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Hepatitis C Indication Report
November 08, 2005
Chronic hepatitis C is the most common blood-borne infection in the U.S. and is four times more common than HIV. Infection with the hepatitis C virus can lead to chronic liver disease that can in turn result in liver cancer or liver failure, necessitating liver transplants. While the incidence of hepatitis C has decreased since 1990, the number of patients presenting with liver damage due to chronic hepatitis C is likely to increase as patients infected via blood transfusions become more apparent.
Chronic hepatitis C is currently being treated by a combination regimen of pegylated interferon alpha and Ribavirin. This drug regimen is effective in approximately half of patients treated (these patients are considered “cured”). There is currently little recourse for the patients who do not respond to this drug regimen and these patients are at high risk of developing liver cancer and liver failure.
There are numerous drugs in development for the treatment of chronic hepatitis C, with several of these drugs aiming to treat the more difficult-to-treat and more prevalent subgroup of patients (genotype 1 HCV). Some drugs in the pipeline are designed to be more efficacious and less toxic alternatives to Ribavirin (such as Viramidine and Valopicitabine) or more potent and longer acting forms of interferon alpha (such as Albuferon). There are also agents in the pipeline that possess novel mechanisms of action such as HCV protease inhibitors (VX-950, SCH 503034 and GS 9132) and the alpha glucosidase inhibitor MX-3253.
Based on data to date, we project that Albuferon (long acting interferon alpha) will become the dominant interferon formulation to be used in all patients (all genotypes) due to its less frequent dosing requirements. We believe that Viramidine and Valopicitabine will eventually replace current formulations of Ribavirin, particularly Viramidine due to its better toxicity profile. We foresee these new generation Ribavirins (in combination with interferon alpha) to become standard of care until the approval of the HCV protease inhibitors. Once HCV protease inhibitors enter the market, we believe that both Viramidine and Valopicitabine will continue to be used in patients with genotypes 2 or 3, while patients with genotype 1 will adopt the HCV protease inhibitors. As for the new small molecule inhibitors in development, it is likely that they will be susceptible to viral resistance (since HCV can mutate rapidly), and thus many are being evaluated in combination with other treatments, particularly with interferon alpha, to provide a broader inhibition of the virus. Therefore, we see peginterferons (or other longer acting forms of interferon alpha) maintaining their role in the standard of care for HCV.
BACKGROUND
Hepatitis C, inflammation of the liver caused by the Hepatitis C virus (HCV), is the most common long-term blood-borne infection in the U.S. and is 4 times more common than HIV. In the U.S., the Centers for Disease Control and Prevention (CDC) estimates that 3.9 million people have been exposed to HCV and 2.7 million people have long-term HCV infection, although this estimate may be too conservative since high risk populations (such as prisoners and drug users) are generally excluded from national surveys. Within the U.S., an estimated 30,000 new infections occur each year and chronic hepatitis C causes an estimated 10,000 to 12,000 deaths each year.
Hepatitis C is one of five naturally occurring viruses: A, B, C, D, and E, all of which can attack or damage the liver. Hepatitis C is viewed as the most serious of the five viruses and can cause cirrhosis (irreversible liver scarring), liver cancer or liver failure. In fact, hepatitis C is the primary cause of liver failure and liver cancer and is hence the main reason for liver transplants. According to the CDC, as many as 70% of chronic HCV patients will eventually develop liver disease.
The Hepatitis C Virus (HCV)
The hepatitis C virus can mutate rapidly and some of these mutations, particularly those involved with envelope proteins, have assisted the virus in evading the immune system. There are at least six known genotypes (strains) of HCV and more than 50 subtypes with different genotypes predominating in different geographical locations. In the U.S., genotype 1 (HCV-1) is the most common genotype accounting for approximately 75% of cases while genotypes 2 and 3 account for 10-20% of cases. The HCV genotype does not change during the course of infection. Although the HCV genotype does not appear to affect the severity of disease, patients infected with genotypes 2 or 3 tend to be more responsive to treatment and therefore the genotype is important in treatment determination.
Risk factors
The HCV was discovered in 1989, before which HCV was described as “non-A non-B hepatitis.” It was not until 1990 that a screening method became available for detecting HCV. As a result, people receiving blood transfusions prior to 1990 were the major risk group for HCV infection. Since the introduction of screening, the incidence of infection has reduced dramatically and it is now extremely rare for HCV to be acquired through blood transfusions.
With the better screening of infected blood products, the most common cause of HCV infection at present is the sharing of infected needles (such as drug use, piercing or tattoos, and in some cases needlestick injuries afflicting healthcare workers). HCV can also be contracted through unprotected sex or through mother-to-child transmission, although these transmission rates are relatively low.
HCV infection
The majority of people infected with HCV are unaware of their infection since infection with HCV is typically clinically silent for decades. Indeed, hepatitis C can take 10-40 years to manifest symptoms. HCV can cause acute or chronic infections. When a person is first infected with HCV, the liver can become inflamed immediately which is known as acute hepatitis. However, the flu-like symptoms result in a misdiagnosis in the majority of individuals. Approximately 15% of individuals infected with HCV are able to clear the virus (which amounts to a cure). The remaining 85% of individuals are at risk of chronic (longer than 6 months) hepatitis. It is estimated that at least 70% of those infected with HCV will eventually develop chronic hepatitis. Approximately 20-30% of chronic hepatitis C patients will develop cirrhosis, a process that usually takes 10-20 years. Approximately 1-5% of chronic patients will develop liver cancer which normally shows up after 20-40 years. Hepatitis C accounts for approximately half of primary liver cancers in the developed world.
