lomibuvir (VX 222) / Vertex, Trek Therapeutics - LARVOL DELTA

Lomibuvir sensitizes radioiodine-resistant thyroid cancer cell lines to radioiodine treatment by targeting hTERT RNA-dependent polymerase activity. (PubMed, J Endocrinol Invest) - "Consequently, the uptake of radioiodine-131 was significantly enhanced in these RAIR cells. Taken together, our research identifies novel therapeutic targets and provides new insights into the management of RAIR-DTC."

Journal • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • ALDH1A1 • CD133 • CDK1 • MIR146B • POU5F1 • SLC26A4 • SMARCA4 • SOX2 • TERT

Repurposed drugs in combinations exert additive anti-chikungunya virus activity: an in-vitro study. (PubMed, Virol J) - "We explored the effect of different combinations of six effective drugs (2-fluoroadenine, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol) at their non-toxic concentrations against CHIKV under post infection treatment conditions in Vero cells. The results suggest an additive anti-viral effect of these drug combinations against CHIKV. The findings could serve as an outline for the development of an innovative therapeutic approach in the future to treat CHIKV-infected patients."

Journal • Preclinical • Chikungunya • Infectious Disease

Drug repurposing approach against chikungunya virus: an in vitro and in silico study. (PubMed, Front Cell Infect Microbiol) - "The findings showed that nine compounds, viz., temsirolimus, 2-fluoroadenine, doxorubicin, felbinac, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol exhibit anti chikungunya activity. Furthermore, in silico molecular docking studies performed by targeting CHIKV structural and non-structural proteins revealed that these drugs can bind to structural protein targets such as envelope protein, and capsid, and non-structural proteins NSP2, NSP3 and NSP4 (RdRp). Findings from in vitro and in silico studies reveal that these drugs can suppress the infection and replication of CHIKV and further in vivo studies followed by clinical trials are warranted."

Journal • Preclinical • Chikungunya • Infectious Disease

A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2. (PubMed, Viruses) - "Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections."

FDA event • Journal • Preclinical • Dengue Fever • Infectious Disease

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review. (PubMed, Bioorg Chem) - "The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection. (PubMed) - Proc Natl Acad Sci U S A - "From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials."

Journal • Biosimilar • Hepatitis C Virus • Immunology

A study to evaluate the efficacy and safety of quadruple therapy (VX-222, telaprevir, peginterferon-alfa-2a, ribavirin) in subjects with chronic hepatitis C with compensated cirrhosis (clinicaltrials.gov) - P2, N=110 -> 103; Sponsor: Vertex; Active, not recruiting -> Completed; Primary completion date: Oct 2013 -> Jan 2014.

Trial completion • Hepatitis C Virus

VX-222 + telaprevir + ribavirin for 12 or 16 weeks in treatment-naive subjects with genotype 1a hepatitis C (clinicaltrials.gov) - P2, N=64; Sponsor: Vertex; Active, not recruiting -> Completed; Primary completion date: Apr 2013 -> Dec 2013.

Trial completion • Hepatitis C Virus

Highly efficient infectious cell culture of three HCV genotype 2b strains and sensitivity to lead protease, NS5A, and polymerase inhibitors (Hepatology) - PMID: 23913364; "NS5B inhibitors Sofosbuvir, Mericitabine, and BI207127 had activity against 1a (strain TN), 2a...and the 2b strains, whereas VX-222 and Filibuvir only inhibited 1a. Genotype 2b strains were least sensitive to seven lead protease inhibitors, including MK-5172....NS5A inhibitor Daclatasvir was exceptionally potent, but efficacy was affected by the HCV strain."

Preclinical • Hepatitis C Virus

Effect of hepatic impairment on the pharmacokinetics of VX-222: Results from a multicenter phase 1 study (AASLD 2012) - Presentation time: Nov 13, 2012; 8:00 AM - 12:00 PM; P1, N=24; Administration of multiple oral doses of 400 mg of VX-222 were considered safe and well tolerated in subjects with mild and moderate hepatic impairment and in healthy volunteers; The results show that VX-222 exposures were higher in subjects with mild to moderate hepatic impairment, but this increase would not be expected to impact virologic response

P1 data • Hepatitis C Virus

Trek Therapeutics acquires two antiviral inhibitors from Vertex Pharmaceuticals (PRNewswire) - "Trek Therapeutics...today announced that it acquired the worldwide development and commercialization rights to treat infectious disease with lomibuvir (VX-222), a non-nucleoside inhibitor of the HCV NS5B polymerase...Vertex will be eligible to receive milestones and royalties based on successful development and commercialization of lomibuvir..."

