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SAFETY, PHARMACODYNAMIC (PD) & PHARMACOKINETIC (PK) PROFILES OF CPG 10101 (ACTILON), A NOVEL TLR9 AGONIST: comparison in normal volunteers & HCV infected individuals
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Reported by Jules Levin
Following the data report from DDW is the Press Release from Coley that was distributed following the presentation at DDW.
B Bacon1, J McHutchison1, S Gordon1, NAfdahl1, I Jacobson1, MShiffman1, A Muir1, E Lewitz1, A Kreig1, S Efler1, ML Morris2, Mal-Adhami2, HL Davis2, T Schmalbach2.
1Alliance for Liver Therapy (ALT Group), 2 Coley Pharmaceuticals
Bruce Bacon reported on the safety, immune modulatory effects, & antiviral activity in this preliminary study. Description of TLR9 (Actilon by Coley Pharmaceuticals:
Actilon is a member of a new class of investigational medicines known as TLR Therapeutics(TM) being developed by Coley and its partners for the treatment of major medical conditions including cancers, infectious diseases, allergy and asthma. TLR Therapeutics target Toll-like receptors (TLRs) which act as immune system sentinels that recognize the distinct molecular patterns characteristic of foreign pathogens. Coley is focusing its efforts initially on the discovery and development of TLR Therapeutics which target and stimulate Toll-like receptor 9 (TLR9), which is found in a subset of dendritic and B cells.
Coley believes that Actilon stimulates TLR9, targeting dendritic cells and B cells, to induce both early and long term immune responses. The short-term innate immune response is thought to drive rapid reductions in viral load in the blood. Longer term, Actilon is thought to promote virus-specific adaptive immunity, including strong T cell responses, to provide sustained anti-viral effects.
SUMMARY & CONCLUSIONS of Study from Bacon
--CPG 10101 TLR9 agonist is well tolerated up to dose of 20mg twice weekly for 4 weeks by subcutaneous injection: there were mild to moderate injection reactions; related hemotologic changes are transient, mild to moderate & require to intervention
--CPG 10101 stimulates the innate immune system in healthy volunteers & HCV+ subjects (predominatly failed or relapsed genotype 1) alike: pharmacodynamic markers reflect immune activation MOA; adverse events reflect immunomodulatory activity
--decreases in HCV RNA levels seen early on treatment of predominantly failed or relapsed genotype 1 subjects: dose-dependent (mean of 1.4 log decrease at 20mg dose); see below for breakdown of viral load reductions for each of the 6 patients receiving 20mg dose.
--these data merit additional randomized trials to optimize activity.
CPG STRUCTURE & ACTIVITY
First in new class of anitiviral immunomodulatory drugs
--synthetic, TLR9 agonist
--well characterized, new chemical entity, sterile injectable
--not antisense to human genes
--antiviral activity in murine models of influenza & vaccine virus
--selective induction & secretion of cytokines & chemokines, including
interferon-alphas, IP-10, & 2’5’-OAS, with known antiviral activity
--activation of natural killer T-cells (NK-T)
--overcome immunologic dysfunction of virus-infectionplasmacytoid dendritic cells ((pDC)
--restores, augments & sustains appropriate TH1 anti-viral CTL function
HEPATITIS C DOSE ESCALATION SAFETY STUDY
--42 subjects (32 active & 10 control—double blind)
--CPG 10101 administered twice weekly for 4 weeks for cohorts 1-5
--subjects followed 4 weeks post last injection
--safety data reviewed at week 5, prior to initiating next cohort
Normal volunteer study was conducted at same dose levels but with two single injections given two weeks apart.
Dose escalation, 2 subjects received placebo at the same time as patients received the new dose:
0.25mg (n=5)
1 mg (n=6)
4mg (n=7)
10mg (n=7)
20mg (n=6)
OBJECTIVES:
--safety & tolerability profile
--pharmacodynamics of selection of variety of biomarkers
--pharmacokinetics
BASELINE DEMOGRAPHICS
--Minimum of 1 log reduction in HCV RNA levels after prior adequate IFN based treatment or treatment naïve due to ineligibility, unwillingness or intolerance to standard therapy
Age: 40-50
Gender: 30-50% female
8 Black, 1 Hispanic, 32 Caucasian
mostly genotype 1; 2 genotype 2, 3 genotype 4
HCV RNA: 1-3 million IU/mL
>1,000 IU/mL
compensated liver disease
seronegative for HIV & HBV
no IFN or antiviral therapies for 30 days
no immune suppressives for 1 year
no history of autoimmune disease
RESULTS
Cmax & AUC are dose related
Tmax 3 hours; return to baseline levels at 24 hrs
PK profile of initial injection similar to later injection
Bacon said PK profile similar in healthy volunteers & HCV+ subjects.
Peak levels at 3 hrs with 20 mg dose & other doses.
