close

Clinical Trials

Date: 2017-02-02

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 10th Annual Congress of the European Association of Haemophilia and Allied Disorders (EAHAD) held February 1 - 3, 2017 in Paris

Company: Alnylam Pharmaceuticals (USA - MA)

Product: fitusiran (SAR439774 - ALN-AT3)

Action mechanism:

  • RNAi. ALN-AT3 is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand. GalNAc-siRNA conjugates are a proprietary, clinically validated delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Pre-clinical studies have shown that subcutaneous administration of ALN-AT3 can normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model.
  • A single subcutaneous dose of ALN-AT3 that resulted in plasma AT reduction of approximately 90% led to normalization of thrombin generation and improvement in hemostasis in hemophilia mice. In wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible silencing of plasma AT. Weekly subcutaneous doses of 0.50 mg/kg resulted in 90% AT knockdown, while an ED50 knockdown was achieved at a dose as low as 0.125 mg/kg. Furthermore, in an NHP “inhibitor” model, in which a hemophilia A (HA) phenotype was induced via administration of a polyclonal anti-factor VIII antibody, ALN-AT3-treated animals showed the expected level of AT knockdown but also showed a statistically significant (p<0.01) dose-dependent increase in thrombin generation, fully restoring this hemostatic parameter back to normal levels.
  • • On November 14, 2016, Alnylam Pharmaceuticals announced that, pursuant to the companies' global alliance signed in January 2014 , Sanofi Genzyme elected to opt in to co-develop and co-commercialize fitusiran, for the treatment of hemophilia and rare bleeding disorders, in the United States , Canada and Western Europe . This expanded right is in addition to their previously exercised opt-in decision to develop and commercialize fitusiran in their rest of world territories.

Disease: hemophilia A, hemophilia B

Therapeutic area: Hematologic diseases - Genetic diseases - Rare diseases

Country: Bulgaria, Russia, Switzerland, UK, USA

Trial details:

  • The AT3 open-label extension study is an open-label, multi-center study designed to evaluate the long-term safety and tolerability of ALN-AT3 in hemophilia patients who were previously enrolled in the Phase 1 study. Eligible patients treated in the Phase 1 study can enroll in the OLE study, where they will receive ALN-AT3 for up to the earlier of two years or until the drug receives regulatory approval and becomes commercially available in their market. In addition to evaluating the long-term safety and efficacy of ALN-AT3 in hemophilia patients, the study will evaluate clinical activity of ALN-AT3, as measured by knockdown of serum AT, increases in thrombin generation, and reduction in the frequency of bleeding events.
  • The  Phase 1 trial of ALN-AT3 is being conducted in Bulgaria , Switzerland , and the UK as a single- and multi-dose, dose-escalation study comprised of two parts. Part A - which is complete - was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3:placebo) in healthy volunteer subjects. The primary objective of this part of the study was to evaluate the safety and tolerability of a single dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. Part A of the study evaluated only low doses of ALN-AT3, with a dose-escalation stopping rule at no more than a 40% knockdown of AT. Based on the level of AT knockdown achieved in this part of the study, only the first and lowest 30 mcg/kg dose cohort of 4 healthy volunteers was enrolled. Part B of the study- which is complete - was an open-label, multi-dose, dose-escalation study enrolling up to 18 subjects with moderate or severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3; thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia ( Dargaud , et al., Thromb Haemost; 93, 475-480 (2005)). In this part of the study, dose-escalation is allowed to proceed beyond the 40% AT knockdown level. Initial results from the ongoing study presented today include safety, tolerability, and clinical activity data from: the single cohort of healthy volunteers in Part A; the lowest (15 mcg/kg), multi-dose cohort of three hemophilia subjects from Part B; and the initial hemophilia subject enrolled in the second multi-dose cohort (45 mcg/kg) from Part B. For the four subjects currently in Part B, three have severe hemophilia A (less than 1% levels of Factor VIII) and one has severe hemophilia B (less than 1% levels of Factor IX).
  • Part C of the study - which is ongoing - is an open-label, multi-dose, dose escalation study of up to 18 patients with moderate or severe hemophilia A or B in which patients are receiving three monthly subcutaneous doses of fitusiran. Four cohorts of three patients each have been enrolled at doses of 225, 450, 900, or 1800 mcg/kg, and two additional cohorts of three patients each have been enrolled at a fixed dose.
  • Part D of the study is an open-label, multi-dose study in hemophilia A or B patients with inhibitors. The primary objective of Parts B, C, and D of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered fitusiran in patients with hemophilia. Secondary objectives include assessment of clinical activity as determined by lowering of circulating AT levels and increase in thrombin generation at pharmacologic doses of fitusiran. In addition, exploratory analyses of bleeding are being performed. In the U.K., enrollment has been aided by the Southern Academic Coagulation Consortium (SACC).

