Boehringer Ingelheim broadens efforts for interferon-free hepatitis C treatments through clinical collaboration with Presidio Pharmaceuticals

Boehringer Ingelheim today announced the completion of patient enrolment for a Phase IIa clinical trial investigating a new interferon-free, all-oral, direct-acting antiviral (DAA) combination treatment for patients with genotype-1a chronic hepatitis C virus (HCV) infection. The trial is conducted in collaboration with Presidio Pharmaceuticals, Inc. and evaluates Boehringer Ingelheim’s investigational compounds, the protease inhibitor faldaprevir+ and non-nucleoside NS5B polymerase inhibitor, deleobuvir+, in combination with Presidio’s pan-genotypic NS5A inhibitor, PPI-668, with and without ribavirin.1

The trial includes 36 treatment-naïve genotype-1a infected patients treated for 12 weeks with this all-oral DAA regimen, with 24 weeks of post-treatment follow-up. The primary endpoint of the trial is sustained virologic response 12 weeks after treatment is completed (SVR12).1 This Phase IIa trial of a novel combination therapy is part of Boehringer Ingelheim’s commitment to develop new, tailored interferon and potentially ribavirin-free HCV regimens for a broad range of HCV patients.

In March 2013, the two companies entered a non-exclusive collaboration to evaluate the three DAAs in combination regimens. Both companies will retain all rights to their respective compounds. Presidio has operational responsibility for this collaborative trial, with oversight by an intercompany project team. Final results are expected in Q2 2014.1

“We are pleased to announce that enrolment is complete in this collaborative Phase IIa trial evaluating a new 12-week interferon-free treatment regimen. This regimen complements and expands our HCV portfolio with the goal of providing interferon-free treatments to patients with HCV,” said Professor Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim. “This study is the next step in our continued commitment to deliver effective and well-tolerated treatment options that are optimised for patients with different hepatitis C genotypes. The pan-genotypic properties of PPI-668 bear the potential to explore the efficacy of this regimen in a wider range of HCV genotypes in the future.”

Eliminating injectable interferon from treatment is a critical goal in hepatitis C management.4 Clinical studies have shown that up to 50 percent of patients may not be eligible for treatment with interferon due to contraindications.5 Patients may also find interferon challenging due to the long treatment duration and side-effects. These side-effects commonly include fatigue, anxiety, depression, gastrointestinal and flu-like symptoms as well as more serious side-effects such as heart failure, sepsis, leukopenia, depression and vision loss.6,7

“Clinical trials evaluating multiple DAAs are exciting because they can help bring us closer to our goal of developing more effective and tolerable interferon-free and potentially ribavirin-free therapies,” said Jacob Lalezari M.D., Director of Quest Clinical Research in San Francisco, CA. “By treating patients with multiple compounds that attack the hepatitis C virus in different ways, we hope to be able to cure more patients in less time with fewer of the side-effects associated with existing treatment options.”

Boehringer Ingelheim has a comprehensive interferon-free clinical trial programme which includes three pivotal Phase III studies (HCVerso®). The HCVerso® studies include approximately 1,100 treatment-naïve HCV genotype-1b patients, including those who are interferon eligible or ineligible and patients with compensated liver cirrhosis.2,3

For more information regarding the trial, please visit www.clinicaltrials.gov.

About Boehringer Ingelheim in hepatitis C

Through pioneering science, Boehringer Ingelheim is striving to find answers to the pressing challenges still faced by the diverse population of hepatitis C patients. The company’s comprehensively designed hepatitis C clinical trial programme includes a broad range of patients, including the challenging to cure, that clinicians see every day in clinical practice.

Boehringer Ingelheim is developing faldaprevir+, an optimised second generation protease inhibitor, as the core component for both interferon-based and interferon-free treatment regimens.

Interferon-based therapy with faldaprevir+ has the potential to improve cure rates with the added convenience of once-daily dosing and no dietary requirements for intake. Faldaprevir+ has proven efficacy in a broad range of genotype-1a and 1b hepatitis C patients. The Phase III STARTVerso® trial programme, which includes treatment-naïve, treatment-experienced and HIV co-infected patients with hepatitis C virus, is nearly complete.13,14,15,16

Deleobuvir+ (BI 207127) is a potent investigational non-nucleoside NS5B polymerase inhibitor to treat patients with genotype-1b hepatitis C virus. Phase III HCVerso® trials, investigating the interferon-free regimen of twice-daily deleobuvir in combination with once-daily faldaprevir+ and ribavirin, are well underway.2,3

As part of Boehringer Ingelheim’s long-term commitment to hepatitis C, the company is also evaluating other combinations of investigational hepatitis C compounds that work in different ways. Boehringer Ingelheim’s recent collaboration with Presidio Pharmaceuticals, Inc. for a Phase II clinical study investigating an interferon-free, all-oral, potentially ribavirin-free combination is part of the company’s continued exploration to discover and develop innovative options for the treatment of HCV.

