Clinical Trials

Date: 2016-04-20

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the 68th Annual Meeting of the American Academy of Neurology (AAN) being held April 15 - 21, 2016 in Vancouver,

Company: Alnylam Therapeutics (USA - MA)

Product: ALN-TTR02 (patisiran)

Action mechanism:

• RNAi. ALN-TTR02 is an intravenously delivered RNAi therapeutic for the treatment of ATTR.
• In January 2014, Alnylam and Genzyme formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. In the case of patisiran, Alnylam will advance the product in North America and Western Europe , while Genzyme will advance the product in the ROW.

Disease: transthyretin-mediated amyloidosis (ATTR), familial amyloidotic polyneuropathy (FAP)

Therapeutic area: Rare diseases - Genetic diseases

Country: Brazil, France, Germany, Portugal, Spain, Sweden, USA

Trial details:

• The Phase II study is an open-label, multi-center, multi-dose, dose-escalation trial to evaluate the safety and tolerability of two doses of ALN-TTR02 and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR. The study enrolled 29 ATTR polyneuropathy patients with ALN-TTR02 administered at doses of 0.01 to 0.30 mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen.
• The ongoing phase 2 open-label extension (OLE) study is designed to evaluate the long-term safety and tolerability of patisiran administration in familial amyloidotic polyneuropathy patients that were previously enrolled in a Phase 2 study. Patisiran is being administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous infusion. The study is measuring a number of clinical endpoints every six months, including mNIS+7 which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time. The change in the mNIS+7 measurement from baseline to 18 months is the primary endpoint in the company's Phase 3 APOLLO trial of patisiran in FAP patients.

Latest news:

• • On April 20 ,2016, Alnylam Pharmaceuticals announced complete 18-month data from its ongoing Phase 2 open-label extension (OLE) study with patisiran for the treatment of hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented in an oral talk at the 68th Annual Meeting of the American Academy of Neurology (AAN) being held April 15 - 21, 2016 in Vancouver. Complete 18-month data (N=27) from the study provide continued evidence that patisiran has the potential to halt neuropathy progression in patients with hATTR-PN. In the first reported exploratory analysis of its kind, the degree of TTR knockdown observed in patients was shown to correlate with improvement in neuropathy impairment scores. Further, in this Phase 2 OLE trial, patisiran was found to be generally well tolerated with up to 25 months of treatment. Dosing continues in the patisiran Phase 2 OLE study, and the Company plans to report initial 24-month data from the trial in mid-2016. New results presented at the AAN meeting were as of a data cut off of February 23, 2016, and showed that mean neuropathy impairment scores were essentially unchanged from baseline values after 18 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 0.8 points, which compares favorably to an estimated mean increase in mNIS+7 of 22 to 26 points over 18 months based upon analysis of historical data sets in untreated hATTR-PN patients with similar baseline characteristics. Similar results were observed in patients with or without concurrent tetramer stabilizer use. In addition, patisiran administration was associated with a statistically significant, approximately 77% median improvement in nerve fiber density as read histologically in a blinded manner from distal thigh sweat gland biopsy samples (p less than 0.001). Over the 18 month period, patients with associated cardiomyopathy (N=11) showed stability in their echocardiographic, biomarker, and functional measures, including 10-meter-walk speed. Serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown for over 24 months with a mean maximal knockdown of 92% over the entire period and a mean post-dose knockdown of 87% at 18 months. In addition, Alnylam also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, inter-subject differences in the degree of TTR knockdown were compared to changes in mNIS+7 at 6, 12, and 18 months to assess the effects of patisiran administration. There was a linear correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement; these results were significant at 6 and 12 months (p less than 0.01) and showed a trend at 18 months (p equal to 0.055). Importantly, this is the first reported evidence that correlates the degree of TTR knockdown with improvements in mNIS+7, supporting the therapeutic hypothesis that reduction of mutant and wild-type TTR may be associated with potential for a halting of neuropathy progression in patients with hATTR-PN. Patisiran administration was also found to be generally well tolerated in hATTR-PN patients with 18 to up to 25 months of treatment. Of the most common adverse events reported in 10% or more of patients, the most frequent drug-related or possibly drug-related adverse events (AEs) were flushing (22.2%) and infusion-related reactions (18.5%), which were all mild in severity and did not result in any discontinuations. There were eight reports of serious adverse events (SAEs) in five patients, all of which were unrelated to study drug, including one discontinuation for gastroesophageal cancer at approximately 20 months in a patient who subsequently died. After the data cut-off date, an additional unrelated SAE of myocardial infarction was reported in a 79 year-old patient who subsequently died after having completed the full 24 months of treatment. Overall, there were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelets. • On November 3, 2015,  Alnylam Pharmaceuticals announced new results from its ongoing Phase 2 open-label extension (OLE) study with patisiran for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis). These new clinical data were presented at the 1st European Congress on Hereditary ATTR amyloidosis (EC-ATTR) held November 2 - 3, 2015 in Paris. Data from the patisiran Phase 2 OLE study provided continued evidence following 18 months of dosing that patisiran has the potential to halt neuropathy progression in patients with Familial Amyloidotic Polyneuropathy (FAP). The company is announcing that it expects to complete enrollment in the APOLLO Phase 3 trial of patisiran over the next three to four months, supporting a potential New Drug Application (NDA) filing in 2017 if the study is positive. Patisiran Results Show Continued Evidence for Potential Halting of Neuropathy Progression and Mark First-Ever Evidence for Positive Effect on Nerve Regeneration: New results for patients (N=20) who reached the 18-month endpoint as of a data cut off of September 22, 2015, showed that neuropathy impairment scores were essentially unchanged from baseline values after 18 months of treatment. Specifically, there was a mean increase in mNIS+7 of only 1.7 points, which compares favorably to an estimated increase in mNIS+7 of 22 to 26 points at 18 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics ( Adams et al., Neurology, 2015;85:675-682; Berk et al., JAMA, 2013;310:2658-67; Tafamidis European Medicines Agency Assessment Report, 2011). At 18 months, patisiran administration was associated with a statistically significant and clinically meaningful mean 4.9 m/mm3 increase from baseline in sweat gland nerve fiber density from distal thigh skin biopsy samples (p less than 0.001) as read histologically by a central lab in a masked manner. Serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown of up to 96% and a mean maximal knockdown of 93% for over 21 months. Patisiran administration was also found to be generally well tolerated in FAP patients out to nearly two years, with minimal drug-related adverse events reported. The most common drug-related or possibly drug-related adverse events were flushing (25.9%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations.
