 |
|
|
| |
Biotron study of lead Hepatitis C drug shows virus undetectable in patients after three months: 'First-in-class, new mode of action drug, Novel p7 inhibitor with the potential to increase the potency of current anti-HCV therapy' - 'BIT225 is a novel antiviral compound that inhibits the viroporin function of HIV-1 Vpu and HCV p7.....and a potentially useful agent to target cellular viral reservoirs'
|
| |
| |
"Robert Murphy, Professor of Medicine at Northwestern University Feinberg School of Medicine in Chicago, commented: "The results from this study provide good evidence that this novel approach to treating HCV infection has significant antiviral activity compared to the standard of care interferon plus ribavirin. Tolerability was reasonable with only one person dropping out of the study because of intolerability."
"HIV Vpu Inhibitor: BIT225 represents a new, first-in-class drug for treatment of HIV. It is a novel, oral small molecule inhibitor of HIV-1 Vpu and specifically targets HIV in the monocyte-macrophage reservoir, which is currently not targeted with existing therapies. Vpu is a well conserved protein that forms a virus ion channel and is involved in the assembly and release of infectious viral particles."
"BIT225 (N-[5-(1-methyl-1H-pyrazol-4-yl)-napthal ene-2-carbonyl]-guanidine:CASNo. 917909-71-8) is a novel small molecule inhibitor of HIV-1 Vpu viroporin function. In addition to its activity against Vpu, BIT225 also abrogates the viroporin function of hepatitis C virus (HCV) protein p7 [44], [45]. Further, BIT225 displays a synergistic effect in HCV infections with interferon α2b (IFNα2b) in vitro [44], which also stimulates tetherin expression as part of the interferon-induced antiviral state [23], [32]. In monocyte-derived macrophages (MDMs), which express high levels of endogenous tetherin and which represent a long-lived virus producing reservoir in HIV-1 infection, BIT225 efficiently blocks HIV-1 virus release and reduces the infectivity of released virus [45], [46]. Tetherin also inhibits the release of ∇vpu virus and renders released virus less infectious [15], [16], [32]. Interestingly, BIT225 exerts higher antiviral efficacy in MDMs than in CD4+ T-cells, even though the latter express lower endogenous tetherin levels [45].
Therefore, we have now investigated whether the antiviral activity of BIT225 might be partly related to inhibition of Vpu-mediated tetherin-antagonism in tetherin expressing CD4+ T-cell lines. However, we were not able to detect a tetherin-mediated impact on BIT225 function, which suggests that BIT225 specifically blocks Vpu viroporin function. These data also support the concept that viroporin function and virus release are separable functions of the Vpu transmembrane domain [42], and that the viroporin function of Vpu may be cell type specific [45]."
The HIV-1 Vpu Viroporin Inhibitor BIT225 Does Not Affect Vpu ...Published: November 14, 2011
www.plosone.org/.../info%3Adoi%2F10.1371%2Fjournal.pone.0027...
by BD Kuhl - 2011
BIT225 is a small molecule inhibitor that specifically targets the Vpu viroporin
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0027660
The Antiviral Efficacy of the Novel Compound BIT225 Against HIV-1 ...
aac.asm.org/cgi/content/abstract/AAC.01308-09v1
by G Khoury - 2009
Dec 7, 2009 - Our lead compound BIT225 blocks Vpu ion channel activity and also shows anti-HIV-1 activity with an EC50 = 2.25 ±0.23 μM with minimal in
---------------------------------
HCV at HepDART study results
Wednesday, December 07, 2011
Biotron (ASX: BIT) has revealed positive results from a phase 2a trial of its lead Hepatitis C drug candidate, BIT225, that show 87% of patients receiving the drug had an undetectable virus after three months of treatment.
BIT225 targets the viral protein p7, which plays a crucial role in virus replication and reproduction. It is a new target, and BIT225 is a first-in-class direct acting antiviral.
The 28 day study treated patients with a combination of BIT225 and current approved standard of care therapies interferon alfa-2b plus ribavirin.
Patients continued on with standard of care for a further 44 weeks, with follow-up visits at two and three months as well as at 48 weeks.
BIOTRON ANNOUNCES POSITIVE THREE MONTH DATA FOR BIT225 - 87% VIRUS FREE
· Phase 2a trial data presented at international conference
· 87% of HCV trial patients receiving BIT225 have undetectable virus at the three month time point
Sydney, Australia 7 December 2011: Sydney drug development company Biotron Limited (ASX: BIT) has presented data from its phase 2a trial of lead Hepatitis C drug candidate, BIT225, at the international HepDART conference, validating the previously released positive interim results, and providing evidence of improved benefit out to three months.
