to 73% of the patients experienced side effects, including flu-like symptoms, nausea, anorexia and local site irritation.
In mice induced with carbon tetrachloride, IL-10 has been shown to control neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis (Louis 1998). Recombinant human (rHu) IL-10 has demonstrated some activity in HCV patients in two pilot studies. McHutchinson and colleagues conducted a 16-patient pilot study to assess the safety of IL-10 and its ability to normalize ALTs (McHutchinson 1999). Three IFN-naive patients and 13 non-responders received 4 or 8 mcg/kg of IL-10 subcutaneously daily for 28 days. With both IL-10 doses, ALT levels normalized in eight patients at the end of treatment, but returned to pretreatment levels in patients during the four-week follow-up period. There were neither significant increases nor decreases in HCV RNA levels. The only adverse event noted was a transient fall in platelet counts (73,000-63,000) in two patients.
Nelson and colleagues randomized IFN non-responders to receive 4 or 8 mcg/kg of IL-10 for 90 days (Nelson 2000). Nineteen of the 22 patients who completed therapy had a normalization of their ALT levels, yet only four remained normal on follow-up. Hepatic inflamation decreased (>2 decrease in HAI score) in 11 of 22 patients and Ishak fibrosis score decreased in 14 (mean change = 3.6-3.2; P = 0.001). Mild anemia occurred during the first four weeks of therapy in most patients with an average decrease in hemoglobin level of 2.2 g/dl. Side effects, including headache (75%), dry mouth (25%), and insomnia (17%) were more common in the 8 mcg/kg arm.
IL-12, which drives TH1 responses, has shown minimal antiviral activity in patients with HCV. It is not considered to have a promising future for treating HCV. IL-12 was originally studied for its demonstrated ability to mount an effective cellular response directed towards intracellular pathogens (Scott 1993). In a multinational, Roche-sponsored phase I/II study, Zeuzem and colleagues randomized 60 HCV patients to receive four doses of IL-12 for ten consecutive weeks: 16, 14, 15, and 15 patients at .03, 0.1, 0.25, and 0.5 mcg/kg, respectively (Zeuzem 1999). Mean age was 41 years; 42 patients were male; 24 had previously received IFN; 39 had genotype 1; and median HCV RNA was 480,000 copies/mL.
No patients achieved a virologic end of treatment response, but 20 of the 60 patients did have a >50% decrease in their baseline HCV RNA: 3, 3, 6, and 8 patients on the .03, 0.1, 0.25, and 0.5 mcg/kg doses, respectively. At the end of follow-up, only 5 of 60 patients had a normalization of their ALT levels and significant anti-rHuIL-12 antibody titers were not detectable in any patients. The most common adverse events on IL-12 were: headache (67%); fatigue (32%); rhinitis (28%); fever (28%); and chills (12%). The most frequent laboratory abnormalities were transient decreases in leukocytes in (31 patients; grade I and II) and transient increases in ALT levels (32 patients) and bilirubin (7 patients), most of which returned to baseline.
Because of their limited activity and side-effect profile, cytokines as monotherapy do not appear to be promising for HCV. As adjuvants to HCV antivirals, cytokines may prove to be beneficial. More research will need to be done in this area.
In a 1997 pilot study, amantadine monotherapy demonstrated improvement in biochemical and virologic markers for some patient with HCV (Smith 1997). Two later clinical studies of amantadine monotherapy failed to support HCV antiviral effects shown previously (Lynch 1998; Senturk 1998). Results have been mixed in amantadine combination therapy studies. Khalili and colleagues randomized 29 IFN non-responders to receive IFN/RBV (N = 14) or IFN plus amantadine for 24 weeks (Khalili 2000). At the end of follow-up, 2 of 13 (15%) patients on IFN/RBV compared to none of the IFN plus amantadine patients achieved a virologic and biochemical SR. In an Italian triple-combination therapy study, Brillanti and colleagues randomized 20 IFN non-responders to receive IFN/RBV or IFN/RBV plus amantadine for 24 weeks (Brillanti 1999). At the end of the 24 week follow-up period, one of the dual therapy patients had a biochemical SR compared to four triple-therapy patients. Virological SR was achieved in none of the dual-therapy patients and in three on triple therapy.
Amantadine is not without its side effects. Two of 22 (9%) had to discontinue therapy due to cardiovascular adverse events in the original monotherapy study. In other HCV amantadine studies, cardiovascular side effects were only 0.1% to 1% (Younossi 1999). Central nervous system and psychiatric side effects (headache, depression, psychosis, and convulsions) have averaged <5%. Other side effects observed include nausea, vomiting, and diarrhea (5-10%).
Rimantadine monotherapy has proven poor as a treatment for HCV. In two recently published pilot studies (one in IFN non-responders, the other in liver-transplant recipients), no patients achieved a biochemical or virologic response (Fong 1999; Sherman 1999).
It is apparent that neither amantadine nor rimantadine is effective as monotherapy. Because the studies have been so small, there is little that can be said about amantadine's effectiveness in combination therapy regimens. Nevertheless, amantadine in combination with IFN/RBV warrants further investigation in larger studies of untreated and pretreated HCV patients.