• • On September 28, 2015, Alnylam Pharmaceuticals announced new results from the company's ongoing Phase 2 open-label extension (OLE) study of patisiran for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). In collaboration with investigators at The Scripps Research Institute and Misfolding Diagnostics , Inc., patisiran administration was shown to reduce pathogenic, misfolded TTR monomers and oligomers in FAP patients in the Phase 2 OLE study. Specifically, patisiran administration resulted in a rapid and sustained reduction of approximately 90% in serum non-native conformations of TTR (NNTTR). Since NNTTR is pathogenic in ATTR amyloidosis, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. In addition, Alnylam presented complete 12-month data from all 27 patients initially enrolled in the patisiran OLE study, showing a mean 3.1-point decrease in the modified Neuropathy Impairment Score (mNIS+7) at 12 months as well as sustained mean maximum reductions in total serum TTR of 91% for over 18 months. Moreover, patisiran administration was found to be generally well tolerated out to 21 months of treatment. In a poster presented at the American Neurological Association (ANA) 2015 Annual Meeting being held September 27 - 29 in Chicago , Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics , Inc., presented the first-ever evidence that patisiran administration reduces pathogenic, misfolded TTR monomers and oligomers in FAP patients. NNTTR was measured using a proprietary sandwich ELISA assay, developed by Misfolding Diagnostics , that specifically recognizes misfolded TTR protein. An approximately 90% reduction in NNTTR was achieved, which was sustained out to Day 248, the full treatment duration during which NNTTR levels were analyzed. Further, the level of NNTTR reduction correlated with total TTR knockdown. The observed reduction in NNTTR provides a mechanistic link between TTR knockdown and potential clinical benefit in patients.
• In a separate poster at the ANA meeting, Alnylam presented complete 12-month results from all 27 patients initially enrolled in the patisiran Phase 2 OLE study. All reported results are from data in the database as of July 15, 2015 . New study findings showed a mean decrease in mNIS+7 of 3.1 points at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics ( Adams et al., International Symposium on Amyloidosis, April 2014; Berk et al., JAMA 310: 2658-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). Previously, the company reported a mean 2.5 point decrease in mNIS+7 at 12 months based on initial results in 20 patients. The effects on mNIS+7 were similar in patients with or without concurrent use of TTR tetramer stabilizers. A number of additional exploratory clinical measures are also being assessed in the OLE study. Updated results (N=27) presented at the ANA meeting showed that these clinical measures remain largely unchanged over the 12-month evaluation period. Finally, repeat dosing with patisiran achieved sustained mean maximum TTR knockdown of 91% for over 18 months, with an up to 96.2% maximal level of TTR knockdown observed in between doses. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.
• Patisiran administration was also found to be generally well tolerated in FAP patients, with minimal drug-related adverse events reported for a period of up to 21 months. As of the time of the current data cutoff on July 15, 2015, 669 doses had been administered with a median of 25 doses per patient. Mean treatment duration was approximately 17 months, and the longest treatment duration was out to 21 months. There were no drug-related serious adverse events. One subject has discontinued the Phase 2 OLE study due to development of gastroesophageal cancer, unrelated to study drug, and has subsequently died; a total of 26 patients remain on study. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations. There were no clinically significant, drug-related changes in liver function tests, renal function tests, or other laboratory or hematologic parameters.
• * On April 21, 2015, Alnylam Pharmaceuticals announced initial 12-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran in patients with familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented at the 67th Annual Meeting of the American Academy of Neurology (AAN) being held April 18 - 25 in Washington, D.C. Study results showed a mean 2.5 point decrease in modified Neuropathy Impairment Score (mNIS+7) at 12 months in patients who had reached the 12-month endpoint (N=20) at the time of data cutoff. This decrease in neuropathy progression compares favorably to the 13 to 18 point increase in mNIS+7 at 12 months that can be estimated from the literature in untreated FAP patients with similar baseline characteristics. In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for approximately 16 months, with an up to 88% mean knockdown achieved between doses. In aggregate, these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. Patisiran was also found to be generally well tolerated out to 17 months of drug administration, with no drug-related serious adverse events to date; all 27 patients enrolled in the study continue to receive patisiran. Alnylam has also announced that it plans to report 18-month OLE data in late 2015.
• New results - presented at the AAN meeting for patients (N=20) who reached the 12-month endpoint as of a data cut off of March 13, 2015 - showed that neuropathy impairment scores were essentially unchanged from baseline values after 12 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 2.5 points, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics (Adams et al., International Symposium on Amyloidosis, April 2014; Berk et al., JAMA 310: 2658-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.4 points at 12 months (N=20), which compares favorably to an estimated 10 to 14 point increase in NIS at 12 months derived from historical data sets in untreated FAP patients with similar baseline characteristics. The effects on mNIS+7 and NIS were similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, complete 6-month results were presented for all 27 patients, and showed mean decreases of 1.4 and 0.7 points in mNIS+7 and NIS endpoints, respectively; these data are consistent with previously reported data for patients that reached the 6 month endpoint (N=19), as reported at the American Neurological Association meeting in October, 2014.
• A summary of mNIS+7 and NIS results (mean ± standard error of the mean (SEM)) at 6 and 12 months is provided in the table below.