The trial's Principal Investigator, Dr Tawesak Tenwandee from Siriraj Hospital, Bangkok, Thailand, presented data from the 28 day study of Biotron's BIT225 used in combination with current approved standard of care (SOC) therapies interferon alfa-2b plus ribavirin. Patients then continued on with SOC for a further 44 weeks, with follow-up visits at two and three month time points as well as at 48 weeks.
Biotron presented data showing that 87% of trial subjects who had received BIT225 achieved a complete early viral response (EVR), defined as virus levels in the blood below the level of detection (<50 IU/ml at 12 weeks). This was compared to 63% of patients who received SOC alone.
Previously announced headline data from the four week time point (i.e. at the conclusion of treatment with BIT225) was also presented. At that time point, patients who had received BIT225 had significantly less virus that those who had received SOC alone, with an average of ~90% less virus (~1 log reduction) in the cohort receiving 400 mg of BIT225. The effect of BIT225 was dose-dependent, with patients receiving 200 mg of BIT225 showing a smaller effect on virus levels at the conclusion of dosing than those receiving the higher dose.
The three month data demonstrates that BIT225 continued to provide additional benefit to patients after the conclusion of dosing.
Biotron CEO Dr Michelle Miller said these results extended the previously released headline results and further validated plans to progress the HCV program.
"These results are impressive. To have close to 90% of patients achieving a complete EVR after three months is extremely encouraging and demonstrates the clinical benefit of BIT225," she said.
"We have now established that BIT225 significantly increases the response to the current approved anti-HCV treatment, with improved outcomes for those patients infected with HCV genotype 1, the most common form of Hepatitis C and the most difficult variant to treat."
It was also demonstrated that BIT225 was generally well tolerated. The SOC treatment is known to be associated with a range of significant side effects. The most common side effect that is possibly associated with BIT225 was nausea during the first week of the study. This may be formulation-related, and expected to be overcome with further formulation development.
Biotron's BIT225 targets the viral protein p7, which has crucial roles in virus replication and reproduction. It is a new target, and BIT225 is a first-in-class direct acting antiviral.
As well as being synergistic with current approved SOC HCV treatments, preclinical studies have demonstrated that BIT225 also works well in vitro with some polymerase inhibitors, another new drug class that is in clinical development.
BIT225 is also in development for treatment of HIV, with a Phase 1b/2a trial currently in progress. BIT225 offers a unique opportunity for potential use in the HIV/HCV co-infected population.
Biotron Limited (Biotron) is leading the way in the development of revolutionary new treatments for serious viral diseases such as HIV and Hepatitis C virus (HCV). Biotron has an impressive pipeline of clinical programs developing first-in-class antiviral drugs.
Biotron's lead drug, BIT225, is a viroporin inhibitor in development for treatment of HCV and HIV infections. The drug has successfully passed through three human trials, with the successful recent completion of a Phase 2a trial of BIT225 in HCV-infected patients in combination with the current approved treatment (Interferon and Ribavirin). A Phase Ib/2a HIV trial is currently in progress and anticipated to conclude in early 2012.
----------------------------------
Positive Results from Biotron's BIT225 Phase 2a Trial on HCV
Published on October 11, 2011
Australian drug development company Biotron Limited (ASX:BIT) has released headline results from its landmark Phase 2a trial of its lead drug candidate, BIT225 in Hepatitis C virus (HCV) infected patients.
Preliminary analysis of trial data confirms that BIT225, an orally administered, small molecule drug, has good antiviral activity against HCV. Patients receiving BIT225 in combination with interferon and ribavirin (the current standard of care for treating HCV) had greater reductions in HCV levels than patients receiving standard of care treatment alone.
Patients receiving the 400 mg dose of BIT225 showed the greatest levels of virus reduction, with an improvement of ~1 log (a measure of the amount of reduction of the virus in the blood of patients) over standard of care treatment at the completion of the dosing phase with BIT225. This is a significant improvement over and above the standard of care treatment in this patient group.
Twenty four patients who had passed a stringent screening process were randomly assigned to receive either 400 mg or 200 mg BIT225, or placebo (ratio of 1:1:1), for the first 28 days of their standard treatment with interferon and ribavirin. The trial was undertaken at the Siriraj Hospital, Bangkok, Thailand. All patients were infected with genotype 1 HCV, which is the most common type of HCV and the most resistant to current treatment.
Since the completion of the clinical phase of dosing with BIT225 in August, samples have been analysed and the resultant data has been subject to preliminary review by the independent Data Safety Monitoring Committee.
The Company's Managing Director, Dr Michelle Miller, commented: "This highly encouraging result is the culmination of 10 years of research and development of Biotron's antiviral program. The trial has shown that BIT225 has good activity against HCV, and validates Biotron's approach to treatment of this virus."
BIT225's antiviral activity in this human trial supports the previously reported highly synergistic activity with interferon and ribavirin that was seen in cell culture models of HCV infection.