The course of chronic hepatitis C can vary significantly between individuals. Some individuals show little signs or symptoms of disease. These patients often have normal liver enzyme levels (elevated liver enzymes can indicate liver disease). At the other end of the spectrum are patients who exhibit severe hepatitis C who will present with symptoms, detectable HCV RNA (viral load) in serum and elevated liver enzymes that can be as high as 20 times above normal. These patients are at high risk of developing cirrhosis or end-stage liver disease (liver failure). Patients who develop cirrhosis are at increased risk of developing hepatocellular (liver) cancer. There are also many patients who fall somewhere in the middle, with few or no symptoms and mild- to-moderate elevation of liver enzymes. These patients have an uncertain prognosis.
Chronic Hepatitis C Treatment
There are no vaccines available for the prevention of hepatitis C. Moreover, development of effective vaccines has been hampered due to the rapid mutation rate of HCV, which could render new vaccines useless with the emergence of new strains. The treatment of chronic hepatitis C has evolved in the last decade with the current standard of care consisting of a combination of pegylated IFN alpha and Ribavirin.
Since patients can be asymptomatic for years despite HCV infection, the optimal time for initiating HCV therapy is not known. The National Institutes of Health Consensus Development Conference Panel (an expert panel convened by the NIH) recommends that treatment should only be initiated in patients who show histological evidence of progressive disease. This means that while all patients with fibrosis, liver inflammation, or liver necrosis should be treated, treatment is not recommended on the basis of HCV RNA or the presence of symptoms.
The aim of current HCV treatment is to reduce viral load in patient’s blood to undetectable levels. While viral levels (measured by HCV RNA) do not correlate with disease severity or poor prognosis, studies have shown that viral load does correlate with response to treatment. In general, patients demonstrating a sustained virologic response (defined as undetectable HCV RNA 6 months after the cessation of treatment) have a high probability of the virus not returning. These patients are classified as being in "remission", although this amounts to a cure in patients where the virus does not return.
Interferon alpha
Interferons (IFN) are naturally occurring cytokines produced by immune cells to combat infections and cancer. There are 3 major classes of interferons: class I which consists of interferon alpha, beta, omega, epsilon, and kappa; class II which consists of interferon gamma; and class III which consists of interferon lambda. Interferon alpha and beta are important in fighting viral infections and cancer development. Interferon gamma, while possessing weak antiviral and anticancer activity, is mainly involved in potentiating the activities of interferon alpha and beta.
Three formulations of interferon alpha have been approved by the FDA for the treatment of hepatitis C: Roferon-A (Interferon alpha-2a; Roche), Intron-A (Interferon alpha-2b; Schering-Plough), and Infergen (Interferon alfacon-1; Intermune). All three agents must be administered three times a week either by intramuscular or subcutaneous injections. Monotherapy IFN-alpha leads to a sustained virologic response in approximately 15% of patients but because of this low response rate, these IFNs are rarely given alone.
The standard forms of interferons have recently been replaced by peginterferons (PEG-IFN). Peginterferon alpha is interferon alpha attached to polyethylene glycol (PEG). This pegylation improves the pharmacokinetic properties of interferon alpha by prolonging its half-life, allowing for more constant blood levels of interferon alpha and less frequent dosing (once a week injections instead of three times a week). More importantly, peginterferons are more active than standard interferon with a sustained response rate of 30-40% for monotherapy peginterferons. Given its better efficacy and ease of administration, peginterferons have replaced standard interferons in the treatment of HCV. Two peginterferons have been approved for hepatitis C: Peg-Intron (Peginterferon alpha-2b; Schering-Plough) and Pegasys (Peginterferon alpha-2b; Roche). These two agents are fairly equivalent in their efficacy and safety with the main difference between the two being their dosing regimen (Pegasys is given as a constant dose of 180 microgram subcutaneous injection per week while Peg-Intron is administered subcutaneously in a weight-based manner at 1.5 microgram per kilogram per week). Because of its constant dose, Pegasys tends to be preferred over Peg-Intron.
Ribavirin
Another agent approved for hepatitis C is Ribavirin (Copegus; Roche and Rebetol; Schering-Plough). Ribavirin is a synthethic nucleoside (modified DNA building block) that can interfere with DNA synthesis and has shown non-specific activity against a broad range of viruses. Ribavirin was first approved as an anti-viral agent for children with viral respiratory infections (as an aerosol). Oral monotherapy ribavirin was tested for HCV in the 1990s and initial results were disappointing, showing the drug, by itself, to be ineffective against HCV. However, two subsequent studies combining Intron-A and Ribivarin demonstrated that the addition of Ribavirin to Intron-A was more effective than Intron-A alone in patients with relapsed hepatitis C (defined as patients who had abnormal liver enzymes (ALT) a year after interferon treatment). In these studies, 6 months after the last treatment was given, 46% of patients who had received Intron-A plus Ribavirin had undetectable HCV RNA (sustained virologic response) compared to 5% of patients given Intron-A alone. Based on these impressive results, the FDA approved Ribavirin for use in combination with interferon alpha in patients who had relapsed after treatment with monotherapy interferon alpha. Multiple studies have since shown that the combination of interferon alpha and Ribavirin to be efficacious in both relapsed and in treatment-naïve patients, leading to the approval for this drug combination to be used in treatment-naïve patients.
Interferon/Ribavirin drug combination
The interferon alpha and Ribavirin combination is the most efficacious drug regimen to date for the treatment of chronic hepatitis C and is the current standard of care. Since the introduction of peginterferons, the gold standard drug regimen for HCV is peginterferon plus Ribavirin. This combination regimen can lead to a rapid reduction in HCV RNA in up to 70% of patients; however some patients can relapse after treatment has finished. Approximately 50% of patients demonstrate a sustained response to the interferon alpha/ribavirin regimen after a 24 or 48-week course of treatment.
