Triple Therapy


Tibotec Pharmaceuticals , one of the Janssen Pharmaceutical Companies

PILLAR Phase 2b Study-TMC435/ Peginterferon alpha-2a/ribavirin

PILLAR, a phase 2b study of the investigational hepatitis C virus (HCV) NS3/4A protease inhibitor TMC435 in treatment-naive patients with chronic genotype 1 HCV.

-- Data show high rates of virologic response and shortened treatment duration; safety and tolerability comparable to placebo --

The goal of HCV treatment is to achieve SVR24, which means the virus is undetectable in patients’ blood six months after they have finished treatment. Patients who achieve SVR are considered cured.

Excerpt From Medpage
The researchers enrolled 386 patients with the difficult-to-treat genotype 1 of hepatitis C and randomly assigned them to placebo or one of two doses of TMC435: 75 or 150 mg daily.

All patients were also given standard therapy with pegylated interferon-alfa and ribavirin for at least the first 24 weeks of the study. Depending on response, some patients in the treatment arms stopped the treatment or were given an additional 24 weeks. Patients in the control arm had 48 weeks of interferon and ribavirin.

Within each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug.

In an intention-to-treat analysis, the researchers found:

• 82% of patients in the 12-week, 75-mg arm had undetectable hepatitis C RNA after 24 weeks.
• In the 150-mg dosing group, 81% in the 12-week arm and 86% in the 24-week arm reached the same endpoint.
• The differences from placebo were significant at P less then 0.005, P=0.013, and P less then 0.001, respectively.

Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said.

A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24.

Side Effects
The most common adverse events (AEs) in the PILLAR study were headache and fatigue, 46 percent and 42 percent in the TMC435 groups and 51 percent and 47 percent in the placebo group respectively. There were no clinically significant differences in frequency of rash, anemia or gastrointestinal events between the TMC435 groups and placebo. Most AEs were mild to moderate in severity. AEs leading to treatment discontinuation of TMC435/placebo were reported in 7.1 percent of patients in TMC435 arms and 7.8 percent in placebo arm.

TMC435 has received “Fast Track” designation by the U.S. Food and Drug Administration (“FDA”) for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435’s potential to address unmet medical needs in the treatment of chronic HCV infection. TMC435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing.

For additional information from these studies, please see www.medivir.com and www.clinicaltrials.gov

NATAP-View Slides
TMC435 in Combination with Peginterferon and Ribavirin in Treatment-naïve HCV Genotype 1 Patients: Final Analysis of the PILLAR Phase IIb Study (TMC435-C205) -

View Press Release

Bristol-Myers Squibb Daclatasvir (BMS-790052) peginterferon alfa/ribavirin in naive, genotype 1 and 4

COMMAND-1 Phase IIb clinical trial - In this study 395 treatment-naive, genotype 1 and 4 hepatitis C infected patients in which two doses of the investigational NS5A replication complex inhibitor daclatasvir (BMS-790052), in combination with peginterferon alfa and ribavirin (alfa/RBV), achieved higher virologic response rates through Week 12 than the alfa/RBV control group, with comparable rates of adverse events.

This randomized, double-blind, placebo-controlled phase IIb study is designed to evaluate the efficacy and safety of two doses of daclatasvir in combination with weekly peginterferon-alfa-2a and ribavirin in treatment-naive patients with HCV genotypes 1 and 4, compared with alfa/RBV and placebo. The study enrolled a total of 395 patients -- 365 with HCV genotype 1 and 30 with HCV genotype 4. Patients were randomized 2:2:1 to receive daclatasvir 20 mg once daily (n=159), daclatasvir 60 mg once daily (n=158) or placebo (n=78) with length of therapy dependent on treatment response. The primary efficacy endpoints of the study are the proportion of genotype 1 patients with undetectable viral load at Weeks 4 and 12 (extended rapid virologic response, or eRVR) and the proportion of genotype 1 patients with undetectable viral load at 24 weeks post-treatment (sustained virologic response, or SVR24). The primary safety endpoint of the study is the frequency of serious adverse events and study discontinuations due to adverse events at Weeks 12 and 24 on treatment and 12 weeks post-treatment.

Interim results - Genotype 1
Of the 365 patients with HCV genotype 1 in the study, 54% in each of the daclatasvir dose groups (20 mg and 60 mg) achieved eRVR vs. 14% in the control group.

The proportion of HCV genotype 1 patients with undetectable viral load at Week 12 was 78% (115/147) and 75% (110/146) in the daclatasvir 20 mg and 60 mg groups, respectively, compared with 43% (31/72) in the control group

Interim results - Genotype 4
Of the 30 patients with HCV genotype 4, undetectable viral load at Week 12 was achieved in 58% (7/12) and 100% (12/12) of patients in the daclatasvir 20 mg and 60 mg groups, respectively, compared with 50% (3/6) of patients in the control group.