Latest news:

  • • On February 2, 2017, Alnylam Pharmaceuticals announced new results from an exploratory analysis of its Phase 1 study with fitusiran in patients with hemophilia A or B with or without inhibitors. This analysis of bleed management during fitusiran administration showed that breakthrough bleeds were effectively managed with replacement factors or bypassing agents, with no thromboembolic events. Additionally, results presented from stability studies of fitusiran support a greater than two-year shelf life at room temperature storage conditions and demonstrated resistance to thermal stress, favoring real world handling of the final drug product. These data were presented at the 10th Annual Congress of the European Association of Haemophilia and Allied Disorders (EAHAD) held February 1 - 3, 2017 in Paris, France . New analyses examined 21 total bleed events in 41 patients treated with fitusiran, after achieving greater than 75 percent antithrombin lowering. This analysis found that dosing of agents was generally within the normal dose range for replacement Factor VIII and Factor IX as well as for the bypassing agent rFVIIa, while at the lower end of the range for the bypassing agent aPCC. Treatment of all breakthrough bleed events resulted in successful hemostasis without any thromboembolic events. An evaluation of fitusiran at refrigerated (i.e., 5ºC), customary room temperature (i.e., 25ºC/60 percent relative humidity) and at accelerated aging conditions (i.e., 40ºC) demonstrated a robust stability profile, with all key quality attributes predicted to be retained at both refrigerated and room temperature conditions for at least 24 months. Further, fitusiran has shown resistance to thermal stress and cyclic temperature fluctuations that may occur during real world storage and handling of the drug product. Consequently, the stability profile of fitusiran could enable convenient transportation and storage, including in parts of the world where cold chain delivery is a challenge. Alnylam Pharmaceuticals is now working to advance toward the start of the ATLAS Phase 3 clinical program in early 2017.
  • • On December 3, 2016, Alnylam Pharmaceuticals  announced positive interim results from Part D of its ongoing Phase 1 study with fitusiran, an investigational RNAi therapeutic, in patients with hemophilia with inhibitors. These results were presented in a poster at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 - 6, 2016 in San Diego, California . New clinical data showed that once-monthly subcutaneous administration of fitusiran achieved lowering of AT and increases in thrombin generation, resulting in a median estimated annualized bleeding rate (ABR) of zero in patients with hemophilia A or B with inhibitors (N=16). In addition, fitusiran was generally well tolerated through the data cut-off date, October 6, 2016 , with no thromboembolic events, including in circumstances when bypassing agents were administered to treat breakthrough bleeding events. Additional data on longer-term administration of fitusiran in patients without inhibitors will be presented in a separate poster presentation at ASH . New results as of an October 6, 2016 data cut-off date were presented from Part D of the ongoing fitusiran Phase 1 study, which included patients with hemophilia A or B with inhibitors who were enrolled in two separate dose cohorts of 50 mg, once-monthly (N=6) or 80 mg, once-monthly (N=10). Treatment with fitusiran resulted in potent and dose-dependent lowering of AT and increases in thrombin generation. In an exploratory analysis of bleeding events, a median ABR of zero was achieved for patients in combined dose cohorts in the observation period, compared to the pre-study median ABR of 31. The majority of patients treated in both cohorts (9 of 16; 56 percent) were bleed-free and most patients (11 of 16; 69 percent) experienced zero spontaneous bleeds. In the 80 mg cohort, 70 percent (7 out of 10) of patients were bleed-free and 90 percent (9 out of 10) of patients experienced zero spontaneous bleeds. Fitusiran was generally well tolerated in the study. All adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of mild injection site reactions (ISRs) in 8 out of 16 patients (50 percent). Asymptomatic and reversible alanine aminotransferase (ALT) increases greater than 3 times the upper limit of normal (ULN), without concurrent elevations in bilirubin greater than 2 times ULN, were observed in three patients, all of whom have medical history of hepatitis C infection (HCV). Non-clinically significant increases in D-dimer were observed in some patients; none were associated with laboratory signs of pathologic clot formation. There were no drug-related serious adverse events (SAEs), no discontinuations due to AEs, and no thromboembolic events through the data cut-off date. All breakthrough bleed events were successfully managed with bypassing agents (recombinant factor VIIa and/or activated prothrombin complex concentrate). As of the data cut-off date, seven inhibitor patients have transitioned to the Phase 2 open-label extension (OLE) study, and continued dosing with fitusiran for up to seven months has been generally well tolerated.