The optimal duration of treatment varies and is primarily based on the HCV genotype. Patients are typically treated for 24 or 48 weeks. Patients with genotypes 2 or 3 are more likely to respond to treatment with up to 80% of patients responding within 24 weeks. Extending the duration of treatment in these patients does not yield better results and thus patients with genotypes 2 or 3 are typically treated for only 24 weeks. Patients with genotype 1 are much more resistant to treatment with only 40-45% of patients responding. These patients are typically given a 48-week course of treatment. Moreover, the dose of Ribavirin varies with the genotype with genotypes 2 or 3 requiring a lower dose (800 mg daily) than those with other genotypes (1000-1,200 daily).
Measuring treatment effectiveness
Treatment effectiveness is typically measured as a log10 drop in HCV RNA and is often expressed as a percentage. An effectiveness of 90% corresponds to a 1 log10 drop in viral load within 24 hours while 99% effectiveness reflects a 2 log10 drop in viral load in 24 hours. The mean effectiveness of IFN in patients with genotypes 2 or 3 is 99.5% (greater than a 2.5 log10 reduction in viral load) while in patients with genotype 1, the mean effectiveness is 95% (1.5 log10 reduction). This equates to IFN-alpha being at least 10 times more effective in patients with genotypes 2 or 3 than in patients with genotype 1.
The viral level at 1 month after treatment is not an accurate predictor of response. Instead, the level of viral load reduction at 12 weeks is an important predictor of successful treatment. A study published in the Journal of Hepatology in 2003 found that 100% of patients who did not experience more than a 2.0 log10 decline in HCV RNA at 12 weeks of peginterferon/Ribavirin treatment failed to respond to further treatment. Prognosis for patients who do show more than a 2.0 log10 drop in viral load at week 12 was much better with 72% of these responsive patients achieving a sustained response. However, the best indicator of effective treatment is a sustained virologic response (SVR) in which HCV RNA falls below the limit of detection at 24 weeks after the end of treatment. This level of HCV RNA is defined as 50 International Units (IU)/ml as measured by polymerase chain reaction (PCR). As mentioned above, a sustained virologic response often equates to remission or cure.
Limitations of current hepatitis C treatments
Despite the high success rate of a sustained virologic response in patients with genotypes 2 or 3, 20% of these patients still do not achieve remission. Moreover, half of patients with genotypes 1 or 4 do not respond to current therapies. With genotype 1 being the dominant genotype found in the U.S. (approximately 75% of cases), there is a need to develop effective therapies for these patients who do not respond to interferon/ribavirin. Currently, there is little recourse for patients who do not respond to this drug regimen. In many of these refractory patients, the development of cirrhosis or other liver abnormalities can lead to liver failure with the only recourse being a liver transplant.
HCV therapy is also very debilitating. It is associated with serious side effects that affect patient quality of life that leads to the discontinuation of treatment in up to 10% of patients. Interferon alpha causes flu-like symptoms such as fatigue, fever, chills, aches and pains. Fatigue is often the most disruptive side effect for patients. Interferon alpha also produces neuropsychiatric effects such as personality changes, irritability, depression or even suicidal tendencies. In addition, bone marrow suppression can also be seen with anemia, thrombocytopenia and neutropenia reported. Ribavirin is also toxic and causes a dose-related hemolysis of red blood cells, leading to a decrease in hemoglobin levels, which can lead to anemia and fatigue. The drop in hemoglobin occurs within 1-4 weeks of treatment initiation and can precipitate angina pectoris in susceptible patients. Acute myocardial infarctions and strokes have been reported in patients receiving Ribavirin combination therapy in hepatitis C patients. The hemolytic anemia due to Ribavirin is the main reason for Ribavirin dose reduction and this dose reduction is associated with reduced effectiveness of the drug regimen.
As such, there remains a need for newer effective agents for nonresponding patients. There are numerous drugs in development for hepatitis C, many of which are designed to target HCV genotype 1. Some drugs in the pipeline are designed to be a more efficacious and less toxic alternatives to Ribavirin (such as Viramidine and Valopicitabine) or more potent and longer acting forms of interferon alpha (such as Albuferon). Other interferons are also being evaluated for the treatment of chronic hepatitis C such as interferon beta (Rebif) and interferon gamma (Actimmune).
There are also agents in the pipeline that possess novel mechanisms of action such as HCV protease inhibitors (VX-950, SCH 503034 and GS 9132) and the alpha glucosidase inhibitor MX-3253. For new small molecule inhibitors in development, it is likely that they will be susceptible to viral resistance (since HCV can mutate rapidly), and thus many are being evaluated in combination with other treatments, particularly with interferon alpha, to provide a broader inhibition of the virus. Therefore, we see peginterferons (or other longer acting forms of interferon alpha) maintaining their role in the standard of care for HCV. We see these newer agents to be used either in combination with interferons (thus potentially replacing Ribavirin) or to be used as monotherapies in treatment-experienced nonresponding patients. We have outlined some of the more compelling drugs in development below.
MAJOR DRUGS IN CLINICAL DEVELOPMENT
Zadaxin (Thymalfasin; SciClone)
Zadaxin is SciClone’s lead drug candidate and is classified as an immune system enhancer. Zadaxin is a synthetic analog of thymosin alpha 1, a peptide naturally produced by the thymus gland that stimulates the immune system by modulating T cell and Natural Killer (NK) cell activity. These cells play critical roles in preventing and clearing infections as well as inhibiting cancer cell growth. In the hepatitis C setting, Zadaxin is being evaluated as an additive to the peginterferon/Ribavirin regimen as part of a triple combination.