					6 months (N=27)					12 months (N=20)
Mean (SEM)Change in mNIS+7					-1.4 ± 2.1					-2.5 ± 2.9
Mean (SEM)Change in NIS					-0.7 ± 1.3					0.4 ± 1.2

• A number of additional exploratory clinical measures are also being assessed in the OLE study, including: quality of life (QOL); timed 10-meter walk test (10MWT) to evaluate mobility; hand grip strength test; modified body mass index (mBMI) as a measure of nutritional status; level of disability by R-ODS; autonomic neuropathy symptoms by COMPASS-31; and nerve fiber density in skin biopsies. New results presented at the AAN meeting showed that these clinical measures were largely unchanged over the 12-month evaluation period. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) in the study, where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three or six months, respectively. Results in the cardiac subgroup showed no clinically significant changes in cardiac biomarkers (N=7-8) or in echocardiographic parameters (N=6-7) after 12 months of dosing. Finally, serum TTR levels are being measured throughout the OLE study. New results showed that repeat dosing with patisiran achieved sustained mean TTR knockdown at the 80% target level for approximately 16 months, and an up to 88% mean level of TTR knockdown was achieved in between doses. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.
• Patisiran administration was also found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to 17 months. As of the time of the current data cutoff on March 13, 2015, 511 doses had been administered with a median of 19 doses per patient. Mean treatment duration was 13 months and the longest treatment duration was out to 17 months. There were no drug-related serious adverse events. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations. Additional reported drug-related adverse events seen in > 5% of patients were mild to moderate in severity and included diarrhea (7.4%) and peripheral edema (7.4%). There were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.
• • On October 13, 2014, Alnylam Pharmaceuticals announced six-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran (ALN-TTR02) in patients with familial amyloidotic polyneuropathy (FAP). These data are being presented at the American Neurological Association's 2014 Annual Meeting being held October 12 - 14 in Baltimore . Results showed a mean 0.95 point decrease in modified Neuropathy Impairment Score (mNIS+7) at six months in 19 patients with mNIS+7 data available for the current analysis. This decrease in neuropathy progression compares favorably with the 7 to 10 point increase in mNIS+7 at six months that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics ( Adams et al., International Symposium on Amyloidosis, April 2014 ; Berk et al., JAMA 310: 26588-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for over nine months, with an up to 89.6% knockdown achieved between doses. Patisiran was found to be generally well tolerated in this study out to one year of therapy, with no drug-related serious adverse events to date, and all 27 patients enrolled in the study continue to receive drug treatment.
• Alnylam's ongoing OLE study is treating patients that were previously enrolled in a Phase 2 study of patisiran in ATTR patients with FAP. The OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration. The two-year study has completed enrollment with 27 patients who receive 0.3 mg/kg of patisiran once every three weeks. This study is also measuring a number of clinical endpoints every six months, including mNIS+7 which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time. The mNIS+7 measurement is the primary endpoint in the company's Phase 3 APOLLO trial of patisiran in FAP patients. A number of additional clinical measures are also being assessed, including: quality of life (QOL); timed 10-meter walk test (10MWT) to evaluate mobility; hand grip strength test; modified body mass index (mBMI) as a measure of nutritional status; level of disability by R-ODS; and nerve fiber density in skin biopsies. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three to six months. In addition, serum TTR levels are being measured throughout the study. The initial results from the ongoing open-label study showed that after six months of treatment with patisiran, neuropathy impairment scores were essentially unchanged from baseline values. As noted above, there was a mean decrease in mNIS+7 of 0.95 points (N=19), which compares favorably to the rapid increase in mNIS+7 of 7 to 10 points estimated at six months from historical data sets in untreated FAP patients with similar baseline characteristics. Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.22 points at six months (N=20). The stabilization in mNIS+7 was similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, no significant evidence for disease worsening was observed in measurements of QOL, 10MWT, mBMI, R-ODS, and nerve fiber density, amongst other clinical assessments performed. In the cardiac subgroup, there were no significant changes in cardiac biomarkers (N=5) or in echocardiographic parameters (N=7) after six months of dosing. Finally, repeat dosing of patisiran achieved sustained TTR knockdown at the 80% target level for over nine months, and an up to 89.6% level of TTR knockdown was achieved in post-dose measurements. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers. Patisiran administration was found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to one year. As of the time of the data cutoff on September 8, 2014 , 282 doses had been administered with a median of 11 doses per patient. Mean treatment duration was seven months and the longest treatment duration was out to one year. There were no drug-related serious adverse events. Infusion-related reactions were infrequent (14.8%), mild in severity, and did not result in any discontinuations. All other reported adverse events were mild to moderate, and there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.
• • On April 28, 2014, Alnylam Pharmaceuticals, a leading RNAi therapeutics company, and collaborators have announced new clinical data for patisiran (ALN-TTR02). These data are being presented at the International Symposium on Amyloidosis (ISA) held April 27 – May 1, 2014 in Indianapolis, Indiana. First, the company presented updated Phase 2 results in patients with Familial Amyloidotic Polyneuropathy (FAP) confirming robust TTR knockdown of up to 96% with a mean TTR knockdown of approximately 80%. Further, Alnylam presented preliminary results from the open-label extension (OLE) study with patisiran in patients that were enrolled in the Phase 2 study. Preliminary results from the OLE study showed that multiple doses of patisiran achieved sustained knockdown of serum TTR protein levels at the 80% target level through 168 days. Moreover, OLE results showed a favorable tolerability profile with up to eight doses administered. Finally, the company presented results of a natural history, cross-sectional analysis study of 283 FAP patients aimed at measuring the rate of neuropathy progression and its correlation with disease severity. These results provide support for Alnylam’s Phase 3 APOLLO trial where patisiran is being evaluated for its potential efficacy and safety in the FAP indication. The company expects to present clinical endpoint data results later this year consistent. Alnylam presented updated results from its Phase 2 study of patisiran, which was conducted in 29 patients with FAP where patients received two doses of drug administered as an intravenous infusion. As previously reported at the International Society of Familial Amyloidotic Polyneuropathy (ISFAP) meeting in November 2013, patisiran demonstrated a rapid, dose-dependent, and durable knockdown of serum TTR of up to 96% and an average TTR knockdown of approximately 80%. The updated data included results from an additional patient dosed in the study and follow up TTR knockdown data from other patients. The company also presented initial results from its Phase 2 OLE study with patisiran. The OLE study is enrolling patients that were treated in the Phase 2 study and is designed to evaluate the long-term safety and tolerability of patisiran administration. The OLE study is also measuring a number of clinical endpoints every six months, including the modified composite Neuropathy Impairment Score, termed "mNIS+7"; this score is also the primary endpoint of the Phase 3 APOLLO trial of patisiran in FAP. Further, serum TTR levels are being measured following the first dose and then pre-dose every six to twelve weeks; since TTR levels are measured pre-dose, the results are a conservative estimate of TTR knockdown achieved over time with repeat dosing. Of the 29 patients eligible for enrollment, 25 have been enrolled to date and an additional two patients are expected to be enrolled by the end of May; the results from 23 patients are currently evaluable for analysis based on a data cut-off as of April 3, 2014.