  • • On July 25 , 2016, Alnylam Pharmaceuticals announced new positive results from its ongoing Phase 1 study with fitusiran for the treatment of hemophilia A and B and rare bleeding disorders (RBD). These new data will be presented in an oral presentation at the World Federation of Hemophilia (WFH) 2016 World Congress , on Wednesday, July 27, 2016 in Orlando, Florida . New clinical data showed that once-monthly subcutaneous administration of fitusiran achieved dose-dependent lowering of AT and increases in thrombin generation, resulting in a median estimated annualized bleeding rate (ABR) of zero in evaluable patients with hemophilia A or B without inhibitors (N=17). In addition, data from an initial cohort of hemophilia patients with inhibitors (N=6) demonstrated AT lowering, increased thrombin generation, and preliminary evidence for reduced bleeding. Importantly, fitusiran was found to be generally well tolerated to date in patients with and without inhibitors, including no thromboembolic events. Finally, the Company announced that it now plans to initiate fitusiran pivotal studies in people with hemophilia with and without inhibitors in early 2017. New results were presented from Part C (N=18) and Part D (N=6) of the ongoing Phase 1 study, and include all available data as of the data transfer up to July 11, 2016. Part C evaluated a monthly subcutaneous regimen at doses ranging from 225 micrograms per kilogram (mcg/kg) to 1800 mcg/kg, and also includes a cohort of six patients that received a fixed dose of 80 mg. Part D is evaluating monthly subcutaneous dosing in people with hemophilia A and B with inhibitors, and is designed to enroll up to a total of 18 patients. The first cohort of six patients with inhibitors received a 50 mg fixed, once-monthly, subcutaneous dose regimen. The second cohort has completed enrollment with six inhibitor patients receiving an 80 mg fixed, once-monthly, subcutaneous dose regimen. Phase 1 Part C Interim Study Results in Hemophilia A or B without Inhibitors Treatment with fitusiran resulted in potent, dose-dependent, and statistically significant lowering of antithrombin. At the 80 mg fixed monthly dose, fitusiran achieved 87 ± 1 percent mean maximal AT lowering with low inter-patient variability. The association between AT lowering and increased thrombin generation was assessed in a post hoc exploratory analysis in which AT lowering was grouped by 25 percent increments for completed patients in Parts B (N=12) and C (N=17) of the study. In the highest quartile of greater than or equal to 75 percent AT lowering (N=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290 percent relative to baseline (p less than 0.001, as compared to the lowest AT lowering quartile). Furthermore, there was a statistically significant, AT lowering-dependent reduction in bleeding frequency, with the greatest effect seen at greater than or equal to 75 percent AT lowering (p less than 0.05, based on a negative binomial regression model). These data support the therapeutic hypothesis that AT lowering of 75 percent or greater is associated with attenuation of the hemophilia phenotype in non-inhibitor patients. To obtain a more comprehensive assessment of potential fitusiran effects on bleeding, a post hoc analysis was performed in evaluable patients from all five cohorts in Part C (N=17). Specifically, bleed events that occurred over the six month period prior to study entry (based on review of medical records) and bleed events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the "onset period") were compared with bleed events that occurred beyond day 29 up to day 112 (the "observation period"), the time period during which fitusiran achieves its therapeutic pharmacodynamic effect. Median estimated ABR values were determined accordingly. In addition, bleed events classified as "spontaneous" were analyzed separately to determine the estimated annualized spontaneous bleeding rate (AsBR). Prior to study entry, evaluable patients (N=17) had an estimated median ABR of 28 for patients receiving on-demand factor therapy (N=4) and an estimated median ABR of two for patients receiving prophylactic factor therapy (N=13). During the prospectively monitored "onset period" interval, the estimated median ABR was 13 among all evaluable patients. In contrast, during the observation period, fitusiran administration achieved an estimated median ABR of zero. In all Part C dose cohorts during the observation period, the majority of patients (9 of 17; 53 percent) were bleed-free, and 82 percent of patients reported no spontaneous bleeds. In the 80 mg fixed dose cohort, the estimated median ABR of zero compared favorably with the pre-study ABR of 6 for the same patients when they were receiving prophylactic replacement factor therapy. While not based on direct comparative studies, the median estimated ABR achieved with once-monthly, subcutaneous fitusiran compares favorably to the range of median ABR values of zero to four reported in clinical studies of frequent prophylactic intravenous infusions of recombinant Factors VIII or IX. Initial Phase 1 Part D Study Results in Hemophilia A or B Patients with Inhibitors Patients with hemophilia A or B with inhibitors were enrolled in the initial Part D dose cohort. Prior to study entry, all patients utilized bypass agents, including recombinant Factor VIIa and activated prothrombin complex concentrate (aPCC), to manage their