In a small pilot study in nonresponding genotype 1 patients conducted in Mexico, Zadaxin was given in combination with peginterferon/ribavirin for 48 weeks. At 24 weeks post treatment cessation, 20% of patients achieved a sustained virologic response. These results are encouraging given that there is little recourse for patients who fail interferon/ribavirin therapy.
Zadaxin is currently in phase III studies for the treatment of genotype 1. These ongoing trials are designed to evaluate the effects of adding Zadaxin to peginterferon (without Ribavirin). It is interesting to note that these studies are being conducted in the absence of Ribavirin since Ribavirin augments interferon antiviral activity. We are concerned that these studies excluded Ribavirin since this may unwittingly dampen the response rate. While the results from the small pilot triple combination (Zadaxin + peginterferon + Ribavirin) study are promising for nonresponding patients, we are more cautious of the effectiveness of Zadaxin plus peginterferon without Ribavirin. Fortunately, Migenix’s European partner, Sigma Tau, has initiated a phase III study evaluating the triple combination of Zadaxin plus peginterferon and Ribavirin in non-responders. Based on results from the small pilot study this triple combination study is likely to yield positive data. If approved, we believe that Zadaxin will be used in genotype 1 nonresponding patients. However, the drug’s mode of administration (subcutaneous injections twice weekly) is likely to hamper its uptake in the market.
Actimmune (Interferon gamma-1b; InterMune)
Actimmune is recombinant interferon gamma. As mentioned above, interferon gamma has weak antiviral activity but is able to augment the activity of interferon alpha and beta. In phase II monotherapy studies in nonresponding HCV patients, Actimmune monotherapy failed to reduce viral load or reverse liver cirrhosis. Actimmune is now being evaluated in phase II studies in combination with Infergen (Intermune’s formulation of standard interferon alpha) in patients who have failed peginterferon/Ribavirin therapy. A retrospective analysis from this study was presented in May 2004 demonstrating that 47% of patients had undetectable viral load at 24 weeks of Actimmune plus Infergen treatment. While this result appears promising, we are concerned by the retrospective nature of the analysis and the lack of a control arm in the study. Also worrisome is the lack of data from this study since the presentation of the prospective analysis. Thus far, we have seen little to suggest that Actimmune has good efficacy in hepatitis C patients and we remain cautious of this drug’s potential.
Rebif (Interferon beta; Serono)
Rebif is recombinant interferon beta. Serono announced earlier in 2005 that they have initiated phase III studies of Rebif in Asian patients. The reason for this race exclusivity comes from a study published in the Journal of Viral Hepatology in 2004 which showed that in 267 interferon alpha nonresponding patients, treatment with interferon beta demonstrated little benefit except in patients of Asian origin. At 24 weeks following 48 weeks of treatment with interferon beta, only 3.4% of patients overall had a sustained virologic response. In contrast, 21.7% of Chinese patients achieved sustained virologic response. Of the responding patients, the Chinese patients cleared the virus much faster than non-Chinese patients (2 weeks versus 30 weeks). It is still unclear as to why Chinese patients respond better to interferon beta than non-Chinese patients. Based on this study, we predict that Rebif can be useful in Asian interferon-alpha nonresponding patients. We therefore predict a much larger uptake of Rebif in Asian countries than in the U.S. or Europe.
Albuferon (Albumin-Interferon alpha; Human Genome Sciences)
Human Genome Sciences is developing a long-acting interferon alpha by fusing the interferon alpha with the blood protein albumin. This delays the elimination of interferon alpha allowing for less frequent dosing. Early pharmacokinetic studies have shown that Albuferon has a half-life of 148 hours, suggested that the drug can be dosed every 2-4 weeks.
In a dose-finding phase II study in 56 treatment-naïve patients with HCV genotype 1, Albuferon demonstrated robust antiviral activity. The mean viral load reduction was 3.2 log10 at day 28 in the two high dose cohorts (900 and 1200 mcg). Moreover, 69% of patients in these cohorts had greater than 2 log10 reductions at day 28. This result is impressive given that these patients were given monotherapy Albuferon (the historical figure for HCV-1 patients achieving greater than 2 log10 reduction in viral load with peginterferon/ribavirin is 42%). Furthermore, 23% of patients in these cohorts had undetectable viral load 28 days after the last injection suggesting a sustained response.
Albuferon is currently being evaluated in combination with Ribavirin in two ongoing phase II studies: one in treatment-naïve and the other in treatment-experienced patients. Both studies only enrolled genotype 1 HCV patients. Preliminary data from the study in treatment-experienced study showed that the combination of Albuferon and Ribavirin was safe, well tolerated, and has antiviral activity. This indicates that Albuferon can be used in combination with Ribavirin. It remains to be seen whether the combination of Albuferon and Ribavirin can induced a sustained response in genotype 1 patients. However, based on the efficacy of Albuferon monotherapy observed to date and given the drug’s longer half-life and less frequent dosing, we predict that Albuferon can displace peginterferons as the standard of care in the front line setting and in treatment-experienced patients, particularly in patients with genotype 1.
Viramidine was designed to make Ribavirin more liver specific in order to reduce the hemolytic anemia associated with high dose Ribavirin. Viramidine is a structural analog of Ribavirin and is converted to Ribavirin by the enzyme adenosine deaminase. It is thought that this conversion mainly occurs in liver cells, thus reducing drug exposure to other cell types, particularly blood cells. Animal studies have shown that Viramidine yields 3 times more drug in the liver (and half the amount in red blood cells) than a comparable dose of Ribavirin, which may allow for lower doses of Viramidine to be used.