Tmax, 24 hrs
Cmax, dose related
Actilon appeared to stimulate the biomarkers the study investigators were looking for in HCV+ subjects: 2’5;-OQS, which is an enzyme induced by interferon & thought to activate RNase present in cells & to hinder protein synthesis of cells or viruses by breaking downb mRNA; and is thought to be directly related to the antiviral action of interferon. Serum IP-10 is an interferon inducible protein, a cemokine associated with the activation & migration of Th1 cells. I think I got these descriptions of these biomarkers correct. Serum IFN-alpha levels increased in a dose related response with 20mg dose achieving biggest response. Interferon alpha are a naturally occurring protein with immune modulatory, anti-proliferative, & antiviral properties.
HCV RNA RESPONSES WITH ONLY THE 20MG DOSE (n=6)
5 of 6 patients >0.5 log reduction
5 of 6 patients >1.0 log reduction
1 of 6 patients >2.5 log reduction
6 >0.25 log
HCV RNA RESPONSES WITH OTHER DOSES
10mg dose (n=7):
1 patient >2 log reduction
1 patient >1.5 log reduction
4 patients >1 log reduction
5 patients >0.5 log
7 >0.25
4.0mg dose (n=7):
6 patients >0.25 log
6 >0.5 log
2 >1 log
1 >1.5 log
0 >2 log
1mg dose (n=6):
6 >0.25 log
4 >0.5 log
1 >1 log
1 >1.5 log
1 >2 log
0.25mg dose (n=6):
4 >0.25 log
no patients receiving this dose had any greater log reduction
Placebo (n=10);
4 >0.25 log
3 >0.5 log
no patients receiving placebo had any greater log reductions
There was a decrease in IP-10 levels that correlated with HCV RNA decrease.
CPG 10101 doses of 0.1 mg/kg generally associated with maximal 1 log HCV RNA reductions
SAFETY & TOLERABILITY
No serious or dose limiting toxicities observed, & dose escalation continues
--one subject in the HCV study withdrew after 5 doses due to grade 2 vomiting & diarrhea (10mg)
--one subject in the HCV study reported an SAE of urticarial rash with pruritis after 5 doses (4-10mg)
injection reactions consistent with MOA, intensity/severity increasing with dose
--local arythema, pain, induration, pruritis common: all subjects with at least one symptom
--systemic symptoms of headache, mylagia, nausea/vomiting, pyrexia common
mild to moderate intensity overall
--increasing incidence of adverse events & intensity with higher dos—premature withdrawals
--one due to related adverse events
--three due to unrelated events (one hip fracture; two lost to followup)
grade 2 hemotologic changes, transient, reversible
--leukopenia: 3 healthy volunteers
--neutropenia: 1 healthy volunteer; 2 HCV subjects
No grade 4 events in any patient administered drug.
In HCV subjects:
--total incidence of events similar across dose groups.
--severity increases with increase in dose
--no obsevable differences between 10 & 20mg dose
In healthy volunteers:
--adverse events incidence increases with dose
--limited grade 2 & 3 adverse events at any dose lower than 20mg
PRESS RELEASE FROM COLEY
Coley Reports Positive Results from Phase Ib Study of Actilon(TM) for Hepatitis C at Digestive Disease Week Meeting
New Drug Candidate Relatively Well Tolerated At Active Antiviral Doses
CHICAGO, May 17 /PRNewswire/ -- Coley Pharmaceutical Group, Inc. today announced at the Digestive Disease Week conference that Actilon(TM) (CPG 10101) was relatively well tolerated and showed antiviral activity in the company's Phase Ib clinical study in chronic Hepatitis C patients.
In this Phase Ib study forty-two adult patients with chronic Hepatitis C virus, or HCV, were enrolled. These patients had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin or were intolerant of interferon-alpha and all but two were virus genotype 1.
Patients receiving 20 mg of Actilon subcutaneously twice weekly achieved a maximum 1.4 mean log decrease (96%) of virus within 4 weeks. Five of the six patients receiving the 20 mg dose of Actilon achieved at least a one log (90%) reduction of virus while on therapy.
Actilon showed good safety and tolerability, pharmacodynamic immune responses consistent with the drug's mechanism of action, and dose-related blood pharmacokinetics when given to HCV patients, as had been previously shown in Coley's Phase Ia clinical trial in normal volunteers.
Initial antiviral activity was observed in this double-blind trial after only 1 mg of Actilon given twice weekly, and dosing has been increased to 20 mg with acceptable tolerability. Measurements of biomarker responses in blood indicated that Actilon stimulates the innate immune system and immune activation induced by Actilon correlates with partial clearance of virus. Decreases in HCV RNA levels began to be observed after a single dose and were observed to be dose dependent.