bleeds, and had a notably high pre-study ABR of up to 80, based on review of medical records. In order to obtain an initial experience with fitusiran, the first cohort (N=6) of inhibitor patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81 ± 2 percent and a mean maximal thrombin generation increase of approximately 368 percent, comparable to results observed from Part C in non-inhibitor patients at similar doses. In addition, preliminary evidence for reduced bleeding was observed, with a 49-100 percent reduction in estimated ABR during the observation period compared with pre-study values. Dose escalation has occurred, and the next cohort of inhibitor patients has been fully enrolled with once-monthly subcutaneous dosing at 80 mg (N=6). The Company expects to present additional data from inhibitor patients in Part D of the study in late 2016. Interim Phase 1 Study Safety Results As of the data transfer on July 11, 2016 , fitusiran continues to be generally well tolerated in patients with hemophilia with or without inhibitors (N=31, with five patients participating in both Parts B and C). There have been no serious adverse events (SAEs) related to study drug, and no thromboembolic events or laboratory evidence (based on D-dimer, platelet count, fibrinogen, and/or PT/INR) of pathologic clot formation. All bleeds were successfully managed with standard replacement factor or bypass agent administration. One non-inhibitor patient in Part C at the 80 mg fixed dose cohort discontinued due to an adverse event considered severe and possibly related to study drug per. This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal, ULN), AST (8x ULN), C-reactive protein, and D-dimer, without increase in total bilirubin. Extensive evaluation was unremarkable, and venous thromboembolism was excluded by serial CT angiograms and liver and lower extremity ultrasound. This patient's event resolved with symptomatic management, including antacids and analgesics. Eleven patients (35 percent) reported mild, drug-related injection site reactions (ISRs), which were mostly pain or erythema at the injection site. Additional AEs reported in greater than or equal to 10 percent of patients included upper respiratory tract infection (10 percent) and arthralgia (10 percent); the majority of these AEs were mild or moderate in severity. With the exception of the case noted above, there were no other clinically significant drug related changes in laboratory parameters. Finally, there have been no instances of anti-drug antibody formation to fitusiran. Additional Data and Development Plans Alnylam plans to report additional data from fitusiran studies in late 2016. These data are expected to include additional results from Part D of the ongoing Phase 1 study and initial results from the Phase 1/2 open-label extension (OLE) study. Twenty-one patients who have completed treatment in the Phase 1 study have now rolled over to the OLE study, where they are receiving monthly fitusiran administration. Additional patients are expected to enroll in the OLE study as they become eligible.
  • • On March 14, 2016, Alnylam Pharmaceuticals  announced that it has initiated dosing of hemophilia patients with inhibitors in Part D of an ongoing Phase 1 clinical trial evaluating a once-monthly subcutaneous dose regimen of fitusiran (ALN-AT3). Patients with hemophilia A with inhibitors and with hemophilia B with inhibitors have now been dosed with fitusiran. Fitusiran is designed to prevent bleeding in patients with hemophilia by lowering levels of antithrombin with the goal of promoting sufficient thrombin generation and fibrin clot formation to restore hemostasis. Consistent with previous guidance, the Company expects to report additional data from the Phase 1 trial in mid-2016 and again in late 2016. In addition, the Company remains on track to begin pivotal studies of fitusiran in hemophilia A and B, including patients with and without inhibitors, in mid-2016. Clinical data from the ongoing Phase 1 clinical study with fitusiran were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando (see below).
  • • On December 7, 2015, Alnylam Pharmaceuticals announced   results from its ongoing Phase 1 clinical study with fitusiran for the treatment of hemophilia A and B and rare bleeding disorders (RBD). Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis, thereby preventing bleeding in patients with hemophilia. The new clinical data were presented in an oral session at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando, Florida.
