Novartis Plunges into Hepatitis C Market
By Malorye A. Branca, Editor-in-Chief, Pharma DD and Lucy Sannes, Ph.D.
June 29, 2006
Novartis has recently invested $750 million in new drug candidates for hepatitis C virus (HCV) treatment, banking on the idea that this market can be reshaped and greatly expanded with breakthrough therapies. In June 2006, Novartis expanded its growing portfolio of emerging HCV therapies with two big licensing agreements: It paid Human Genome Sciences (HGS) $550 million for Albuferon and another $200 million to Genelabs for its HCV non-nucleoside drug discovery program. Novartis is not new to the HCV market, however. The company has earlier agreements covering HCV therapies with Idenix Pharmaceuticals and Anadys Pharmaceuticals along with its own emerging HCV therapy, NIM811, in early development.
HCV infection is a major healthcare problem worldwide. According to the Centers for Disease Control and Prevention (CDC), an estimated 4.1 million persons have been infected with HCV in the US, and 3.2 million Americans have a chronic HCV infection. Long-term chronic HCV infection can lead to significant morbidity (including cirrhosis and liver cancer), and in some cases, death.
The current therapy of choice for HCV is conjugation of polyethylene glycol (PEG) to interferon—creating pegylated interferon—which is then combined with the nucleoside analog ribavirin. This process, known as pegylation, extends the half-life of interferon in the bloodstream, improving efficacy while reducing the number of injections that are required. The Centers for Disease Control reports that the current combination therapy eradicates the virus in 80% of patients with HCV genotypes 2 or 3, and up to 50% of patients with HCV genotype 1, which is the most common genotype in the US. More effective therapy with fewer side effects is clearly needed.
It is becoming increasingly clear that with new and improved therapies, the HCV market could be much larger. When safer and more effective breakthrough HCV therapies eventually reach the market, the number of patients treated is expected to expand substantially. The worldwide market for Hepatitis C is currently more than $3 billion and could quadruple by 2015.
HGS is developing Albuferon (albumin-interferon alpha), which was created by fusing the gene for human albumin to the gene for interferon alpha 2b. The resulting protein is a long-acting form of interferon alpha. Based on recently released interim data from Phase II trials, compared with current therapy Albuferon may offer equivalent efficacy with less-frequent dosing (once every two weeks versus weekly). Also, data from these clinical trials suggest that it may be worthwhile to evaluate administering higher doses of Albuferon once a month. Albuferon may provide steadier levels of interferon in the bloodstream with less-frequent dosing, thereby reducing side effects. HGS plans to start Phase III trials of Albuferon by the end of 2006.
Novartis has exclusively licensed with HGS for development and commercialization of Albuferon. Commercialization of Albuferon outside the US will be handled solely by Novartis, while the two companies will co-commercialize it within the US. Novartis’ payments to HGS could total $507.5 million.
While Albuferon represents a potentially significant improvement in the treatment of HCV, it nonetheless works by the same mechanism of action as interferon. There is considerable interest in finding completely novel approaches, including development of therapies that target HCV-specific enzymes HCV NS3 serine protease and HCV RNA polymerase, which are required for viral replication. Specific inhibitors of these enzymes should theoretically block HCV without affecting the patient.
Novartis jumped into the HCV enzyme inhibitor race in March 2006 when it licensed Idenix Pharmaceuticals’ valopicitabine (NM283), currently in Phase IIb trials. Valopicitabine is an orally available prodrug of a ribonucleoside analog that inhibits HCV polymerase. Novartis agreed to pay Idenix up to $70 million in license fees for valopicitabine, including $25 million up front and $45 million when valopicitabine advances into Phase III clinical trials for treatment of treatment-naïve and treatment-refractory patients in the US. Idenix can also collect up to $455 million in milestone payments.
In June 2006, Novartis broadened its pipeline of HCV polymerase inhibitors when it licensed rights to Genelabs’ non-nucleoside drug discovery program. Novartis agreed to pay Genelabs approximately $20 million in research funding over two years, including an up-front payment of $12.5 million. Novartis also agreed to make additional milestone payments that could exceed $175 million. Genelabs is responsible for drug discovery research, and Novartis will be responsible for development and commercialization. Novartis was also granted an option to extend the research funding for a third year, and has the right of first negotiation for Genelabs’ HCV NS5A polymerase drug discovery compounds.
Recent agreements have also expanded Novartis’ ongoing HCV drug development activities. In June 2005, Anadys Pharmaceuticals and Novartis entered an exclusive agreement covering ANA975, an oral prodrug of Anadys’ molecule isatoribine, which is a TLR 7 (Toll-like receptor 7) agonist. ANA975 is an immunomodulator, which Anadys believes could be used to replace interferon in combination with ribavirin. The agreement between Anadys and Novartis covers ANA975 and additional TLR 7 oral prodrugs for treatment of chronic HCV and HBV infections as well as potentially other infectious diseases. Novartis made an initial payment to Anadys of $20 million and committed up to an additional $550 million in milestone payments. When the agreement commenced, ANA975 was in preclinical development; it is now in Phase I for HCV.
In late June 2006, Anadys experienced a setback with ANA975, and announced that it had suspended dosing HCV patients in its ongoing Phase Ib trial pending additional analysis of recently obtained information from preclinical studies in animals. In its announcement, Anadys reported that a preliminary analysis of the information from these preclinical studies showed an intense immune stimulation in the animals. Anadys reports that there have been no serious adverse events in clinical studies with ANA975, but the company has suspended the clinical trial until it can better understand the recent preclinical data. Anadys is evaluating the observations to determine future course of action.
Independently, Novartis is developing NIM811, an oral cyclosporin analog that binds to cyclophilins but is not immunosuppressive. Cyclophilin B is a host protein that is required for replication of HCV. This program is at an early stage of development at Novartis.
Despite its significant investments in emerging therapies for HCV, Novartis will face stiff competition in this market. If Albuferon gains market approval, it will have to compete against current HCV therapies. The immunomodulator ANA975 is at an earlier stage of development, but will also compete directly against interferon-based therapies. Two combinations of pegylated interferon and ribavirin are currently available in the US: Schering-Plough's peginterferon alfa-2b (PEG-Intron) and ribavirin (Rebetol), and Roche's peginterferon alfa-2a (Pegasys) and ribavirin (Copegus). Generic ribavirin is also available. HGS appears to be positioning Albuferon to compete with and replace PEG-Intron and Pegasys.
Longer term, Albuferon and other immunomodulators will likely face competition from emerging HCV therapies that operate by completely different mechanisms of action including the HCV polymerase inhibitors being developed by Novartis and others. The accompanying table shows some examples of emerging HCV therapies, demonstrating the wide range of approaches being pursued to develop more effective and safer therapies for HCV.
The HCV therapeutic market is attractive due to its large size and significant potential for growth. Many patients with chronic HCV are not being treated with current therapies. In 2005, Roche reported combined worldwide Pegasys and Copegus sales of almost USD $1.5 billion. Also in 2005, Schering-Plough reported combined sales of $1.1 billion for PEG-Intron and Rebetol.
In the current climate, Novartis’ significant investments in multiple therapeutic approaches for treatment of HCV might just pay off handsomely.
Click
here to view table in PDF Format
Email
this page to a friend
|
