Peginterferon alfa-2b(Merck & Co)

GSK is on the lookout for deals that will further expand its oligonucleotide portfolio. Summarizing GSK’s vision to investors last month, CEO Emma Walmsley reaffirmed that the British Big Pharma had decided to “end our investment in cell and gene therapy.” While this was hardly news to the audience—especially coming months after GSK axed cell therapy deals with Lycell and Immatics—it still served as a stark reminder that the company's development portfolio is swimming against the industry tide. But rather than racing to get an “off-the-shelf” CAR-T into the clinic or going all-in on a solid tumor strategy, GSK believes its genetic expertise will offer the smoothest path to market success. “About 70% of the entire GSK portfolio now has strong human genetic underpinning and even higher than that in the research phase,” the company’s head of research, John Lepore, M.D., tells Fierce Biotech in an interview. The theory is that genetically validated targets have at least a twofold higher chance of becoming medicines. “It's not a cure-all,” says Lepore. “But on a portfolio basis, if you can have a twofold inflection, that's fundamental for our company and for the industry in general—and we’ve made significant progress on that.” It sounds simple, but there’s a reason not every Big Pharma is betting the house on genetic targets. Lepore says that as novel potential targets are identified through genetics, half of them can't be targeted with a small molecule or an antibody. That’s where oligonucleotides come in. These short strands of synthetic DNA or RNA can reduce, restore or modulate RNA through several different mechanisms. Biotechs like Alynlam and Ionis were among the early pioneers in the field, but “the science of the platform of oligonucleotides is growing beyond what those two companies originally started with,” says Lepore. Riding the wave   It’s for this reason that GSK spent $170 million upfront in December to collaborate with Wave Life Sciences. Wave’s pitch is that it’s the only oligonucleotide platform offering three RNA-targeting modalities, in the form of editing, splicing and silencing. “As we look at the range of potential drug targets coming out of genetics, all three of those modalities are of interest to us,” Lepore says. A major attraction for GSK is the belief that Wave’s chemistry could broaden the use of subcutaneously delivered oligonucleotides beyond the liver, where these therapies have primarily been limited to until now. “The chemistries are starting to show evidence of the molecules being able to be directed towards other organs: kidney, lung, etc.,” he says. “As we have insight into drug targets from genetics in those organs, we think we can leapfrog to starting to have oligonucleotide therapies for those.” The deal with Wave has the potential to cover up to eight targets from GSK’s side. While Lepore won’t go into details on the targets they have in mind, “our ambition clearly is for targets in liver and beyond liver,” he says. As well as those potential future targets, the crown jewel in the Wave deal was WVE-006, a preclinical RNA editing therapy targeting alpha-1 antitrypsin deficiency, an inherited disorder that can cause lung and liver disease. “It's really cool because it's an oligonucleotide that actually corrects gene defect at the RNA level, and therefore allows normal production of the alpha-1 antitrypsin protein,” says Lepore. “[It] could be an oligo therapy that obviates the need for replacement of this protein, which is what patients are stuck with now. So it's a really neat proof of principle of what the technology could look like over time.” While exciting, WVE-006 will for the time being remain at the back of the pack when it comes to GSK’s oligonucleotide pipeline. Leading the charge is bepirovirsen, a collaboration with Ionis that is now in a pair of phase 3 trials as a potential “functional cure” for hepatitis B virus infection. By using olignucleotides as an antisense, bepirovirsen’s modality is the opposite of WVE-006, explains Melanie Paff, GSK’s global clinical development head of infectious disease therapy. “So we're trying to knock down protein, knock down the virus.” Bepirovirsen’s dual activity of knocking down the hepatitis B surface antigen as well as having an innate immune activity is “absolutely unique,” Lepore adds. Results from the phase 2 B-Clear trial showed that 9% of patients with chronic hepatitis B on stable nucleoside/nucleotide analogue (NA) treatment and 10% of those not on NA treatment achieved the study’s primary outcome of a sustained clearance of their hepatitis B surface antigen levels and hepatitis B virus DNA levels. At the time, GSK was keen to point out that even a 10% effectiveness rate among patients is around tenfold higher than the current standard of care. Now, the company is pursuing patients with lower baseline hepatitis B surface antigen levels, a cohort that the previous study suggested responded best to the therapy. The hope, according to Paff, is to see a higher response in this patient group.  