Side effects
One death was reported in the daclatasvir 20 mg group and was determined by the study investigator to be unrelated to treatment.

Discontinuations due to adverse events were similar across the daclatasvir regimens and alfa/RBV control group, with 3.8% (6/159) of patients in the daclatasvir 20 mg group, 5.1% (8/158) in the daclatasvir 60 mg group and 7.7% (6/78) in the control group discontinuing treatment. Serious adverse events occurred in 7.5% (12/159) and 7.6% (12/158) of patients in the daclatasvir 20 mg and 60 mg groups, respectively, and in 6.4% (5/78) of patients in the control group.

The most commonly reported AEs across all groups were fatigue (daclatasvir 20 mg:55%)(daclatasvir 60 mg:53%)(control:59%) and headache (daclatasvir 20 mg:42%)(daclatasvir 60 mg:41%)(control:44%). Among commonly reported AEs, a greater-than or equal to 10% difference between either dose daclatasvir and placebo was observed with nausea (daclatasvir 20 mg:35%)(daclatasvir 60 mg:33%)(control:23%) and dry skin (daclatasvir 20 mg:29%)(daclatasvir 60 mg:25%)(control:19%).

Anemia is a recognized adverse event associated with alfa/RBV treatment of HCV. Erythropoietin was administered to 5.0% (8/159) and 7.0% (11/158) of patients in the daclatasvir 20 mg and 60 mg groups, respectively, and to 3.8% (3/78) of patients in the control group. The use of filgrastim in the study groups was: daclatasvir 20 mg: 1.3% (2/159), daclatasvir 60 mg: 3.2% (5/158), and control: 0% (0/78).
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InterMune / Genentech-Danoprevir(RG7227)- PEG IFN alfa-2a/RBV naïve genotype 1

ATLAS Study

Danoprevir Helps Treatment-Naïve Patients With HCV Achieve Sustained Virologic Response: Presented at AASLD

By Bob Roehr

SAN FRANCISCO -- November 8, 2011 -- Final safety and efficacy data from the ATLAS study of danoprevir shows promising efficacy but also potential concerns for toxicity and resistance, researchers said here November 7 at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

ATLAS was a dose-ranging study of the NS3/4A protease inhibitor danoprevir when added to a background regimen of pegylated interferon alfa-2a and ribavirin (PEG IFN alfa-2a/RBV) in treatment-naïve, noncirrhotic patients with hepatitis C virus (HCV) genotype 1.

Patients were randomised to receive danoprevir 300 mg every 8 hours, danoprevir 600 mg every 12 hours, danoprevir 900 mg every 12 hours, or placebo for 12 weeks.

All patients were continued on PEG IFN/RBV for an additional 12 weeks. Patients who did not achieve an early rapid virologic response (eRVR) and undetectable viral load (HCV RNA less then 15 IU/mL) between weeks 4 and 20 continued to receive PEG IFN alfa-2a/RBV through week 48.

The highest dose arm of the study (danoprevir 900 mg) "was discontinued prematurely due to the development of ALT [alanine aminotransferase] elevations [grade 4] early in the course of the study," said Norah A. Terrault, MD, University of California at San Francisco, San Francisco, California. The elevations resolved upon discontinuation.

Patients who had started on danoprevir 900 mg were continued on PEG IFN alfa-2a/RBV, while those who had been randomised to it but not yet started were rerandomised to the remaining arms of the study.

"Among those patients receiving danoprevir who had an extended RVR, the sustained virologic response rates were 87% to 96%," said Dr. Terrault. The highest rate of response was seen in the 600-mg arm, in part because only a portion of the higher dose group completed the full 12-week regimen prior to that dosage being discontinued.

Overall response rates, as measured by undetectable HCV RNA, were high across all IL28B genotypes: 81% to 95% in those with the CC allele, 63% to 79% in the non-CC alleles. Response was better in patients with HCV genotype 1b (67%-93%) compared with genotype 1a (57%-79%).

Three patients had resistance mutations to danoprevir (D168E, R155R/K, or D168D/E) at baseline measurement. "All 3 of these patients responded to therapy, and 2 of these patients achieved SVR," said Dr. Terrault.

 "Viral resistance-related breakthrough and partial response occurred in 8 patients or 4%; 5 in the 300 mg dose group and 3 in the 600-mg group. All of them were genotype 1a and all had the R155R/K mutation."

Viral breakthrough during the PEG IFN alfa-2a/RBV phase of the regimen occurred in 5 out of 140 patients (3.6%) who completed 12 weeks of danoprevir. They were associated with the same genotype and point mutation seen with the earlier examples of breakthrough.

Viral relapse was seen in 12 of 172 patients (12%) on danoprevir who had achieved undetectable HCV RNA by end of treatment.

Dr. Terrault said follow-up studies are using lower doses of danoprevir with ritonavir as a boosting agent to improve pharmacokinetics and reduce toxicity.