  • Results demonstrated that subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88 percent. In addition, AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and decreases in bleeding frequency in patients with hemophilia. In particular, fitusiran administration resulted in an 85 percent reduction in median estimated annualized bleeding rates (ABR) in nine evaluable patients. Importantly, fitusiran was found to be generally well tolerated to date, including no clinically significant increases in D-dimer, a biomarker of excessive clot formation. Consistent with previous guidance, the company expects to begin a Phase 3 program in hemophilia A and B, including patients with and without inhibitors, in mid-2016. New results were presented from 24 patients with hemophilia in Parts B (N=12) and C (N=12) of the ongoing Phase 1 study, and include all available data as of the data cutoff date of November 12, 2015 . Preliminary Phase 1 Study Clinical Activity Results: Monthly subcutaneous doses of fitusiran resulted in potent, dose-dependent, and statistically significant lowering of AT of up to 88 percent. At the top dose of 1800 micrograms per kilogram (mcg/kg), the mean maximum AT lowering was 79 ± 3 percent. The dose response for fitusiran was examined by comparing the mean maximum AT lowering with the monthly equivalent doses administered to volunteers and patients in Parts A, B, and C of the study (N=27). As anticipated, dose-dependent AT lowering and durability were demonstrated upon exploring the full spectrum of doses in the MAD phases. AT lowering with fitusiran was associated with statistically significant increases in thrombin generation, providing continued evidence for the potential restoration of hemostasis in patients with hemophilia. The association between AT lowering and increased thrombin generation was assessed in a post hoc exploratory analysis in which AT lowering was categorized into quartiles. In the highest quartile (greater than 75 percent AT lowering) (N=9), fitusiran administration resulted in mean increases in thrombin generation of 285 ± 165 percent (p less than 0.001 based on paired t-test). At this level of AT lowering, the mean peak thrombin generation was 62 ± 27 nM, and the range of peak thrombin generation values was found to overlap with those observed in healthy volunteers (64 - 210 nM). A sub-study was performed to correlate patient-specific thrombin generation levels achieved following fitusiran administration with those achieved with Factor VIII dosing. Severe hemophilia A patients (N=3) received a single intravenous dose of recombinant Factor VIII prior to receiving their first dose of subcutaneous fitusiran. Following Factor VIII administration, both Factor plasma levels and thrombin generation were measured at various time points to generate a patient-specific standard curve relating Factor level to thrombin generation. Thrombin generation values achieved after washout of Factor VIII and following fitusiran administration were then converted to Factor equivalence levels based on the patient-specific standard curve. In this sub-study, fitusiran dosing resulted in peak thrombin generation values equivalent to those achieved at plasma Factor VIII levels greater than 40-50 percent of normal. Accordingly, in these three subjects, subcutaneous fitusiran treatment resulted in restoration of thrombin generation to levels consistent with what are essentially normal functional levels of Factor VIII. An exploratory post hoc analysis was performed by examining the frequency of prospectively measured, on-study bleeding events in all patients in Parts B and C of the study (N=24). During the period of time when patients had AT lowering less than 25 percent, a total of 43 bleeding events were reported in 24 patients, and the mean and median estimated ABRs were 34 ± 10 and 13, respectively. In the ongoing Phase 1 fitusiran study, an AT lowering-dependent reduction in the mean and median estimated ABR values was achieved. At the highest quartile of greater than 75 percent AT lowering, where 9 patients experienced an aggregate exposure of 304 days, the mean and median estimated ABR values were reduced to 6 ± 3 and 0, respectively. The reduction in mean estimated ABR associated with increased AT lowering was statistically significant (p less than 0.05 based on a negative binomial regression model). An additional post hoc analysis was performed in patients from three cohorts in Part C of the study to evaluate fitusiran effects on bleeding (data for the 1800 mcg/kg cohort were not sufficiently mature for this analysis). Here, the effect of fitusiran administration on estimated ABR was evaluated through prospective measurement of bleeding events during an "onset period" (the period from day 0 through day 28 when initial AT lowering is ongoing) and an "observation period" (defined as the period from day 29 to the last day available, to a maximum of day 112, during which AT levels exhibit sustained lowering). In addition, and where available, data on patient-reported, historical on-demand ABR were collected. In this analysis, there was a marked 85 percent reduction in the median estimated ABR during the observation period as compared with the median historical on-demand ABR for all nine evaluable Part C patients. Specifically, the median historical on-demand median ABR was 28 and the onset period median estimated ABR was 12.6. In contrast, the median estimated ABR during the post-fitusiran dosing observation period was 4.3. In the highest two evaluable dose cohorts (N=6), the median estimated ABR during the observation period was even lower at 2.2. Notably, this median estimated ABR achieved with once monthly, subcutaneous fitusiran compares favorably to the range of median ABR values of 1.1 to 3.7 reported in clinical studies of prophylactic intravenous infusions of recombinant Factor VIII or IX1-4 and the median ABR of 7.9 reported in a clinical study of prophylactic bypass agent regimen in hemophilia patients with inhibitors5. Preliminary Phase 1 Study Safety Results: As of the current data cutoff of