In a phase II study in treatment-naïve patients (with all genotypes), Viramidine plus peginterferon resulted in significantly fewer cases of hemolytic anemia than Ribavirin plus peginterferon (4% versus 27%). However, Viramidine appears to be slightly less efficacious than Ribavirin although the difference was not statistically significant. In the Viramidine/peginterferon arm, the sustained virologic response ranged from 23-37% (depending on the dose of Viramidine) compared to 44% in the Ribavirin/peginterferon arm. While we are mildly concerned by the slightly lower sustained virologic response, we are encouraged by the markedly reduce rate of hemolytic anemia. Based on results thus far, we predict that Viramidine may be widely adopted, particularly in patients who are unlikely to tolerate Ribavirin or those at risk of acute myocardial infarctions or strokes. However, we predict that Viramidine (and Ribavirin or Ribavirin alternatives) will lose market share once HCV protease inhibitors enter the market, especially in patients with genotype 1 HCV.
Valopicitabine (NM283; Idenix)
Valopicitabine, a novel nucleoside analog that inhibits viral RNA polymerase, was developed to be a more potent version of Ribavirin for genotype 1 patients. Valopicitabine is currently in phase IIb studies. Results are only available from a phase IIa study in 30 HCV genotype 1 treatment-naïve patients who were either given Valopicitabine alone or Valopicitabine in combination with Peg-Intron. This study is still ongoing and interim data were presented at the European Association for the Study of Liver (EASL) in April earlier this year. Of the 30 patients enrolled in the study, 25 patients have passed 12 weeks of treatment while 10 patients have reached 24 weeks of treatment. After 12 weeks of treatment, Valopicitabine plus Peg-Intron reduced viral load by a 3 log10 International Units (IU)/ml, corresponding to a 99.9% reduction in viral load. As expected, Valopicitabine alone was not as efficacious reducing viral load only by 0.87 log10 IU/ml which corresponded to an 86.5% reduction in viral load. Of the 10 patients who have been treated for at least 24 weeks, 9 out of the 10 were given Valopicitabine plus Peg-Intron. In these 9 patients, the mean viral load reduction is 4.5 log10 IU/ml which corresponds to over a 99.99% reduction in viral load.
Six out of 9 patients (66.7%) had their viral load reduced to undetectable levels at 12 weeks in the combination group, as determined by real-time PCR (<10 IU/ml). At 24 weeks, only 4 out of the 9 patients (44.4%) had undetectable viral load in the combination treatment group as determined by real time PCR. These results are encouraging; however, the 44% of patients with undetectable viral load at 24 weeks is similar to that observed with Ribavirin and peginterferon in genotype 1 patients, although it must be pointed out that the real-time PCR assay used in this study is slightly more sensitive than typical PCR assays (10 vs 50 IU/ml).
The ongoing head to head phase IIb study will be critical in determining whether Valopicitabine is more efficacious than Ribavirin in genotype 1 patients. This phase IIb study completed enrollment in mid 2005 and prelimininary data are expected by the end of 2005. We expect Idenix to present updated results from the phase IIa study and perhaps preliminary phase IIb results at the upcoming liver meeting AASLD in San Francisco (November 11-14, 2005). These results will be critical in evaluating whether Valopicitabine presents any advantages over Ribavirin for the treatment of genotype 1 HCV. If Valopicitabine demonstrates superior efficacy to Ribavirin, then we see Valopicitabine plus peginterferon (or perhaps Albuferon) as becoming the new standard of care for HCV-1 patients. However, if Valopicitabine’s efficacy is only comparable to that of Ribavirin, its uptake will face stiff competition from Viramidine due to Viramidine’s comparable efficacy and superior safety profile.
MX-3253 is an orally available antiviral agent that has a unique mechanism of action. MX-3253 inhibits the enzyme alpha glucosidase I, an enzyme involved in the development of viral envelopes. Inhibiting alpha glucosidase I prevents the correct folding of viral envelope glycoprotein, thus inhibiting the replication of enveloped viruses such as HCV. Results from a small dose-finding phase IIa study evaluating different doses of monotherapy MX-3253 showed limited efficacy with few meaningful reductions in viral load in both treatment-naïve patients and those intolerant of interferon/Ribavirin therapy. Migenix is currently conducting a phase IIb study of MX-3253 in combination with peginterferon/Ribavirin in nonresponding genotype 1 patients. While results from monotherapy MX-3253 have been disappointing thus far, it must be remembered that Ribavirin monotherapy had little effects on viral load. Therefore, there is still a chance that MX-3253 may be efficacious when combined with current standard therapy. However, based on results thus far, we are cautious of MX-3253’s potential and see little uptake of the drug.
VX-950 has a novel mechanism of action – it targets HCV protease, an enzyme required for HCV replication. It is currently in phase I studies for the treatment of HCV-1. In a dose-finding study that only enrolled patients with genotype 1 HCV (both treatment-experienced and treatment-naïve), patients were given either 450 mg or 750 mg of VX-950 every 8 hours or 1250 mg of VX-950 every 12 hours for 14 days. Reductions in viral load were seen in all 3 dose groups, with the median reduction (across the 3 dose groups) of more than 3 log10. The study found that the optimal dose group was 750 mg every 8 hours, and in patients treated with this dose, a median viral reduction of 4.4 log10 was observed (which corresponds to a 25,000 fold reduction). Moreover, 50% of patients in this dose group had undetectable viral load (<10 IU/ml) at the end of the 14 day treatment period.
These results suggest that VX-950 can rapidly reduce viral load in genotype 1 HCV patients. The reduction in viral load by monotherapy VX-950 appears to be superior to that by peginterferon/Ribavirin treatment in genotype 1 patients since VX-940 reduced viral load by 4.4 log10 which compares favorably to the mean reduction of 1.5 log10 with interferon/Ribavirin treatment in genotype 1 patients.