The plan is to have an interim readout on a regimen of bepirovirsen and a pegylated interferon treatment “sometime mid this year,” followed by final data ready for an international congress toward the end of 2023, according to Paff. “Oligonucleotides have actually been around for a very long time,” Paff says. “But they've been relegated to rare disease settings, very small volume plays. Bepi is one of the first big pipeline plays to come across. And now that we've … figured out the manufacturing, that really opens it up to allow us to go into broader and broader disease areas.” Coming up behind is GSK4532990, a collaboration with Arrowhead that’s about to enter phase 2 for the notoriously tricky liver indication nonalcoholic steatohepatitis. And it doesn’t sound like the oligonucelotide pipeline will be limited to three therapies for too long. Lepore makes no secret of the fact that GSK is “thoughtful about potential business development in this space.” “It's a really important area for us, where the technology of oligos fits so nicely with our expertise in genetics and novel targets, and we're going to be looking to optimize that,” he adds. “You can envision all sorts of business development deals, ranging from single asset acquisitions through to additional platform plays.” Sticking with antibiotics   Oligonucleotides aren’t the only research area where GSK seems to be going against the grain. November saw the pharma announce positive results from two new antibiotics—for tuberculosis and urinary tract infection—with the latter candidate slated for FDA submission this year. Despite the looming threat of antimicrobial resistance, Big Pharmas have been giving antibiotics a wide berth for decades due to the low return on investment. “It's an area that someone absolutely has to continue to develop,” Paff says. “We can't let that go.” There are also other headline grabbers coming up this year, including a May FDA decision for the respiratory syncytial virus vaccine, which—if approved —could be the first to market, ahead of close rival Pfizer. With all this considered, do the executives still think the company has made the right decision to turn away from the red hot research areas of cell and gene therapy? “For us it is the right call,” Lepore says. “This is a capital allocation question for GSK.” While there have been big wins targeting CD19 and CD20 against liquid tumors, the space has become “very crowded,” he explains. “The prospect of expanding to solid tumours has become more challenging than we originally thought. And for us to stay in, with all the manufacturing costs and the risk, it's not the best place for GSK to put its capital at the moment.” So far, it doesn’t sound like the Big Pharma has any regrets about its genetics focus or sending back its cell therapy programs to “the companies that we think could bring them further better than we can.” “Over time, you're going to see more and more proof points coming from GSK of molecules with genetic validation, coming through to clinical development with positive data,” Lepore adds.

- Lonafarnib/ritonavir response rate of 10.1% (p=0.0044) - Lonafarnib/ritonavir in combination with peginterferon alfa response rate of 19.2% (p<0.0001) - Peginterferon alfa comparator arm, included for contribution of effect, response rate of 9.6% - Key secondary endpoint of proportion of patients with improvement in histological response rate demonstrated with statistical significance in combination arm vs placebo PALO ALTO, Calif., Dec. 8, 2022 /PRNewswire/ -- Eiger BioPharmaceuticals, Inc (Nasdaq: EIGR), a commercial-stage biopharmaceutical company focused on the development of innovative therapies for hepatitis delta virus (HDV) and other serious diseases, today announced topline primary Week 48 data from its landmark Phase 3 D-LIVR study (N=407) evaluating lonafarnib, a first-in-class prenylation inhibitor, in two regimens in patients with chronic HDV: lonafarnib boosted with ritonavir alone (all-oral) and in combination with peginterferon alfa (combination). The composite primary endpoint was a ≥2 log decline in HDV RNA and normalization of alanine aminotransferase (ALT) at the end of 48 weeks of treatment compared to placebo. Topline Week 48 results showed that both treatment arms achieved statistical significance over placebo in the composite primary endpoint as well as the component virologic and biochemical responses. Study participants receiving the all-oral therapy and combination therapy showed a composite response of 10.1% (p=0.0044) and 19.2% (p <0.0001), respectively, compared to those