November 12, 2015 , fitusiran continues to be generally well tolerated in all patients with hemophilia (Parts B and C, N=24). As noted above, this includes a total of 9 patients who achieved a greater than 75 percent lowering of AT for an aggregate of 304 days. There have been no serious adverse events (SAEs) related to study drug, no discontinuations, and no significant changes in physical exams, vital signs, or electrocardiography. One patient was hospitalized due to re-activation of hepatitis C, which was not related to fitusiran administration. There were three drug related adverse events (AEs), all of which were mild. Among these AEs, there were two injection site reactions (ISRs), each consisting of mild, transient pain. There have been no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There have been no thromboembolic events or clinically significant increases in D-dimer. All bleeds were successfully managed with standard replacement factor administration, with no associated adverse events. Finally, there have been no instances of anti-drug antibody formation to fitusiran.
  • * On August 18, 2015, Alnylam Pharmaceuticals announced that it has initiated a Phase 1 open-label extension (OLE) study with ALN-AT3, a subcutaneously administered, investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. The Phase 1 OLE study will evaluate the long-term safety and efficacy of ALN-AT3 and provide people with hemophilia enrolled in the Phase 1 study the opportunity for continued dosing. The company plans to report clinical data from the Phase 1 OLE study at least once per year, beginning in 2016.
  • • On January 12, 2015, Alnylam Pharmaceuticals announced updated results from its ongoing Phase 1 study of ALN-AT3  for the treatment of hemophilia and rare bleeding disorders. New results were presented at the 2015 Goring Coagulation Conference , being held January 11 - 12 in London. Specifically, data were presented from the study's second dose cohort in hemophilia subjects (n=3), where subcutaneous administration of ALN-AT3 resulted in an up to 70% knockdown of AT. New results provide initial evidence for potential correction of the hemophilia phenotype associated with ALN-AT3 administration and AT knockdown. Specifically, ALN-AT3 administration resulted in an increase in thrombin generation of up to 334% and a marked improvement in whole blood clotting. In addition, the most advanced severe hemophilia A subject in the cohort has remained bleed free for 47 days without replacement factor prophylaxis. Finally, ALN-AT3 administration continues to be generally well tolerated. Alnylam intends to provide additional results from the ongoing Phase 1 study in mid-2015 and then in late 2015, and expects to start a Phase 2 study of ALN-AT3 in late 2015.
  • Initial evidence for the potential correction of the hemophilia phenotype was observed in the severe hemophilia A subjects. Specifically, ALN-AT3 administration resulted in thrombin generation increases of up to 334%. Increase in thrombin generation was closely correlated with degree of AT knockdown. When AT knockdown levels exceeded 50%, the mean increase in thrombin generation was 112 +/- 38% (p less than 0.05) relative to baseline. Thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia ( Dargaud , et al., Thromb Haemost; 93, 475-480 (2005)), and the results achieved following ALN-AT3 administration are consistent with thrombin generation levels measured in mild hemophilia. Moreover, the observed maximal increase in thrombin generation in the hemophilia subjects (peak thrombin of 71 nM) remained at the low end of the range for peak thrombin levels in the healthy volunteers enrolled in Part A of the study (mean of 92 +/- 15 nM; range from 69-135nM). These data show that AT knockdown of up to 70% in hemophilia subjects should not lead to an excessive increase in thrombin generation beyond normal.
  • Further evaluation of the effects of ALN-AT3 employed the use of ROTEM® thromboelastometry, which measures clotting time and clot strength in whole blood following a physiologic coagulation stimulus; this assay method was available for a single severe hemophilia A subject in the second dose cohort, who happens to be the most advanced subject. ALN-AT3 administration was found to result in AT knockdown-dependent improvements in whole blood clotting in this subject. As described in the table below, ALN-AT3 administration resulted in marked improvements in clotting time (CT) - which is a measure of the initiation phase of clot formation - and clot formation time (CFT) - which is a measure of the propagation phase of clot formation; both parameters that are known to be significantly impaired in people with hemophilia. As with observed effects on thrombin generation, the improved CT and CFT values following ALN-AT3 administration were found to be similar to those reported in the literature in subjects with mild hemophilia. Finally, as of the current data cut-off date of January 6, 2015 , this hemophilia subject was free of any bleeds for 47 days, which compares favorably to his physician-reported Annual Bleeding Rate (ABR) of 10-12 bleeds/year during on-demand therapy prior to enrolling in the study.
  • Summary of AT Knockdown and Improvement in Whole Blood Clotting in Most Advanced Subject
Day % AT Knockdown