[Presentation title: High Sustained Virologic Response (SVR24) Rates With Response-Guided Danoprevir (DNV; RG7227) Plus PegIFN alfa-2a (40KD) and Ribavirin (P/R) in Treatment-Naive HCV Genotype 1 (G1) Patients: Results From the ATLAS Study. Abstract 79]

View All Data/Slides @ NATAP
High sustained virologic response (SVR24) rates with response-guided danoprevir (DNV; RG7227) plus PegIFN alfa-2a (40KD) and ribavirin (P/R) in treatment-naive HCV genotype 1 (G1) patients: results from the ATLAS study -

Achillion Pharmaceuticals -ACH-1625/peginterferon alfa-2a/ribavirin
ACH-1625, is a once-daily NS3 protease inhibitor

High Rapid Virologic Response(RVR) with ACH-1625 Daily Dosing plus PegIFN-alpha 2a/RBV in a 28-day Phase 2a Trial

Study Design In this first of a two segment Phase 2a trial, a total of 64 patients were enrolled and randomized across three doses of ACH-1625 given once daily (200mg, 400mg or 800mg) or placebo with peginterferon alfa-2a and ribavirin, and were dosed for 4 weeks of therapy. Patients then continue on SOC for up to an additional 44 weeks. Subjects were randomized and stratified by HCV genotype and IL28B genotype.

Interim results
The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient's diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:

Week 4 RVR Subjects with HCV RNA Less Then 25 IU/mL

ACH-1625
200 mg QD N=16 - 13/16 (81%)
400 mg QD N=16 - 12/16 (75%)
800 mg QD N=17 - 13/17 (76%)
Placebo . N=15 - 3/15 (20%)

Mean maximum HCV RNA decline through Week 4 (log10)
ACH-1625

200 mg QD N=16 - 13/16 4.90
400 mg QD N=16 - 12/16 4.63
800 mg QD N=17 - 13/17 4.96
Placebo . N=15 - 3/15 2.25

Genotype 1 treatment-naïve patients demonstrated that the number of patients who achieved an RVR (4-week HCV RNA undetectable) was 55 to 61% higher in the groups that received ACH-1625 compared to placebo.

Side Effects
The most commonly reported AEs in patients receiving ACH-1625 were headache, fatigue, nausea, and pain (general), were mild or moderate and were transient.

Safety results from a planned safety analysis included 56 patients from this segment of the trial and indicated that adverse events (AEs) were similar to those observed in the previously reported Phase 1a and 1b trials of ACH-1625. Over 4 weeks of co-administration of ACH-1625 with SOC, there were no discontinuations due to adverse events and there were no serious adverse events (SAEs) reported. Most reported AEs in patients receiving ACH-1625 were classified as mild to moderate and were transient. The most common AEs were consistent with peginterferon alfa-2a and ribavirin.

A phase 2 trial with 12 weeks of ACH-1625 with PegIFN-alpha 2a/RBV is ongoing.

View All Data/Slides @ NATAP
HIGH RAPID VIROLOGIC RESPONSE (RVR) WITH ACH-1625 DAILY DOSING PLUS PEGIFN- ALPHA 2A/RBV IN A 28-DAY PHASE 2A TRIAL -


Pharmasset- PSI-7977  pegylated interferon/ribavirin In Naive Genotype 1 Patients

PSI-7977 plus interferon/ribavirin shows "a rapid and complete suppression in 95% of patients," said PROTON lead investigator Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas. Excerpt From Medscape

PSI-7977, a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food, has previously shown activity in a broad range of HCV patient genotypes. There have been no drug-related viral breakthroughs reported to date, demonstrating a high barrier to resistance.

PROTON phase 2 study

PROTON was a double-blind placebo-controlled dose-ranging phase 2 study that enrolled 121 treatment-naïve patients with HCV genotype 1. Participants were 18 years or older, with an HCV RNA level of at least 50,000 IU/mL, a platelet count above 90,000/mm3, a hemoglobin level of at least 11 g/dL, and no evidence of cirrhosis.

Subjects were randomized in a 2:2:1 ratio to 1 of 3 treatment groups: 12 weeks of interferon/ribavirin plus PSI-7977 200 mg, PSI-7977 400 mg, or placebo. All patients then received 12 weeks of interferon/ribavirin, and those who had still not achieved a rapid viral response received another 24 weeks of interferon/ribavirin.

"Duration of therapy was response-guided," said Dr. Lawitz. "Those who achieved rapid viral response discontinued therapy at 24 weeks, and those who did not continued for a total of 48 weeks." The control group consisted of the interferon/ribavirin standard combination for 48 weeks.

At baseline, median age was 51 years, 15% self-identified as black and 10% as Hispanic, median HCV load was 6.6 log IU/mL, median body mass index was 28 kg/m2, roughly 95% had mild fibrosis (F0 to F2), and 41% of the cohort had the IL28B C/C genotype.

Results showed a dramatic improvement with the triple drug combination, compared with placebo.