While it is still too early to determine whether VX-950 monotherapy can induce a sustained virologic response, the results thus far suggests that the drug given alone is superior to interferon/Ribavirin in genotype 1 patients. However, as mentioned above, there are concerns that HCV small molecule inhibitors are at risk of developing viral resistance (as often seen with HIV small molecule inhibitors) due to the ability of HCV to rapidly mutate. Therefore, positive data from the combination of VX-950 plus peginterferon is critical to the development of VX-950 and other HCV protease inhibitors. To address this, Vertex recently commenced a Phase Ib evaluating VX-950 in combination with peginterferon. In addition, Vertex expects to initiate by the end of the year a one-month Phase II study of VX-950 co-administered with peginterferon.
While it is conceivable that VX-950 may be used as a monotherapy agent in interferon/ribavirin nonresponding genotype 1 patients, we see more potential for the drug if it can be combined with interferon to lower the risk of resistance development. Should the addition of peginterferon to VX-950 demonstrate comparable or better efficacy than monotherapy VX-950, we would expect this combination to become the new gold standard for genotype 1 patients.
Schering also has a HCV protease inhibitor in development called SCH 503034, which is also in phase I studies. This phase I study is evaluating SCH 503034 both as a monotherapy and in combination with peginterferon (Peg-Intron). Detailed results from this study are not yet available but are expected at the upcoming AASLD meeting. It will be interesting to see how SCH 503034 compares to VX-950 and whether the combination of SCH 503034 and Peg-Intron yields additional benefits over SCH 503034 alone. Data from the combination regimen is of particular interest since it will likely set the tone for other HCV protease inhibitors in development. Like VX-950, we see some potential use of SCH 503034 as a monotherapy in nonresponding patients, but we see the biggest potential for the drug in combination with interferon. Schering is also planning a larger phase II study to evaluate SCH 503034 in combination with Peg-Intron in HCV-1 nonresponding patients. This study is expected to start enrolling by the end of 2005.
It is still too early to determine which of these two protease inhibitors (VX-950 or SCH 503034) will become more dominant. Results presented at the upcoming AASLD meeting will give us better insights into the efficacy and safety profiles of these drugs. While VX-950 appears to be furthest along in development, the initiation of a large phase II study of SCH 503034 may mean that SCH 503034 may advance more quickly. The presence of other HCV protease inhibitors also in clinical development (Gilead recently initiating phase I dose-escalating studies with their protease inhibitor GS 9132) means the race to be the first on the market is quite competitive.
Overall, HCV protease inhibitors are very promising thus far and with their unique mechanism of action, could provide new ways to combat HCV, particularly the difficult-to-treat genotype 1. However, it must be cautioned that Boehringer Ingelheim’s protease inhibitor BILN 2061 (which also demonstrated impressive viral load reductions) was dropped due to cardiotoxicity in animal studies. It is not yet known whether these other protease inhibitors also have cardiotoxic side effects, thus the adverse effect profile of these drugs will need to be monitored carefully.
Market Summary
Based on data to date, we project that Albuferon will become the dominant interferon formulation to be used in all patients (all genotypes). We foresee Viramidine and Valopicitabine to eventually replace current formulations of Ribavirin. We believe that the combination of Viramidine or Valopicitabine plus interferon (Albuferon) to be the standard of care for all patients until the approval of HCV protease inhibitors. Once HCV protease inhibitors enter the market, we believe that both Viramidine and Valopicitabine will lose significant market share, particularly in genotype 1 patients, but will remain in use in patients with genotypes 2 or 3. We see HCV protease inhibitors (in combination with interferons) to be the new standard of care for patients with genotype 1 although they will likely also be used in interferon/Ribavirin nonresponding patients with other genotypes.
REVENUE MODEL UPDATE
The Hepatitis C revenue models were updated on 2/8/06. Please click here for a summary of the changes. We have created 12 revenue models for the following drugs: Pegasys, Peg-Intron, Copegus, Rebetol, Albuferon, Viramidine, Valopicitabine, Zadaxin, MX-3253, VX-950, SCH 503034, and GS 9132.
Pegasys was approved in 2002 and has been taking market share away from Schering-Plough’s Peg-Intron during the last several years. We expect revenue to climax in 2009 before Albuferon enters the market in 2010. We predict peak U.S. and worldwide revenues of $688.1 million and $1.7 billion. Peg-Intron (Schering-Plough)
Peg-Intron arrived in the U.S. market in early 2001. Due to the continued loss of market share to Pegasys, we believe that US revenue has already peaked. Worldwide revenue however, may continue to grow slowly as the Peg-Intron combination therapy is approved overseas. We predict worldwide revenues to grow to $682.7 million in 2009. Copegus (Roche)
Copegus was approved in late 2002 and although a generic version of Ribavirin is now available in the US, Roche continues to see an increase in sales as their drug is competitively priced. We predict peak U.S. and worldwide revenues of $326.1 million and $678.2 million in 2009. Rebetol (Schering-Plough)
Rebetol was approved in 1998 and Schering-Plough has watched U.S. revenue diminish over the years due to competition from both Copegus and now the lower-priced generic versions of Ribavirin. Worldwide sales will remain as the drug continues to be used in combination therapy overseas. We predict worldwide sales of Rebetol will grow to $482.3 million in 2009. Albuferon (Human Genome Sciences)
Since Albuferon requires less frequent dosing than peginterferons, we predict the drug will enjoy a good uptake in both treatment-naïve and treatment nonresponders. Since the drug is a reformulation of interferon alpha, it can be broadly used by patients of all genotypes. We predict peak U.S. and worldwide revenues of $789.9 million and $2.0 billion in 2014.