Clotting Time (CT), seconds (Mean +/- SEM)

Clot Formation Time (CFT), seconds (Mean +/- SEM)
1 1 1254 +/- 280 1441 +/- 394
8 30 1105 +/- 57 625 +/- 43
21 57 547 +/- 14 289 +/- 5
  • As of the current data cut off, ALN-AT3 continues to be generally well tolerated in all subjects receiving study drug in the study (n=9), including subjects enrolled in the second dose cohort (n=3). There have been no serious adverse events, no discontinuations, no injection site reactions, and no significant changes in physical exams, vital signs, or electrocardiography. Further, there have been no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There have been no clinically significant increases in D-dimer, a marker of fibrin clot formation, or any thromboembolic events. The most common adverse event observed in hemophilia subjects was the occurrence of mild to moderate bleeds unrelated to study drug. All bleeds were successfully managed with replacement factor administration. In the second dose cohort and as of the data cut-off date, all five reported bleeds occurred on day 6 or earlier - at low levels of AT knockdown - with the exception of a trauma-related bleed in one subject at day 16, which was managed with a low, 1000 IU dose of Factor VIII. The ALN-AT3 Phase 1 study continues to enroll hemophilia subjects in additional dose cohorts, including the potential to explore a once-monthly subcutaneous dose regimen following a protocol amendment. The company plans to present additional data from the Phase 1 study in mid-2015, and then additional results in late 2015. In addition, Alnylam expects to initiate a Phase 2 study of ALN-AT3 in late 2015. • On December 9,2014, Alnylam Pharmaceuticals announced positive initial Phase 1 data for ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Preliminary results were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) from a single dose cohort in healthy volunteers (n=4) and from the initial multiple dose cohorts of hemophilia subjects (n=4) in the ongoing Phase 1 clinical trial. Amongst other data presented, subcutaneous administration of ALN-AT3 given once weekly for three weeks at low doses of 15 or 45 micrograms/kg (mcg/kg) resulted in an up to 57% knockdown of AT in hemophilia subjects. The effects of ALN-AT3 lasted for about 60 days after a single dose. ALN-AT3 was found to be well tolerated in both healthy volunteers and hemophilia subjects enrolled in the study. These initial results show preliminary evidence for potency and durability of RNAi therapeutics at mcg/kg subcutaneous doses in human studies, and are the first clinical data to be reported for Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology.
  • Preliminary results from the Phase 1 study to date show that ALN-AT3 was well tolerated in both healthy volunteers and hemophilia subjects. There were no serious adverse events, no discontinuations, no injection site reactions, and no significant changes in physical exams, vital signs, or electrocardiography. Further, there were no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There were no clinically significant increases in D-dimer, a marker of fibrin clot formation, or any thromboembolic events. The most common adverse event observed in hemophilia subjects was mild to moderate bleeds unrelated to study drug. All bleeds were successfully managed with replacement factor administration. Clinical activity of ALN-AT3, including knockdown of AT and thrombin generation, was measured in serial blood samples following study drug administration. In the healthy volunteer Part A of the study, subjects received a single subcutaneous dose of 30 mcg/kg. ALN-AT3 administration resulted in an up to 28% knockdown of AT with a mean maximum knockdown of 19% ±4.4% which was statistically significant relative to placebo (p < 0.01 by ANOVA). The nadir for AT knockdown was achieved at approximately day 21, and the overall effects from a single dose were found to be durable for approximately 60 days. ALN-AT3 knockdown of AT resulted in temporally related increases in thrombin generation of up to 152%, with a mean maximum increase of 138% ±8.9% that was statistically significant relative to placebo (p < 0.01 by ANOVA). In healthy volunteers, there was a statistically significant correlation of AT knockdown with thrombin generation increase with r=0.44, p=0.004 (post-hoc).