"The rapid viral response for the 200 mg dose was 98%, with an end-of- treatment response at 24 weeks of 91%," reported Dr. Lawitz. The same response rate was seen with the 400 mg dose. In the placebo group, the rapid viral response was 19%, and end-of-treatment response was 50%. The reported sustained viral response at 12 weeks was 88% for the 200 mg group, 91% for the 400 mg group, and roughly 40% for the placebo group (an estimate because observation is ongoing).

Significantly, a subanalysis of patients with the difficult-to-treat IL28B T/T mutation (n = 13) showed that "all had a rapid response and all became HCV-negative by week 3," said Dr. Lawitz.

These cohorts went on to achieve a 100% sustained viral response.

There were several failures reported. In the 200 mg group, 3 patients experienced viral breakthrough during the 12 weeks of interferon/ribavirin treatment immediately after the discontinuation of PSI-7977, and 1 patient relapsed at the end of treatment. "In contrast, in the 400 mg arm, there were no breakthroughs, suggesting that the 400 mg dose achieved a deeper viral suppression," said Dr. Lawitz. "There was 1 failure prior to [a sustained viral response at 4 weeks], but this was not due to any S282T resistance mutation."

The adverse events reported in the PROTON trial were typical of those seen with interferon/ribavirin treatment, with the single exception of a modest increase in the incidence of insomnia in the PSI-7977 treatment groups. No serious hematologic events were reported, and no dose-related changes in event rates were observed.

Optimism for the Novel Drug, With Caveats

"Part of the problem of working with a new product is all the unanswered questions due to the size of early trials," said Mauricio Lisker-Melman, MD, director of the hepatology program at the University of Washington, St. Louis, Missouri. What are the potential adverse effects of this medication that will only emerge with a larger dataset? How do these data translate into the community setting?

"There is a significant group of patients in my practice who have cirrhosis that may be more prone to develop some of the side effects," said Dr. Lisker-Melman, noting that patients with cirrhosis were excluded from PROTON.

"We should be very careful, especially when we analyze effects on the bone marrow — anemia, thrombocytopenia, and other complications related to these new targeted inhibitors," Dr. Lisker-Melman cautioned. "That's why analyzing different subgroups of patients is so important."

Dr. Lisker-Melman is also concerned that the racial make-up of PROTON did not reflect what he and others see in the clinic; responses to HVC medications have been found to vary widely by race.

"Don't get me wrong — it's a great study, a great beginning. The sister study, ELECTRON, just presented here, suggested that we can even be successful without the use of interferon. That offers a lot of hope," he said.

With these data and the results from other drugs in development for HCV infection, Dr. Lisker-Melman predicts that an interferon-free HCV regimen is less than 5 years away.

View Slides/Data @NATAP
PROTON: PSI-7977 & Peg/RBV in Treatment-naïve Patients with HCV GT1: Sustained Virologic Response -


Boehringer Ingelheim -BI 201335,pegylated interferon/ribavirin in treatment-naïve genotype-1

SILEN-C3
Data from the SILEN-C3 study showed the potential for BI 201335 to shorten patients’ treatment duration to 12 weeks and improve the likelihood of viral cure (sustained viral response; SVR) compared to the former traditional standard of care – 48 weeks of treatment with PegIFN/RBV alone.1,3 Furthermore, the SILEN-C1 study demonstrated the ability for BI 201335 to improve SVR in traditionally difficult to treat populations

The results from SILEN-C3 indicate that among patients achieving an extended rapid viral response (eRVR), 12 weeks of treatment with BI 201335 was sufficient to achieve SVR. Patients with undetectable HCV RNA in the blood prior to week 12 had similar SVR rates, whether they were treated for 12 or 24 weeks with BI 201335 (82% and 81%, respectively).1

In addition to the SILEN-C3 study, the overall analysis of the SILEN-C1 study shows that 83.1% of patients treated with BI201335 240 mg QD achieved SVR, compared with 56.3% of patients on PegIFN/RBV alone (p less then 0.0001). The majority of patients with difficult to treat HCV subtypes, such as patients with the viral GT1a or the IL-28B non-CC gene variant (polymorphism), achieved SVR:

• Specifically, among patients with GT1a HCV (n=32), a virus type that is more likely to resist treatment than GT1b, 82% achieved SVR, while for GT1b HCV patients (n=38), 84% achieved SVR
• In addition, SVR was 71% for patients with the non-CC polymorphism of the IL-28B gene (n=29). While patients with the CC polymorphism (n=11) achieved 100% SVR and those where IL-28B genotyping was missing (n=31) achieved 86% SVR. Patients exhibiting the non-CC polymorphism are less likely to achieve SVR with PegIFN/RBV treatment2

GT1 HCV is the most challenging genotype of HCV to treat3 and those carrying the IL-28B non-CC polymorphism are less likely to achieve SVR than those with the CC polymorphism, with some studies showing an almost seven fold difference in treatment response.6