Viramidine has demonstrated almost comparable efficacy to Ribavirin with much less toxicity. Therefore, we predict the drug to be used in patients who cannot tolerate the side effects of Ribavirin or those with heart disease. We also project that Viramidine will lose market share in the treatment-naïve patients (particularly in those with genotype 1) when HCV protease inhibitors come onto the market. We predict peak U.S. and worldwide revenues of $361.5 million and $914.3 million in 2012.
Valopicitabine will likely replace current formulations of Ribavirin; however, it will face stiff competition from Viramidine. We currently project peak U.S. and worldwide revenues of $187.1 million and $473.3 million in 2013.
We currently forecast little adoption of Zadaxin and project that the drug will only be used in a small number of patients who fail all other treatments. We predict peak U.S. and worldwide revenues of $61.4 million and $156.6 million in 2012.
MX-3253 has demonstrated little efficacy to date and thus we currently project limited utility in the hepatitis C market. We predict peak U.S. and worldwide revenues of $18.7 million and $47.3 million in 2013.
VX-950 has demonstrated impressive results thus far. As such, we predict the drug to be widely adopted especially in patients with genotype 1 HCV. We predict peak U.S. and worldwide revenues of $339.1 million and $864.7 million in 2015.
Without available data to compare SCH 503034 to VX-950, we assume that the drug will yield some efficacy. We currently predict that the drug will also be used in patients with genotype 1 HCV but are more cautious on the drug’s uptake in the absence of trial data. We currently project peak U.S. and worldwide revenues of $242.2 million and $617.6 million in 2015.
GS 9132 is a HCV protease inhibitor that recently entered phase I studies. Given that the drug is lagging behind the other 2 protease inhibitors, it will lose market share due to its late entry into the market. We predict peak U.S. and worldwide revenues of $100.3 million and $253.7 million in 2015.
MX-3253 is an orally available antiviral agent that has a unique mechanism of action. MX-3253 inhibits the enzyme alpha glucosidase I, an enzyme involved in the development of viral envelopes. Inhibiting alpha glucosidase I prevents the correct folding of viral envelope glycoprotein, thus inhibiting the replication of enveloped viruses such as HCV. Results from a small dose-finding phase IIa study evaluating different doses of monotherapy MX-3253 showed limited efficacy with few meaningful reductions in viral load in both treatment-naïve patients and those intolerant of interferon/Ribavirin therapy. Migenix is currently conducting a phase IIb study of MX-3253 in combination with peginterferon/Ribavirin in nonresponding genotype 1 patients. While results from monotherapy MX-3253 have been disappointing thus far, it must be remembered that Ribavirin monotherapy had little effects on viral load. Therefore, there is still a chance that MX-3253 may be efficacious when combined with current standard therapy. However, based on results thus far, we are cautious of MX-3253’s potential and see little uptake of the drug.
VX-950 has a novel mechanism of action – it targets HCV protease, an enzyme required for HCV replication. It is currently in phase I studies for the treatment of HCV-1. In a dose-finding study that only enrolled patients with genotype 1 HCV (both treatment-experienced and treatment-naïve), patients were given either 450 mg or 750 mg of VX-950 every 8 hours or 1250 mg of VX-950 every 12 hours for 14 days. Reductions in viral load were seen in all 3 dose groups, with the median reduction (across the 3 dose groups) of more than 3 log10. The study found that the optimal dose group was 750 mg every 8 hours, and in patients treated with this dose, a median viral reduction of 4.4 log10 was observed (which corresponds to a 25,000 fold reduction). Moreover, 50% of patients in this dose group had undetectable viral load (<10 IU/ml) at the end of the 14 day treatment period.
These results suggest that VX-950 can rapidly reduce viral load in genotype 1 HCV patients. The reduction in viral load by monotherapy VX-950 appears to be superior to that by peginterferon/Ribavirin treatment in genotype 1 patients since VX-940 reduced viral load by 4.4 log10 which compares favorably to the mean reduction of 1.5 log10 with interferon/Ribavirin treatment in genotype 1 patients.
While it is still too early to determine whether VX-950 monotherapy can induce a sustained virologic response, the results thus far suggests that the drug given alone is superior to interferon/Ribavirin in genotype 1 patients. However, as mentioned above, there are concerns that HCV small molecule inhibitors are at risk of developing viral resistance (as often seen with HIV small molecule inhibitors) due to the ability of HCV to rapidly mutate. Therefore, positive data from the combination of VX-950 plus peginterferon is critical to the development of VX-950 and other HCV protease inhibitors. To address this, Vertex recently commenced a Phase Ib evaluating VX-950 in combination with peginterferon. In addition, Vertex expects to initiate by the end of the year a one-month Phase II study of VX-950 co-administered with peginterferon.
While it is conceivable that VX-950 may be used as a monotherapy agent in interferon/ribavirin nonresponding genotype 1 patients, we see more potential for the drug if it can be combined with interferon to lower the risk of resistance development. Should the addition of peginterferon to VX-950 demonstrate comparable or better efficacy than monotherapy VX-950, we would expect this combination to become the new gold standard for genotype 1 patients.
Schering also has a HCV protease inhibitor in development called SCH 503034, which is also in phase I studies. This phase I study is evaluating SCH 503034 both as a monotherapy and in combination with peginterferon (Peg-Intron). Detailed results from this study are not yet available but are expected at the upcoming AASLD meeting. It will be interesting to see how SCH 503034 compares to VX-950 and whether the combination of SCH 503034 and Peg-Intron yields additional benefits over SCH 503034 alone. Data from the combination regimen is of particular interest since it will likely set the tone for other HCV protease inhibitors in development. Like VX-950, we see some potential use of SCH 503034 as a monotherapy in nonresponding patients, but we see the biggest potential for the drug in combination with interferon. Schering is also planning a larger phase II study to evaluate SCH 503034 in combination with Peg-Intron in HCV-1 nonresponding patients. This study is expected to start enrolling by the end of 2005.