IMPDH Inhibitor: VX-497 (Vertex)
VX-497, a new oral antiviral, is a potent IMPDH inhibitor. In vitro studies suggest that VX-497 has increased synergy with IFN and greater activity than that of RBV against DNA and RNA viruses, including HBV, respiratory syncytial virus, and bovine diarrhea virus (Markland 1999). A phase II randomized double-blind placebo-controlled study investigating the PK, safety and antiviral activity of VX-497 was recently presented by Wright and colleagues (Wright 1999). Thirty IFN non-responders were randomized to receive VX-497 at doses of 100, 200, or 400 mg every eight hours or placebo for 28 days. The 200- and 400-mg doses, but not the 100-mg dose, had a mean reduction in ALT levels of 25% and 21%, respectively, compared to placebo (P = 0.01 & 0.04). No significant change in HCV RNA was observed. Studies of VX-497 in combination with IFN are currently being conducted.
Hammerhead Ribozymes: LY466700 (Ribozyme Pharmaceuticals & Eli Lilly)
Ribozyme Pharmaceuticals, under the direction of Lawrence Blatt (the wunderkind who shepherded Amgen's Infergen through its FDA approval) has developed LY 466700, a nuclease resistant hammerhead ribozyme targeting the 5' untranslated region (UTR) of the HCV genome at site 195. In female C57/B16 mice, the labeled ribozyme is retained in hepatocytes and endothelial cells lining the sinusoid (Lee 1999). It has been shown to inhibit (>90%) replication of a HCV 5' UTR-poliovirus chimera in cell culture (Macejak 2000). A single-dose safety study of LY 466700 was just completed in healthy normals, and additional clinical studies, including PK, safety, and combination therapy trials with IFN are being planned.
Histamine Dihydrochloride (Maxamine, Maxim Pharmaceutical)
Maxamine in combination with IFN is also being studied in HCV patients. A 12-week interim analysis of a phase II dose-ranging study of Maxamine plus IFN was recently presented by Lurie and colleagues (Lurie 2000). One hundred twenty-nine IFN-naive patients were randomized to receive 3, 5, 6, or 10 mg subcutaneously daily plus 3 MU of IFN tiw. All patients received 12 weeks of therapy, and those responding will continue treatment for an additional 36 weeks. Mean age of patients was 30 years; mean HCV RNA level was 6.7 million copies/mL, and 47% had genotype 1. After 12 weeks on therapy, 53-83% of all patients became undetectable (< 1,000 copies of RNA). In those with genotype 1 and high viral loads, 48 - 77% achieved a virologic response. Side effects included flushing, headache, hypotension, and increased heart rate. Not much can be said about Maxamine until the 72-week data are analyzed. Nonetheless, the company is already planning studies of Maxamine in combination with IFN/RBV.
The major drawbacks of antisense oglionucleotides relate to the potential for non-antisense effects, such as destruction of untargetted cellular mRNA, and inappropriate activation of cellular enzymes (2'5' oligoadenylated sythetase, protein kinases, endonuclease RNase L) and upregulation of interferon production of double-stranded RNA in uninfected cells. (Davis 1999)
Inhibition of Viral Replication by Enzyme Inhibition: HCV Protease & Helicase Inhibitors
The lawsuits involving HCV drug R&D center on efforts to find drugs that block the viral protease enzyme, on which Chiron holds patents. The company [Chiron], arguing that its competitors need this enzyme to screen for compounds that inhibit it, filed suit against Agouron, Gilead, and collaborators Vertex and Eli Lilly to try to force them to pay licensing fees and then royalties if one of their protease inhibitors goes to market. (Cohen 1999)
These patent lawsuits also cover development of an HCV helicase inhibitor. The three- dimensional X-ray crystal structure of the HCV helicase was first solved by Yao and colleagues from Schering in 1997 and later by Kim and colleagues from Vertex in 1998 (Yao 1997; Kim 1998). The lawsuits have not prevented researchers from screening numerous compounds. No one will speak publicly about their development plans for protease or helicase inhibitors or even mention particulars about the lawsuits. One high-profile chemist I recently spoke with was reticent to give me much pertinent information on his company's protease inhibitor drug discovery effort, but when asked if he was bothered that the lawyers were making more money than he was, he laughed and said, "Yes."
Progress on the vaccine front is also very slow. The EASL Guidelines committee sadly concludes that "A traditional vaccine is unlikely to become available in the foreseeable future" (EASL 1999). Vaccine research is hampered by the same three reasons mentioned above, as well as by the high mutability of the HCV viral envelope proteins (E1/E2).
The NIH and subsequent NIDDK guideline are fortunately devoid of pharmaceutical company oversight and approval. Cost-benefit analyses, and data funded by Schering which say that current treatments are beneficial for HCV patients with "mild" histologic disease, appear to be more marketing ploys than hard science (Wong 1998; Fang 1999). According to Robert Levine, rationally sound advice is warranted:
I will continue to advise a tincture in time for most of my patients with histologically mild chronic hepatitis C, both because I do not believe that their prognosis is as daunting as is often stated and because the outlook for new and more effective therapies is promising. (Levine 1998)
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This article was provided by Treatment Action Group. It is a part of the publication The Hepatitis Report.