"We are very encouraged by the results of this Phase Ib study showing antiviral effects with Actilon given to patients with relapsed or treatment resistant genotype 1 Hepatitis C," said John Whisnant, M.D., Senior Vice President, Drug Development of Coley Pharmaceutical Group. "Actilon's observed ability to direct the immune system therapeutically is consistent with its mechanism and with our experience with other Coley TLR Therapeutics in clinical development."
Data from the Phase Ib study were presented by Dr. Bruce Bacon, Professor of Internal Medicine at Saint Louis University School of Medicine in an oral presentation entitled "Safety and Pharmacodynamic (PD) and Pharmacokinetic (PK) Profiles of CPG 10101 (Actilon(TM)), a Novel TLR9 Agonist: Comparison in Normal Volunteers and HCV-Infected Individuals". Interim results from this study were presented previously at The American Association of Liver Disease (AASLD) meeting in November 2004.
About the Study
The Phase Ib double-blind study was designed to assess antiviral responses, safety and tolerability of Actilon over an 80-fold dose range. Forty-two adult subjects with chronic Hepatitis C virus were enrolled; virtually all were virus genotype 1 patients who had previously failed to achieve a sustained viral response after 24-48 weeks of standard therapy with interferon-alpha plus ribavirin. Patients were randomized to receive placebo or Actilon in sequentially higher dose cohorts (0.25, 1, 4, 10 and 20 mg) by twice weekly subcutaneous injections for four weeks.
Researchers observed responses in immune system markers including drug- related increases in interferon-alpha plasma levels and other markers indicative of antiviral activity. Actilon was relatively well tolerated at all doses in most patients, including 20 mg, the highest dose cohort completed, with no dose limiting toxicities. Mild to moderate injection site reactions and mild flu-like symptoms were consistent with the expected pharmacological mode of action of Actilon.
About Actilon(TM)
Actilon is a member of a new class of investigational medicines known as TLR Therapeutics(TM) being developed by Coley and its partners for the treatment of major medical conditions including cancers, infectious diseases, allergy and asthma. TLR Therapeutics target Toll-like receptors (TLRs) which act as immune system sentinels that recognize the distinct molecular patterns characteristic of foreign pathogens. Coley is focusing its efforts initially on the discovery and development of TLR Therapeutics which target and stimulate Toll-like receptor 9 (TLR9), which is found in a subset of dendritic and B cells.
Coley believes that Actilon stimulates TLR9, targeting dendritic cells and B cells, to induce both early and long term immune responses. The short-term innate immune response is thought to drive rapid reductions in viral load in the blood. Longer term, Actilon is thought to promote virus-specific adaptive immunity, including strong T cell responses, to provide sustained anti-viral effects.
About Hepatitis C Virus
Hepatitis C virus, which infects the liver and certain immune cells, leads to serious liver diseases such as cirrhosis and liver cancer more frequently than any other form of hepatitis. HCV is an RNA virus known to undergo a high rate of mutation that may help it both to avoid control by the immune system and to develop resistance to direct antiviral medications. According to the World Health Organization, HCV infects approximately 170 million people worldwide, including at least 2.7 million in the United States, and 10-20 percent of those chronically infected with HCV will ultimately develop liver cirrhosis, making HCV the leading cause of liver transplants in the United States. The Hepatitis Foundation International estimates that between 8,000 and 10,000 people die annually from HCV-related cirrhosis or liver cancer.
Coley believes, there is an unmet need for therapies with better side effect profiles and equivalent or superior efficacy, especially in the difficult-to-treat population of genotype 1 patients, who have failed to achieve a sustained virologic response following interferon-alpha and ribavirin therapy.
About Coley Pharmaceutical Group
Coley Pharmaceutical is an international biopharmaceutical company, headquartered in Wellesley, Massachusetts, USA, that discovers and develops TLR Therapeutics(TM), a new class of investigational drug candidates that direct the human immune system to treat cancers, infectious diseases, asthma and allergy. Coley has established a pipeline of four TLR Therapeutic product candidates currently advancing through clinical development either independently or with partners, and has additional product candidates in preclinical development. Coley has product development, research and license agreements with Pfizer, sanofi-aventis, Chiron, the United States Government and GlaxoSmithKline.
Safe Harbor Statement
Certain statements in this news release concerning Coley's business are considered "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, those relating to the timing and results of future clinical development of Actilon and the ability of Actilon to achieve a sustained virologic response in patients with HCV and other infectious diseases. Any or all of the forward-looking statements in this press release may turn out to be wrong. They can be affected by inaccurate assumptions Coley might make or by known or unknown risks and uncertainties, including, but not limited to: the early stage of product development; uncertainties as to the future success of ongoing and planned clinical trials; and the unproven safety and efficacy of products under development. Consequently, no forward-looking statement can be guaranteed, and actual results may vary materially. Coley undertakes no obligation to publicly update forward-looking statements, whether because of new information, future events or otherwise, except as required by applicable law.
Source: Coley Pharmaceutical Group, Inc.
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