About SILEN-C3:
Treatment for 12 or 24 weeks with BI 201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype-1 HCV infection1

In this open-label Phase II trial, 159 treatment-naïve GT1 HCV patients were randomised to receive 120 mg QD BI 201335 for 12 or 24 weeks, each after three days lead-in (LI) with pegylated interferon and ribavirin (PegIFN/RBV). In both groups, PegIFN/RBV was given for 24 weeks. Patients who did not achieve an eRVR, continued PegIFN/RBV to week 48. eRVR was defined as viral load less than 25 IU/mL at week 4 and undetectable at weeks 8-18.1

SILEN-C1
Results from the SILEN-C1 study in difficult to treat virus types are also encouraging and we are keen to see the outcomes of our BI 201335 Phase III studies in 2013

SILEN-C1 is a double-blind, randomised, placebo-controlled trial, that randomised 429 treatment-naïve GT1 HCV patients (1:1:2:2) to receive either placebo or BI 201335 120 mg with three days Lead-in (LI) of PegIFN/RBV, BI 201335 240 mg QD with three days LI or BI 201335 mg 240mg QD without LI. In each treatment group, BI 201335 was given for 24 weeks together with PegIFN/RBV for 24 or 48 weeks. This presented analysis of SILEN-C1 evaluated SVR according to various baseline characteristics. SVR results from all SILEN-C1 study groups were previously presented at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in April 2011.2
View Press Release

Article Of Interest

Herb Favored by Hep C Patients Has No Medical Benefit: Study

By Rob Goodier
NEW YORK (Reuters Health) Nov 10 - Milk thistle extract, an herbal supplement popular among patients with chronic liver disease, had no benefit for hepatitis C patients, a new study found.

In a randomized multicenter trial, milk thistle-the botanical compound silymarin-did not beat the placebo at improving liver function test results.

"The study was not able to document specific efficacy in hepatitis C virus," said Dr. Henry Bodenheimer, Jr., a hepatologist at the Beth Israel Medical Center in New York City who chaired the study's data safety monitoring committee.

"Milk thistle is also used in many other forms of liver disease, but has not often been systematically studied," Dr. Bodenheimer added in an email to Reuters Health.

Dr. Michael Fried, at the University of North Carolina at Chapel Hill, who led the study, presented the results November 8 at the American Association for the Study of Liver Diseases annual meeting in San Francisco.

Patients take silymarin as an alternative to, or to supplement, conventional HCV therapy, which can be toxic and have a limited effect, Dr. Bodenheimer said.

Accordingly, Dr. Fried's team restricted the study to 154 hepatitis C patients who had not responded to interferon therapies. The patients also had serum alanine aminotransferase (ALT) enzyme levels greater than 65 IU/L, with a median of 106 IU/L. A normal level is 45 IU/L, Dr. Fried's team writes.

The researchers randomly assigned the patients to one of three groups, two of which took high doses of a standardized form of silymarin at 420mg or 700mg three times daily. The third group took a placebo.

The silymarin doses in the study were 4.5-7.5 times higher than customary, the researchers said in their abstract for the meeting. The doses were chosen based on results of an earlier phase I study.

Of the 138 patients who completed the 24-week study, 90% were able to adhere to at least 80% of the pill regimen. In spite of the compliance, however, the mean drop in serum ALT was not significantly different between the three groups. And only two patients in each group met the primary endpoint, either normalization of ALT or a drop of at least 50% from baseline.

Silymarin is a polyphenolic flavenoid that, in vitro, is an antioxidant and anti-inflammatory. Its pharmacokinetics in this study, and its effect on hepatitis C virus RNA, have not yet been reported.

"In my experience, the use of this agent is patient driven rather than being prescribed by physicians," Dr. Bodenheimer said.

Records Show Deaths Associated with Hepatitis C Have Overtaken Deaths Caused by HIV

By examining multiple-cause death records, researchers from the Centers for Disease Control and Prevention have determined that deaths from viral hepatitis are insufficiently appreciated and by 2007 were exceeding reported deaths caused by HIV.Approximately 21. 8 million records were included in the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases on Tuesday, November 8.

Those records were examined for mention of hepatitis B or C and for HIV. For the period of 1999 to 2007, deaths associated with hepatitis B remained constant, HIV declined, and hepatitis C increased –- significantly. Almost three-quarters of HCV-related deaths occurred in the 45-64 year-old age group. HIV was one of the comorbidities associated with viral hepatitis, as were chronic liver disease, other hepatitis virus, and alcohol-related conditions.

Scott Holmberg, MD, the study's presenter at the Liver Meeting® spoke directly to the conclusion of his team's study, which states a change in policy direction to improve detection and access to care for patients with hepatitis is required to decrease mortality associated with hepatitis, "Without reducing allocation of resources that have diminished HIV deaths, we think a commitment to detect and treat chronic HCV will markedly improve the growing wave of disability and death from this under-appreciated viral infection."