It is still too early to determine which of these two protease inhibitors (VX-950 or SCH 503034) will become more dominant. Results presented at the upcoming AASLD meeting will give us better insights into the efficacy and safety profiles of these drugs. While VX-950 appears to be furthest along in development, the initiation of a large phase II study of SCH 503034 may mean that SCH 503034 may advance more quickly. The presence of other HCV protease inhibitors also in clinical development (Gilead recently initiating phase I dose-escalating studies with their protease inhibitor GS 9132) means the race to be the first on the market is quite competitive.
Overall, HCV protease inhibitors are very promising thus far and with their unique mechanism of action, could provide new ways to combat HCV, particularly the difficult-to-treat genotype 1. However, it must be cautioned that Boehringer Ingelheim’s protease inhibitor BILN 2061 (which also demonstrated impressive viral load reductions) was dropped due to cardiotoxicity in animal studies. It is not yet known whether these other protease inhibitors also have cardiotoxic side effects, thus the adverse effect profile of these drugs will need to be monitored carefully.
Market Summary
Based on data to date, we project that Albuferon will become the dominant interferon formulation to be used in all patients (all genotypes). We foresee Viramidine and Valopicitabine to eventually replace current formulations of Ribavirin. We believe that the combination of Viramidine or Valopicitabine plus interferon (Albuferon) to be the standard of care for all patients until the approval of HCV protease inhibitors. Once HCV protease inhibitors enter the market, we believe that both Viramidine and Valopicitabine will lose significant market share, particularly in genotype 1 patients, but will remain in use in patients with genotypes 2 or 3. We see HCV protease inhibitors (in combination with interferons) to be the new standard of care for patients with genotype 1 although they will likely also be used in interferon/Ribavirin nonresponding patients with other genotypes.
REVENUE MODEL UPDATE
The Hepatitis C revenue models were updated on 2/8/06. Please click here for a summary of the changes. We have created 12 revenue models for the following drugs: Pegasys, Peg-Intron, Copegus, Rebetol, Albuferon, Viramidine, Valopicitabine, Zadaxin, MX-3253, VX-950, SCH 503034, and GS 9132.
Pegasys was approved in 2002 and has been taking market share away from Schering-Plough’s Peg-Intron during the last several years. We expect revenue to climax in 2009 before Albuferon enters the market in 2010. We predict peak U.S. and worldwide revenues of $688.1 million and $1.7 billion. Peg-Intron (Schering-Plough)
Peg-Intron arrived in the U.S. market in early 2001. Due to the continued loss of market share to Pegasys, we believe that US revenue has already peaked. Worldwide revenue however, may continue to grow slowly as the Peg-Intron combination therapy is approved overseas. We predict worldwide revenues to grow to $682.7 million in 2009. Copegus (Roche)
Copegus was approved in late 2002 and although a generic version of Ribavirin is now available in the US, Roche continues to see an increase in sales as their drug is competitively priced. We predict peak U.S. and worldwide revenues of $326.1 million and $678.2 million in 2009. Rebetol (Schering-Plough)
Rebetol was approved in 1998 and Schering-Plough has watched U.S. revenue diminish over the years due to competition from both Copegus and now the lower-priced generic versions of Ribavirin. Worldwide sales will remain as the drug continues to be used in combination therapy overseas. We predict worldwide sales of Rebetol will grow to $482.3 million in 2009. Albuferon (Human Genome Sciences)
Since Albuferon requires less frequent dosing than peginterferons, we predict the drug will enjoy a good uptake in both treatment-naïve and treatment nonresponders. Since the drug is a reformulation of interferon alpha, it can be broadly used by patients of all genotypes. We predict peak U.S. and worldwide revenues of $789.9 million and $2.0 billion in 2014.
Viramidine has demonstrated almost comparable efficacy to Ribavirin with much less toxicity. Therefore, we predict the drug to be used in patients who cannot tolerate the side effects of Ribavirin or those with heart disease. We also project that Viramidine will lose market share in the treatment-naïve patients (particularly in those with genotype 1) when HCV protease inhibitors come onto the market. We predict peak U.S. and worldwide revenues of $361.5 million and $914.3 million in 2012.
Valopicitabine will likely replace current formulations of Ribavirin; however, it will face stiff competition from Viramidine. We currently project peak U.S. and worldwide revenues of $187.1 million and $473.3 million in 2013.
We currently forecast little adoption of Zadaxin and project that the drug will only be used in a small number of patients who fail all other treatments. We predict peak U.S. and worldwide revenues of $61.4 million and $156.6 million in 2012.
MX-3253 has demonstrated little efficacy to date and thus we currently project limited utility in the hepatitis C market. We predict peak U.S. and worldwide revenues of $18.7 million and $47.3 million in 2013.
VX-950 has demonstrated impressive results thus far. As such, we predict the drug to be widely adopted especially in patients with genotype 1 HCV. We predict peak U.S. and worldwide revenues of $339.1 million and $864.7 million in 2015.
Without available data to compare SCH 503034 to VX-950, we assume that the drug will yield some efficacy. We currently predict that the drug will also be used in patients with genotype 1 HCV but are more cautious on the drug’s uptake in the absence of trial data. We currently project peak U.S. and worldwide revenues of $242.2 million and $617.6 million in 2015.
GS 9132 is a HCV protease inhibitor that recently entered phase I studies. Given that the drug is lagging behind the other 2 protease inhibitors, it will lose market share due to its late entry into the market. We predict peak U.S. and worldwide revenues of $100.3 million and $253.7 million in 2015.