receiving placebo (1.9%). Study participants receiving the all-oral therapy and combination therapy showed statistically significant improved rates of ALT normalization of 24.7% (p=0.003) and 34.4% (p<0.0001), respectively, compared to those receiving placebo (7.7%). A peginterferon alfa comparator arm was included in the study to show contribution of effect. The composite response rate in the all-oral arm was comparable to the peginterferon alfa arm (10.1% vs 9.6%). The composite response rate in the combination arm was twice that of the peginterferon alfa arm (19.2% vs 9.6%). The key secondary histological endpoint was defined as ≥2-point improvement in histological activity index (HAI) and no worsening of Ishak fibrosis scoring as determined by blinded assessment of paired liver biopsies (n=229) collected at baseline and Week 48. This was demonstrated in 35 of 66 patients (53%, p=0.0139) with statistical significance in the combination arm versus 8 of 30 patients (27%) receiving placebo. Response was demonstrated in 35 of 107 patients (33%, p=0.61) in the all-oral arm versus placebo. Response in the peginterferon alfa comparator arm was 10 of 26 patients (38%). Remaining secondary endpoints including virologic, biochemical, and composite responses at Week 72 (24-weeks post-treatment) are being collected and are expected to be reported mid-2023. "We would like to extend our sincere gratitude to the patients, investigators, and clinical study sites for their participation in this well-controlled, landmark study," said David Cory, President and CEO, Eiger. "As we continue to analyze these topline data to fully understand the efficacy and safety pro lonafarnib-based treatments in chronic HDV, we look forward to a pre-NDA meeting with FDA in the coming quarter and seeing the full dataset including the 24-week post-treatment data." "The results of this landmark study highlight three key findings," said Ohad Etzion, MD, Director, Department of Gastroenterology and Liver Diseases at Soroka University Medical Center and D-LIVR study co-lead investigator. "First, a small subset of patients with chronic HDV infection may achieve virologic and biochemical improvements with an all-oral regimen after 48 weeks of treatment. Second, combining lonafarnib and ritonavir with peginterferon alfa demonstrated the potential to nearly double the response rate. And third, and perhaps most importantly, based on these data, combination treatment may lead to significant histologic improvement, a generally accepted surrogate for improved future clinical outcomes for patients. We look forward to the 24-week post-treatment results of this study for assessment of the potential for finite therapy for chronic HDV infection." The majority of treatment emergent adverse events (TEAEs) were mild or moderate in severity. The most frequent TEAEs associated with lonafarnib treatment were gastrointestinal. Nine percent and 8% of patients discontinued treatment from the lonafarnib oral and combination therapy arms, respectively, compared to 2% of patients in each of the peginterferon alfa and placebo groups. In the lonafarnib treatment groups, 8% and 14% of patients, respectively, reported serious treatment-emergent adverse events, compared with 10% in the peginterferon alfa group and 4% in the placebo group. There were two deaths in the study: one patient treated with peginterferon alfa died due to decompensated cirrhosis that was attributed to drug therapy. The other death in the lonafarnib/ritonavir arm was deemed unrelated to study drug. Summary of Topline Data Eiger plans to engage with regulatory agencies, beginning with a pre-NDA meeting with FDA anticipated in Q1 2023, to discuss pathways for regulatory submissions. The full D-LIVR dataset, including analyses of the 24-week post-treatment period, would be included in potential regulatory submissions. Eiger intends to present D-LIVR study results at a future medical congress and publish in a peer-reviewed journal. ABOUT D-LIVR D-LIVR (Delta Liver Improvement and Virologic Response in HDV) is a global, multi-center, Phase 3 study to evaluate two lonafarnib-based treatments: an all-oral arm of lonafarnib boosted with ritonavir (n=178) and a combination arm of lonafarnib boosted with ritonavir combined with peginterferon alfa (n=125), with each arm compared to a placebo arm (n=52), in HDV-infected patients after 48 weeks of treatment. The study also includes a peginterferon alfa comparator arm (n=52) used to demonstrate contribution of effect only. The two lonafarnib containing arms are not required to demonstrate superiority over peginterferon alfa. The study also includes a 24-week post-treatment follow up period. The primary endpoint is a composite of a ≥2 log decline in HDV RNA and ALT normalization at end of 48 weeks of treatment. Key virological and