Interferon-free treatment regimens


Interferon-free treatment regimens, if successful-could be beneficial for those people with decompensated cirrhosis and for the population of HCV infected individuals who are unable to take interferon and/or ribavirin.

Boehringer Ingelheim- BI 201335 plus BI 207127-with and without ribavirin in genotype 1 naïve patients.
 
Phase IIb study/SOUND-C2-combination of two oral direct acting anti hepatitis C virus compounds (the protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, with and without ribavirin in genotype 1 naïve patients.

Interferon-free combination of BI 201335 plus BI 207127 and ribavirin shows up to 76% of patients achieve a virological response at week 12, and 59% achieve SVR12 with 16 weeks treatment

Interim Results
All five treatment arms of the interferon-free oral combination therapy of BI 201335/BI 207127/RBV showed high virologic response rates through week 12, defined by measuring the level of HCV RNA in patient blood:

• 70–76% of patients who received BI 201335 once daily (QD) + BI 207127 three times daily (TID) or twice daily (BID) with RBV achieved undetectable HCV RNA at week 12, with 13–21% of patients developing a viral load breakthrough during treatment
• 57% of patients who received BI 201335 QD + BI 207127 TID without RBV achieved viral response at week 12
• SVR12, which is considered highly predictive of SVR and cure of the infection, was achieved after 16 weeks of treatment in 59% of patients.

The safety and tolerability profile was comparable to other direct acting antiviral regimens

Five treatment arms
Results of this open-label, randomised, Phase IIb study were presented as a late breaking poster titled, “Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: Week 12 interim results of the SOUND-C2 study,” by Professor Stefan Zeuzem. In the study, 362 treatment-naïve GT1 HCV patients were randomised into five interferon-free treatment groups, each with 120mg BI 201335 once daily but with different dosing of BI 207127 and treatment durations as follows:

• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 16 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 28 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 40 weeks;
• BI 201335 120mg QD + BI 207127 600mg BID + RBV for 28 weeks; or
• BI 201335 120mg QD + BI 207127 600mg TID without RBV for 28 weeks.

View Press Release

View Slides/Data @ NATAP
Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Week 12 interim results of the SOUND-C2 study


Merck MK-5172 second-generation NS3 protease inhibitor Monotherapy-Genotype 1 and 3

MK-5172, a second-generation NS3 protease inhibitor from Merck Sharpe & Dohme, was administered in several doses, by itself (monotherapy), for seven days. MK-5172 was designed to have activity against strains of HCV that are resistant to the first-generation HCV protease inhibitors and against multiple HCV genotypes.

In the study, researchers gave doses ranging from 50 milligrams (mg) to 800mg once daily to 40 men with HCV genotype 1, and doses ranging from 100mg to 800mg in 24 men with HCV genotype 3. In both groups, the drug was compared with placebo.

Anti-HCV activity was quite high. In those with genotype 1, MK-5172 lowered HCV levels by up to 5.39 logs in those taking the 200mg dose. In those with genotype 3, the 600mg dose lowered HCV levels by 5.22 logs. When researchers looked at the percentage of people whose HCV levels became undetectable after only 7 days of dosing, 75% of those with genotype 1 and 38% of those with genotype 3 reached undetectable.

Side Effects
The most common adverse experienced reported were headache, fatigue, nausea, diarrhea and itchiness. There was a trend toward an increase in a liver enzyme called bilirubin.

View Slides/Data @ NATAP
Safety and Antiviral Activity of MK-5172, a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients

MK-5172, a Second Generation HCV NS3/4A Protease Inhibitor is Active Against Common Resistance Associated Variants (RAVs) and Exhibits Cross-Genotype Activity -


Inhibitex- polymerase inhibitor; INX-08189-or INX-189 Naïve Genotype 1

Inhibitex said the mid-stage trial showed INX-189 had potent and dose-dependent antiviral activity and had a median 4.25 log viral load reduction.

"This compares favorably to the 4.5 log drop observed with (Pharmasset's) PSI-7977 in a similar treatment setting," Canaccord's Farmer said.

INX-08189 from Inhibitex, is a different type of DAA than the recently approved drugs Incivek and Victrelis, and MK-5172. It is a nucleotide polymerase inhibitor, which should also have activity against HCV that has become resistant to the first generation of protease inhibitors.

In all, 80 people with HCV genotype 1 were studied on a variety of once-daily doses of INX-08189 or a placebo for seven days. In some of the dosing schemes, INX-08189 or the placebo was combined with ribavirin.

INX-08189 was quite potent against HCV at the highest dose. HCV levels dropped by 4.25 logs by day 8 in those taking the 200mg dose. Drops in HCV in the lower doses did not exceed 2.54 logs. There were also significant drops in alanine aminotransferase (ALT), a key liver enzyme, in those taking the higher doses of the drug.


Side Effects
There were no serious adverse experiences in those taking INX-08189. Milder adverse events included nausea, abdominal pain, diarrhea and nasal congestion.