  • In the ongoing Part B of the study, which is in early stages of dose escalation, hemophilia subjects are receiving three weekly subcutaneous doses of ALN-AT3. All clinical activity results presented at the meeting are from a data cutoff date of December 5 , and are subject to change upon final analysis. In the first, lowest dose cohort of 15 mcg/kg, ALN-AT3 administration resulted in an up to 52% knockdown of AT in the most advanced subject, with nadir achieved on day 35. The mean maximum knockdown for this group was 27% ±13% through day 28, and is expected to increase when all subjects reach nadir levels. In the first subject in the second multi-dose cohort of 45 mcg/kg, ALN-AT3 administration resulted in an up to 57% knockdown of AT as measured on day 14; knockdown in this subject has not yet reached expected nadir levels. Plasma samples from the 15 mcg/kg cohort were also evaluated for potential increases in thrombin generation. Excluding increases in thrombin generation observed around the time of replacement factor administration, no conclusions can be drawn from thrombin generation measurements at this dose and level of AT knockdown. This result is in line with data from an induced hemophilia model in non-human primates, where levels of AT knockdown greater than or equal to 60% were required to achieve consistent and significant increases in thrombin generation in the background of reduced levels of factor VIII. The ALN-AT3 Phase 1 study is continuing to enroll hemophilia subjects in the second dose cohort of 45 mcg/kg, and additional multi-dose cohorts are planned. The company expects to present complete results from the Phase 1 study in mid-2015. Finally, in a symposium at ASH, Alnylam presented new pre-clinical data with ALN-AT3. In a study conducted in non-human primates, monthly subcutaneous dosing of ALN-AT3 was found to result in robust, durable, and dose-dependent knockdown of AT. Alnylam believes these data, combined with the emerging human durability data, may support monthly dosing of ALN-AT3 in hemophilia subjects. In addition, new results from a chronic toxicity study performed in hemophilia A mice showed that weekly dosing of ALN-AT3 confers a statistically significant survival benefit as compared with animals receiving placebo. Hemophilia A mice are prone to premature death due to their bleeding diathesis, and these results suggest that ALN-AT3 may be able to achieve a disease modifying effect by rebalancing the coagulation cascade through AT knockdown.
  • • On January 22, 2014, Alnylam Pharmaceuticals has announced that it has initiated a Phase 1 study with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). The company expects to present initial data from the Phase 1 study in late 2014. ALN-AT3 is a key program in the company’s “Alnylam 5x15” product strategy, which is aimed at advancing multiple RNAi therapeutic genetic medicine programs into clinical development. Alnylam recently announced that it expects to exceed its original “Alnylam 5x15” guidance with six to seven genetic medicine programs in clinical development by the end of 2015, including at least two programs in Phase 3 and five to six programs that will have achieved human proof-of-concept results supporting further development.
  • Alnylam presented pre-clinical data at the XXIV Congress of the International Society on Thrombosis and Haemostasis (ISTH) in July 2013. Results showed that ALN-AT3 achieves rapid, dose-dependent, and durable knockdown of AT in rodents and non-human primates. In non-human primates, weekly subcutaneous doses as low as 0.125 mg/kg led to a 50% knockdown of AT, while weekly doses of 0.50 mg/kg led to approximately 90% knockdown. In addition, ALN-AT3 administration was found to normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model. More recently, at the 55th Annual Meeting of the American Society of Hematology (ASH) in December 2013, Alnylam presented pre-clinical results showing that repeat administration of ALN-AT3 was well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than those required to achieve 50% AT knockdown. Results from these studies also demonstrated that ALN-AT3 administration achieved complete correction of the activated Partial Thromboplastin Time (aPTT) - an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia - in HA mice.
• On October 29, 2013, Alnylam Pharmaceuticals has announced  that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia, including people with “inhibitors.” By knocking down AT, ALN-AT3 administration is expected to increase thrombin generation and reduce disease burden, including annualized bleeding rate, severity of bleeding, and requirement for replacement factor or bypass agent, and to potentially improve quality of life.

Is general: Yes

Pages
Archives
BIOPHARMANALYSES
BioPharmAnalyses est un site d'information sur le secteur biopharmaceutique européen qui vous propose à la fois des articles en libre accès, des lettres d'informations mensuelles et des bases de données sur les accords, les essais cliniques, les rachats, les levées de fonds et la vie réglementaire des produits dans la sphère européenne.
Partenaires

© 2024 Biopharmanalyses - Powered by Samacom+