About Hepatitis C

Hepatitis C is a blood-borne infectious disease caused by the hepatitis C virus which lives and replicates in the liver. Hepatitis C is a leading cause of chronic liver disease, liver cancer and transplantation.8 Chronic hepatitis C is a major public health issue and one of the most prevalent infectious diseases worldwide, affecting around 170 million people,9 with 3-4 million new cases occurring each year.10

It is common for hepatitis C patients to remain undiagnosed due to the initial unspecific symptoms of the disease. Consequently, a large number of patients first present to their physician when they experience symptoms or already have liver disease.11 Patients with advanced liver disease are challenging to cure, yet have the greatest need for more effective and better tolerated treatments.

Of patients with chronic hepatitis C, 20 percent will develop liver cirrhosis, of which 2-5 percent will die every year.12 Advanced liver disease due to hepatitis C currently represents the main cause for liver transplantation in the western world.12

About Presidio in HCV

Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company focused on the discovery and development of oral pan-genotypic therapeutics for HCV patients. Efforts are currently focused on novel inhibitors of both the HCV NS5A and NS5B genes. PPI-668 is an investigational, pan-genotypic, once daily, NS5A inhibitor. In earlier clinical studies in healthy volunteers and HCV-infected patients, PPI-668 has been well-tolerated to date with no serious or severe adverse events and no apparent pattern of treatment-related clinical side effects or laboratory abnormalities. PPI-668 achieves plasma concentrations high enough to inhibit most pre-existing resistant variants and achieves steady-state levels after a single dose. In a clinical study of PPI-668 monotherapy in GT1 HCV-infected patients, viral load reductions of 3.5 to 3.7 log10 HCV were achieved in 1-2 days. Activity was also noted in GT3 HCV-infected patients.17

Presidio’s NS5B inhibitor, PPI-383, is a novel pan-genotypic non-nucleosidic inhibitor with potential to inhibit all of the major HCV genotypes. This compound is currently in Phase 1 studies in healthy subjects. For more information, please visit our website at: www.presidiopharma.com.

+ Faldaprevir and BI 207127 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established

References

1. ClinicalTrials.gov. Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C
2. ClinicalTrials.gov. IFN-free Combination Therapy in HCV-infected Patients Treatment-naive:HCVerso1. http://clinicaltrial.gov/ct2/show/NCT01732796?term=faldaprevir+bi+207127&rank=3 [Last accessed 17/04/13]
3. ClinicalTrials.gov. Phase 3 Study of BI 207127 in Combination With Faldaprevir and Ribavirin for Treatment of Patients With Hepatitis C Infection, Including Patients Who Are Not Eligible to Receive Peginterferon: HCVerso2. http://clinicaltrial.gov/ct2/show/NCT01728324?term=faldaprevir+bi+207127&rank=2 [Last accessed 17/04/13]
4. Jazwinski and Muir. Direct-Acting Antiviral Medications for Chronic Hepatitis C Virus Infection. October 2012.
5. Kramer JR. et al. Gaps In The Achievement Of Effectiveness Of HCV Treatment In National VA Practice. J Hepatology 2012; 56:320-5
6. National Institutes of Health; US Department of Health and Human Services. Chronic Hepatitis C: Current Disease Management. Bethesda, MD: National Institutes of Health; 2010. NIH Publication 10-4230 4
7. World Health Organization. Global Alert and Response: Hepatitis C Prevention and Treatment. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index5.html
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9. Centers for Disease Control and Prevention (2012) Hepatitis C available at: HYPERLINK “http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm” [Last accessed on 23/07/13]
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11. Chen S.L., Morgan T.R. The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3:47-52. Available from http://www.medsci.org/v03p0047.htm [Last accessed on 16/07/13]
12. Soriano, Vincent et al. New Therapies for Hepatitis C Virus Infection. Clinical Infectious Disease, February 2009
13. ClinicalTrials.gov. Efficacy and Safety of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients. http://clinicaltrials.gov/ct2/show/NCT01343888?term=bi+201335&rank=4 [Last accessed 17/04/13]
14. ClinicalTrials.gov. BI 201335 Used in Treatment Naive Patients Infected With Genotype 1 Chronic Hepatitis C Infection. http://clinicaltrials.gov/ct2/show/NCT01297270?term=bi+201335&rank=5 [Last accessed 17/04/13]
15. ClinicalTrials.gov. Pivotal Trial Treatment Experienced Patient Infected With Hepatitis C Virus (HCV) Genotype 1 (GT1). http://clinicaltrials.gov/ct2/show/NCT01358864?term=bi+201335&rank=14 [Last accessed 17/04/13]
16. ClinicalTrials.gov. Phase III Trial of BI 201335 in Treatment Naive (TN) and Relapser Hepatitis C Virus (HCV)- Human Immunodeficiency Virus (HIV) Coinfected Patients. http://clinicaltrials.gov/ct2/show/NCT01399619?term=bi+201335+HIV&rank=1 [Last accessed 17/04/13]
17. Lalezari, J. Et al. PPI-668, A Potent New Pan-Genotypic HCV NS5A Inhibitor: Phase 1 Efficacy and Safety. Poster Presented at 63rd Annual Mtg. of the American Association for the Study of Liver Diseases. November 2012