View Slides/Data @ NATAP
Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Naïve Genotype-1 HCV Patients


Bristol-Myers Squibb-Daclatasvir (BMS-790052) and Asunaprevir (BMS-650032)

Phase II study of Genotype 1b patients who had previously not responded to peginterferon alfa and ribavirin.

About the Study
In this Phase II open-label clinical trial, a sentinel cohort of ten Japanese patients with chronic HCV genotype 1b infection with null response to prior alfa/RBV treatment (HCV RNA less-than or equal to 2 log10 IU/mL at 12 weeks of alfa/RBV therapy) were treated with daclatasvir (BMS-790052) 60 mg once daily and asunaprevir (BMS-650032) initially 600 mg twice daily and reduced to 200 mg twice daily, for 24 weeks. The primary efficacy endpoint was the proportion of patients with undetectable viral load (HCV RNA less then 15 IU/mL) at 12 weeks post-treatment.

Sentinel Cohort Results
90% Sustained Virologic Response (SVR12) in Phase II Study Sentinel Cohort of Genotype 1b Null Responders

Of the 10 patients enrolled in the study, nine completed 24 weeks of treatment. Rapid and persistent viral suppression was observed in all nine patients, with undetectable viral load achieved by week 8 and sustained through the end of the 24 week post-treatment follow-up period. One patient discontinued the study at Week 2. This patient had a low viral load at the time of study discontinuation (1.8 log10 IU/mL) and as reported by the investigator achieved and maintained an undetectable viral load through 24 weeks of follow-up post-discontinuation. Despite the evidence of baseline viral substitutions in some patients, there was no apparent association between those substitutions and response to treatment in this study.

Side Effects
Serious adverse events occurred in two patients. One patient experienced Grade 3 fever (pyrexia) and one patient developed Grade 4 elevated bilirubin levels (hyperbilirubinemia) that led to study discontinuation at week 2. As reported by the investigator, this patient achieved SVR with normalization of laboratory values upon discontinuation.

The most commonly reported on-treatment adverse events occurring in at least three patients were Grade 1 diarrhea (n=7), headache (n=4) and liver enzyme increases (n=3 ALT and AST). Of the liver enzyme increases, two patients experienced transient Grade 1 elevations and one patient had a Grade 2 elevation that began at week 16 of treatment and resolved within two weeks post-treatment.

View Press Release

HIV and Hepatitis-AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders


Novartis DEB025 (alisporivir) Phase II data -monotherapy or with ribavirin in  Naïve genotypes 2 and 3

The clear conclusion from a clinical trial of alisporivir (DEB025, from Swiss drug major Novartis an oral host-targeting cyclophilin inhibitor, is that treatment based on it may be an effective, interferon (IFN)-free alternative for individuals with genotype 2 or 3 

DEB025 (alisporivir) may produce early viral elimination (or clearance) in interferon-free regimens (as monotherapy or with ribavirin), in previously untreated patients infected with the hepatitis C virus (HCV) genotypes 2 and 3.

About the study
An international multicentre, randomized, parallel-group, open-label, multi-dose, exploratory 12-week interim analysis of 334 previously untreated chronic hepatitis C patients with genotypes 2 and 3. It evaluated the efficacy and safety of DEB025 either alone or in combination with ribavirin in terms of negative HCV RNA.

Side Effects
In addition, the study examined the effect of add-on interferon treatment. There was a low incidence of serious adverse events, with rates of adverse events comparable between treatment groups.

A low number of patients experienced a transient increase in bilirubin more than five times the upper limit of normal and all without any signs of liver toxicity.

Markedly lower rates of flu-like symptoms (fatigue, pyrexia, myalgia and arthralgia) were reported for alisporivir-based IFN-free as compared with IFN-containing treatment. For example, fatigue, headache and pyrexia were reported at percent rates of around13, 12 and 3, respectively, in the IFN-free arms and at about 27,27 and 23, respectively, in the add-on IFN arms. Overall, fewer adverse events were reported in the alisporivir arm of the trial.
There were no reports of grade 3&4 anemia. Also, neutropenia, found in 17% of patients in the PR arm, was not observed in the alisporivir-based IFN-free arms. Only two patients discontinued treatment on account of adverse events.

Results
Almost half the patients (49%) in the study on DEB025 plus ribavirin achieved viral clearance (negative HCV RNA) as early as week six[1]. One third of patients (32%) receiving DEB025 alone also achieved viral clearance after six weeks[1]. In addition, 97% of patients with viral clearance who continued to receive interferon-free DEB025 plus ribavirin maintained this viral clearance up to week 12[1]. Achieving an early viral clearance is considered one of the most important predictors of sustained viral response, also known as viral cure. After genotype 1, genotypes 2 and 3 are the second most prevalent forms of HCV worldwide[4].