• Preliminary results showed that the TTR knockdown observed following the first dose in the OLE study closely matched TTR knockdown shown in the Phase 2 study, with essentially superimposable pharmacodynamic effects. Moreover, repeat dosing of patisiran led to a sustained TTR knockdown of approximately 80% through up to day 168, equivalent to up to eight doses of drug, as measured in pre-dose blood samples. These data provide the first clinical evidence of sustained, RNAi-mediated TTR knockdown in FAP patients beyond two doses of patisiran. Repeat dosing of patisiran was found to be well tolerated, with minimal adverse events. Importantly, the incidence of infusion-related reactions (IRR) was found to be significantly reduced to 2% in patients from the Phase 2 and Phase 2 OLE studies receiving study drug with a proprietary micro-dosing regimen, as compared with an incidence of 15% in patients receiving a standard infusion (p=0.03). All other reported adverse events were mild to moderate, and there were no changes in liver function tests, renal function, or hematological parameters. Consistent with earlier guidance, Alnylam continues to plan on reporting initial clinical endpoint data from the OLE study in late 2014. Specifically, the company expects to have 6-month mNIS+7 data from approximately 20 patients at that time. The company intends to provide recurrent updates from the OLE study at least annually thereafter. “These preliminary clinical activity and safety data from the OLE study with patisiran are promising. In particular, the potent, rapid, and durable knockdown of TTR achieved by patisiran, which is now confirmed to be sustained with multi-dosing, is important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit. It is also encouraging to see the favorable tolerability profile for multiple dose administration of patisiran, including the clear reduction in the occurrence of infusion reactions with micro-dosing,” said David Adams, Head of Department of Neurology and Coordinator of the French Reference Center for FAP (NNERF)/APHP/CHU Bicêtre/France.  Finally, Alnylam and collaborators announced the results of a 283-patient natural history study of patients with FAP. The aim of the study was to characterize neuropathy severity and rate of progression in a multinational population of FAP patients. The retrospective cross-sectional analysis showed a change in the NIS rate of 14.3 points per year, consistent with the rate of 11.6 points per year observed in the placebo arm of the diflunisal Phase 3 trial, which included both V30M and non-V30M FAP patients. This change in NIS rate corresponds to a change in the mNIS+7 rate of approximately 17.8 points per year.
• • On November 25, 2013, Alnylam Pharmaceuticals has announced that it has earned a $7 million milestone from its partner Genzyme, a Sanofi company, for achieving Phase II success with patisiran (ALN-TTR02).
• • On September 30, 2013, Alnylam Pharmaceutical has announced that it has completed enrollment in its Phase II trial with ALN-TTR02 for the treatment of TTR-mediated amyloidosis (ATTR). Recent interim results from this Phase II study showed that ALN-TTR02 achieved up to 93% knockdown of transthyretin– the disease-causing protein in ATTR. ALN-TTR02 activity was found to be rapid, dose dependent, and durable, with similar levels of TTR knockdown observed toward both wild-type and mutant protein. In addition, ALN-TTR02 was found to be generally safe and well tolerated in this study.
• The open-label extension (OLE) study with ALN-TTR02 is now open for enrollment. The OLE study will evaluate the long-term safety and tolerability of ALN-TTR02 and will also measure effects of treatment toward a number of clinical endpoints, including a Neuropathy Impairment Score, or “NIS;” the company intends to report clinical data from this study about once per year, with initial data in 2014. Eligible patients treated in the Phase II study can enroll in the study, where they will receive ALN-TTR02 at a dose of 0.3 mg/kg every three weeks for up to two years. The primary objective of this study is to evaluate the long-term safety and tolerability of ALN-TTR02 administration. In addition, the study will measure a number of clinical endpoints at baseline and every six months thereafter. This includes measurement of a modified composite NIS, termed “mNIS+7,” which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance across a 304-point scale, where neuropathy progression leads to an increased score over time. A number of additional clinical endpoints will be assessed, including: quality of life; timed 10-meter walk test to evaluate mobility; modified body mass index as a measure of nutritional status; level of disability; and nerve fiber density in skin biopsies. Initial data from the OLE study are expected to be presented in 2014, with periodic updates thereafter approximately once a year.

 

Is general: Yes