P7 Inhibitor
Biotron's HCV program is focused on developing drugs to target the HCV p7 protein. HCV p7 is highly conserved and present in all 6 clades, with a critical role in virus assembly and release, and is a potential new target for therapeutic intervention. BIT225 is a novel small molecule viral assembly inhibitor that targets p7 and is in development for treatment of chronic HCV infection.
Preclinical data
· Identified as "hit" in HCV p7 bacterial assay
· Inhibits p7 (HCV 1a) ion channel in planar lipid bilayers
· Inhibits infectious clone JFH1 (HCV 2a)
· Also inhibits HCV model viruses GBV-B & BVDV
· Synergy with IFN, IFN/ribavirin, and polymerase inhibitors in BVDV in vitro
· High barrier to antiviral resistance in vitro
· Good preclinical safety and toxicology data
· Phase 1b data showed antiviral efficacy against genotype 1-3
· Viral assembly inhibitor with antiviral kinetics that suggest efficacy increases with treatment duration
Clinical data
Phase 1a safety trial (BIT225-001) in healthy volunteers was completed in late 2007.
Phase 1b, repeat-dose monotherapy study (BIT225-003) in HCV-infected patients was completed in late 2009. The results demonstrated that BIT225 showed antiviral efficacy against genotype 1-3, significantly reducing viral loads compared to placebo, and that the drug was well tolerated. The antiviral kinetics suggested that efficacy increased with treatment duration.
Phase 2a, 28-day, repeat-dose, combination trial (BIT225-005) of BIT225 with standard of care (pegylated interferon and ribavirin) in treatment-naive, genotype 1 HCV-infected patients commenced in Sept 2010, and concluded in August 2011. Preliminary headline results were released in October 2011, and demonstrated that BIT225 is able to significantly reduce viral loads over and above that seen with standard of care. Data from the trial is anticipated to be presented at the HepDART conference in December 2011.
Advantages
BIT225 has the following advantages:
· First-in-class, new mode of action drug
· Novel p7 inhibitor with the potential to increase the potency of current anti-HCV therapy
· Highly synergistic with ribavirin and rIFNa-2b
· Potential for use in HCV and HIV-1 co-infected patients.
---------------------------------------
Background
Current antiretroviral therapy (ART) results in rapid suppression of viral load and improves the health and lifespan of the individual. However, ART does not cure HIV infection and chronic therapy requires surveillance for drug side effects and drug-resistant virus. The majority of drugs approved or in clinical development for HIV seek to improve on the potency and/or safety of these same drug classes and antiviral resistance; however, over time the emergence and dominance of drug-resistant viruses to these drug classes increases.
Biotron is developing a new class of drug that attacks virus in cellular reservoirs that are poorly penetrated by ART. This approach aims to utilise the potency of current ART regiments that inhibit viral replication primarily in T cells and combine it with a novel inhibitor that reduces viral replication in cells of the monocyte-macrophage lineage. The aim is to reduce HIV-1 replication in a cellular reservoir that can act as a factory of virus production and potentially eliminate the vault of drug-resistant virus that infects these cells over the course of the HIV-1 infection.
Vpu Inhibitor
BIT225 represents a new, first-in-class drug for treatment of HIV. It is a novel, oral small molecule inhibitor of HIV-1 Vpu and specifically targets HIV in the monocyte-macrophage reservoir, which is currently not targeted with existing therapies. Vpu is a well conserved protein that forms a virus ion channel and is involved in the assembly and release of infectious viral particles.
Preclinical data
BIT225 is a late-acting drug, interfering with production and release of productive, infectious virus, and preventing transmission of virus to uninfected CD4 T cells. It is active against multiple-drug resistant strains of HIV in vitro and synergistic or additive with current several current HIV drugs. Biotron has developed a transfer assay, which quantitates HIV transfer from the infected macrophage compartment to CD4 T cells; we have demonstrated that BIT225 can significantly reduce both the virus spread within the monocyte/macrophage compartment and the transfer of virus to CD4 T cells. Additionally, we have demonstrated that BIT225 can prevent transfer of HIV from endogenously infected monocyte cells isolated from HIV+ patients.
Clinical data
Phase 1b/2a trial (BIT225-004) is currently in progress. This trial is a placebo-controlled, randomized study of the safety, pharmacokinetics (PK) and antiviral activity of BIT225 in treatment-naive patients with high HIV viral loads. The primary objective is to assess the safety and tolerability of BIT225, given twice daily, for 10 consecutive days. The secondary objectives are to assess the PK and antiviral efficacy of BIT225 in these patients. The trial is expected to conclude early in 2012.
Advantages
BIT225 has the following advantages:
· New mode of action drug
· Novel Vpu inhibitor with the potential to eliminate one of the major reservoirs of HIV in the body
· Active against multiple-drug resistant strains of HIV
· Potential for use in HCV and HIV-1 co-infected patients
|
| |
|
|
|
|
|