biochemical secondary endpoints include the components of the primary endpoint. The key secondary histological endpoint is defined as ≥2-point improvement in histological activity index (HAI) and no worsening of fibrosis by Ishak score. Blinded baseline and Week 48 paired liver biopsies were read by a single, central reader. Additional secondary endpoints were included in the post-treatment follow up period. An independent data safety monitoring board reviews the safety data from D-LIVR throughout the conduct of the trial, including during the post-treatment follow-up phase. With 407 patients enrolled across 116 clinical trial sites in 22 countries, D-LIVR is a landmark study generating the single largest source of HDV patient data from a well-controlled clinical trial to better understand and characterize this devastating disease. About Hepatitis Delta Virus (HDV) HDV is the most severe form of human viral hepatitis, occurring only as a co-infection in individuals infected with hepatitis B virus (HBV). HDV leads to more severe liver disease than HBV alone and is associated with accelerated liver fibrosis, liver cancer, and liver failure. It is estimated that 60% of HDV infected patients die within ten years. Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not affect HBsAg and have no impact on HDV. HDV is a disease with a significant impact on global health, which may affect up to 15-20 million people worldwide. Globally, HDV infection is reported to be present in approximately 4% to 6% of patients with chronic HBV. About Lonafarnib Lonafarnib is a well-characterized, first-in-class, oral prenylation inhibitor which inhibits a host enzyme, blocking a critical step in HDV viral assembly. Lonafarnib has been dosed in over 450 chronically infected HDV patients across global clinical sites, including the Phase 3 D-LIVR study. Lonafarnib was previously approved by the FDA and in Europe under the trade name Zokinvy® for the treatment of progeria (Hutchinson-Gilford progeria syndrome and progeroid laminopathies). Lonafarnib is not FDA-approved for the treatment of patients with chronic HDV. Lonafarnib has been granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), Fast Track designation and Breakthrough designation by FDA and PRIME designation by EMA. Eiger licensed exclusive worldwide rights to lonafarnib from Merck, known as MSD outside of the U.S and Canada. About Eiger Eiger is a commercial-stage biopharmaceutical company focused on the development of innovative therapies for HDV and other serious rare diseases. The Eiger HDV platform includes two first-in-class therapies in Phase 3 that target critical host processes involved in viral replication. All five Eiger rare disease programs have been granted FDA Breakthrough Therapy designation. For additional information about Eiger and its clinical programs, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts, including statements regarding our future financial condition, timing for and outcomes of clinical results, prospective products, preclinical and clinical pipelines, regulatory objectives, business strategy and plans and objectives for future operations, are forward-looking statements. Forward-looking statements are our current statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the timing of our ongoing and planned clinical development; the timing of additional analyses from our Phase 3 D-LIVR study, including virologic, biochemical, and composite responses at Week 72 (24-weeks post-treatment) and histologic improvement; the potential benefits of lonafarnib-based treatments for patients with hepatitis delta virus (HDV), including the potential response rate of lonafarnib boosted with ritonavir in combination with peginterferon alfa; the ability to submit an application for, and obtain marketing approval from, FDA or any other regulatory body for lonafarnib-based treatments for the treatment of HDV; and the potential for success of any of our products or product candidates. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Eiger makes, including additional applicable risks and uncertainties described in the "Risk Factors" sections in the Quarterly Report on Form 10-Q for the quarter ended September 30, 2022 and Eiger's subsequent filings with the SEC. The forward-looking statements contained in this press release are based on information currently available to Eiger and speak only as of the date on which they are made. Eiger does not undertake and specifically disclaims any obligation to update any forward-looking statements, whether as a result of any new information, future events, changed circumstances or otherwise. Contacts Investors: Sylvia Wheeler Wheelhouse Life Science Advisors swheeler@wheelhouselsa.com Media: Sarah Mathieson SVP, Corporate Affairs smathieson@eigerbio.com Company Codes: NASDAQ-NMS:EIGR