View Press Release

View Slides/Data @ NATAP
Novartis DEB025 data showed viral clearance as early as six weeks and potential for interferon-free therapy in hepatitis C patients


Pharmasset- PSI-7977 plus ribavirin in naïve genotype 2/3

Medscape
New HCV Drug Achieves 100% Cure Rate Without Interferon

ELECTRON

Excerpt From Medscape;
The aim of the ELECTRON trial was to determine the shortest duration of interferon, if any, required to achieve SVR when PSI-7977 plus ribavirin are administered for 12 weeks

ELECTRON investigators recruited 40 patients who were randomized to 1 of 4 treatment groups: PSI-7977 400 mg plus ribavirin for 12 weeks plus interferon for 0, 4, 8, or 12 weeks.

Patients were treatment-naïve, noncirrhotic, infected with HCV genotype 2 or 3, and stratified by interleukin (IL)28B single-nucleotide polymorphisms (SNP) and HCV RNA levels. Mean age was 47 years and mean baseline HCV RNA was 6.49 log10 IU/mL, with 42.5% exhibiting the CC genotype at the IL28B SNP.

"We selected a genotype 2/3 population because this represents a population that would be more easily rescued with interferon in the event of virologic breakthrough," Dr. Gane explained.

Results after treatment initiation were dramatic. "All patients achieved a rapid virologic response, with over 80% being nondetectable at 2 weeks," reported Dr. Gane.

All patients had undetectable HCV at 3 weeks; furthermore, all patients achieved end-of-treatment response. No cases of treatment resistance were observed.

"Even following cessation of interferon, or with no interferon, there were no virologic breakthroughs on treatment." Also encouraging was the fact that all patients in the study experienced a rapid normalization of alanine aminotransferase.

There were no serious adverse events, and the mild to moderate events observed were attributed to either interferon or ribavirin. Significant improvements in safety and tolerability were seen in the interferon-free treatment group. No safety signals for PSI-7977 were observed, and there were no treatment-related discontinuations.

Results of the 12-week analysis prompted study investigators to add an exploratory treatment group of open-label PSI-7977 monotherapy for 12 weeks (n = 10). "The response was the same as with combination treatment with ribavirin," said Dr. Gane. Although this study is ongoing, 6 of 10 patients have achieved SVR at 4 weeks.

"These data clearly demonstrate that PSI-7977 exhibits high potency and has a high barrier to resistance," Dr. Gane said, noting that the drug is being advanced in phase 3 investigations in all HCV genotypes.

Too Good to be True?

Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, has doubts about PSI-7977. "If you use it with ribavirin and no interferon, you get a 100% SVR; if you use it alone, you get a 100% SVR."

Dr. Bernstein accepts the efficacy of PSI-7977 for the moment, but is concerned that ELECTRON isn't powered to say much about the tolerability or resistance profiles of the drug.

"What we've found with most of these [polymerase inhibitors] is that if you use them by themselves, you get resistance; if you don't, they can be very difficult to tolerate," said Dr. Bernstein. "There was a drug being investigated at Mount Sinai — a polymerase inhibitor, NM286 — and those patients got severe diarrhea and could not tolerate it. According to the ELECTRON study, everything was perfect — no gastrointestinal issues, no apparent adverse events of any kind, and it worked 100% of the time without interferon, or ribavirin.... If it's true, it will be great. The holy grail is to try to rid HCV treatment regimens of interferon."

Although sincerely impressed, Dr. Bernstein, who has seen many drugs come and go, suspects that as larger phase 3 trials of PSI-7977 are conducted, polymerase-associated adverse events, tolerability issues, and treatment resistance patterns will emerge.

Dr. Gane reports advisory board relationships with Pharmasset, Gilead, Roche, Janssen-Cilag, and Boehringer-Ingelheim. Dr. Bernstein has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 34. Presented November 6, 2011.

View Slides/Data @ NATAP
PSI-7977: ELECTRON Interferon is not required for Sustained Virologic Response in Treatment-Naïve Patients with HCV GT2 or GT3 -

HIV and Hepatitis
PSI-7977 + Ribavirin Cures Hepatitis C in 12 Weeks

Article Of Interest

Protons, Electrons, and Hepatitis C
By Jessica Wapner
The PLoS BLOGS NETWORK
Posted: November 9, 2011

Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).

The Latest Findings
There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.

PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.

After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.

Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.

Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.

The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.

In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.

Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.

Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.

Other New Drugs for Hepatitis C
If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied. These include:

• Second-generation protease inhibitors (telaprevir and boceprevir are protease inhibitors) such as TMC435, danoprevir, GS 9256, BMS 791325, ACH-1625, MK-7009, and BI 201335

• Inhibitors of nonstructural protein 5A, which is involved with viral replication. BMS 790052 is one such compound currently being evaluated

• R7128, another nucleoside polymerase inhibitor (same class as PSI-7977)

• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)

• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.

• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.

HCV and the History of the Human Race
On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm. For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.

But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s. (Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.

Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the CDC’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)

Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.

You see? There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.

There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?

Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.

Source