Licensing / partnership • Hepatitis C Virus

Pharmacokinetics of multiple ascending doses of VCH-222 in subjects with chronic hepatitis C infection (clinicaltrials.gov) - P1/2, N=49; Active, not recruiting -> Completed; Completion date: NA -> Sep 2012; N=110 -> 49

Trial completion • Hepatitis C Virus

VX-222 + telaprevir + ribavirin for 12 or 16 weeks in treatment-naive subjects with genotype 1 hepatitis C (clinicaltrials.gov) - P2, N=100; Not yet recruiting; New P2 trial

New trial • Hepatitis C Virus

Molecular modeling and residue interaction network studies on the mechanism of binding and resistance of the HCV NS5B polymerase mutants to VX-222 and ANA598 (Antiviral Res) - "Molecular dynamics (MD) simulations results combined with binding free energy calculations indicated that the mutations significantly altered the binding free energy and the interaction for the drugs to polymerase. The further per-residue binding free energy decomposition analysis revealed that the mutations decreased the interactions with several key residues, such as L419, M423, L474, S476, I482, L497, for VX-222 and L384, N411, M414, Y415, Q446, S556, G557 for ANA598."

Preclinical • Hepatitis C Virus

HCV variants in genotype 1 treatment-naïve patients administered combination telaprevir and VX 222-based therapy in dual and quad arms of zenith study (HCV 2012) - P2, N=47; "The DUAL regimens of telaprevir+VX-222 resulted in rapid initial declines in HCV RNA but were associated with >25% on-treatment vBT...The DUAL regimens of telaprevir+VX-222 resulted in rapid initial declines in HCV RNA but were associated with >25% on-treatment vBT"

P2 data • Hepatitis C Virus

VX-222, telaprevir and ribavirin in treatment-naïve patients with genotype 1 chronic hepatitis C: Results of the ZENITH study interferon-free regimen (AASLD 2012) - Presentation time: Nov 13, 2012; 8:00 AM - 12:00 PM; P2, N=46; ZENITH; In all oral, interferon-free regimen of telaprevir, VX-222, RBV, the majority of pts had undetectable HCV RNA at wks 4 and 12, with a higher rate of HCV RNA less than LOD at wk 4 in genotype 1b; Among pts eligible to stop at wk 12, high SVR12 rates were observed in this small pilot study, and the regimen was well-tolerated

P2 data • Hepatitis C Virus

All IL28B genotypes have high SVR rates in patients treated with VX-222 in combination with telaprevir / peginterferon / ribavirin in the ZENITH study (EASL 2012) - Presentation time: 21.04.2012, 09:00-18:00; P2, N=150; ZENITH; SVR12 rates in CC, CT and TT pts were 92% (11/12), 64%, (7/11) and 100% (6/6), respectively in arm C (100mg VX-222) and 88% (7/8), 94%, (15/16) and 83% (5/6), respectively, in arm D(400mg VX-222); There was an association between IL28B genotype and undetectable HCV RNA at Week 2 in arms C and D, however this disappears by Week 4 due to high RVR rates across all IL28B genotypes

P2 data • Hepatitis C Virus

Vertex announces 12-week on-treatment data and SVR4 from phase 2 study of interferon-free (all-oral) treatment regimen of incivek, VX-222 and ribavirin in people with genotype 1 hepatitis C (Vertex) - P2, N=152; ZENITH; Vertex announced interim data from two treatment arms of the P2 ZENITH study; Interim data showed viral loads were below the lower limit of quantification (< 25 IU/mL: < LLOQ) for 80% (37/46) of pts with genotype 1 hepatitis C at week 2 and 83% (38/46) at week 12; Company intends to pursue a P2b study in Q3 2012 based on these data with goal of submitting a NDA to FDA for Vertex's first interferon-free regimen for genotype 1 (1a and 1b) pts by Q4 2014 or Q1 2015

Anticipated NDA filing • Anticipated P2b initiation • P2 interim results • Hepatitis C Virus

Safety of telaprevir in absence of interferon and/or ribavirin: Analysis of on-treatment data from ZENITH (APASL 2013) - Presentation time: 08.06.2013, 08:30-17:30; P2, N=152; ZENITH (NCT01080222); Sponsor: Vertex; "TRIPLE AEs were generally mild or moderate ...Incidence and severity of rash were lower in TRIPLE vs QUAD ...Mean changes in hemoglobin (Hgb) were lowest in DUAL and lower in TRIPLE than QUAD. Incidence of Hgb < 10-g/dL was 3% (DUAL), 15% (TRIPLE), and 40% (QUAD); Hgb < 8.5-g/dL observed only in QUAD (7%)."

P2 data • Hepatitis C Virus

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection (Eur J Gastroenterol Hepatol) - P2a, N=152; ZENITH (NCT01080222); Sponsor: Vertex; "Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy."

P2a data • Hepatitis C Virus

Vertex: Annual Report 2012 (Vertex) - Anticipated patent expiry in US in 2030; Anticipated patent expiry in EU in 2027

Anticipated patent expiry • Hepatitis C Virus