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Clinical Trials

Date: 2017-09-07

Type of information: update on patient enrollment

phase: 1

Announcement: update

Company: Alnylam Pharmaceuticals (USA - MA)

Product: givosiran (ALN-AS1)

Action mechanism:

  • RNAi. Givosiran (ALN-AS1) is a subcutaneously administered, investigational RNAi therapeutic that utilizes Alnylam's proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. This RNAi is targeting aminolevulinic acid synthase 1 (ALAS1). ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. In pre-clinical studies, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED50 of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of ALA and PBG, the toxic heme intermediates in AIP. Pre-clinical studies with RNAi therapeutics targeting ALAS1 have been published by Alnylam and collaborators previously (Yasuda et al., Proc Natl Acad Sci USA 2014;111(21):7777-7782).
  • In January 2014, Alnylam and Genzyme, a Sanofi company, 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. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-AS1, in the rest of the world.

Disease: hepatic porphyrias, including acute intermittent porphyria (AIP)

Therapeutic area: Rare diseases - Metabolic diseases

Country: Sweden, UK

Trial details:

  • The purpose of this study is to evaluate the safety and tolerability of ALN-AS1 in AIP patients as well as to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of ALN-AS1 in AIP patients. The Phase 1 trial is being conducted in three parts. Parts A and B are randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE subjects. Per protocol, ASHE subjects in the study have a defined mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary levels of ALA and PBG, but do not have a recent history of porphyria attacks or disease activity. The primary objective of Parts A and B is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urinary levels of ALA and PBG. Exploratory objectives include the impact of ALN-AS1 on liver ALAS1 mRNA as measured from circulatory or excreted exosomal mRNA preparations in serum or urine, respectively. Part C will be a multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, pharmacodynamics (i.e., lowering of serum and urine ALA and PBG, as well as liver ALAS1 mRNA) and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks and other disease symptoms, use of hematin and pain medications, number and duration of hospitalizations, and quality of life. (NCT02452372)

Latest news:

  • • On September 7, 2017, Alnylam Pharmaceuticals announced an update on its givosiran investigational RNAi therapeutic program.  The company has reached alignment with the FDA on a Phase 3 study design which includes an interim analysis based on reduction of a urinary biomarker, aminolevulinic acid (ALA), as a surrogate endpoint reasonably likely to predict clinical benefit for the treatment of acute hepatic porphyrias (AHP). Based on the new givosiran Phase 3 design, the company is now guiding that pending FDA review of the program at the time of interim analysis and assuming positive results, it expects to submit an NDA at or around year-end 2018.
  • • On June 26, 2017, Alnylam Pharmaceuticals announced new positive interim results from Part C, cohorts 1-3, of its ongoing double-blind, randomized, placebo-controlled Phase 1 study, in addition to initial results from an open-label extension (OLE) study with givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias.
  • These results were presented in an oral presentation at the 2017 International Congress on Porphyrins and Porphyrias (ICPP), being held from June 25 - 28, 2017 in Bordeaux, France . Results provide evidence that givosiran has the potential to prevent porphyria attacks in patients with acute intermittent porphyria suffering with recurrent attacks. Based on initial results from the OLE study, prolonged administration of givosiran appears to be associated with consistent reductions in the incidence of porphyria attacks. Givosiran administration was generally well tolerated with up to 12 months of treatment. In addition, the Company plans to present updated results from the EXPLORE natural history study of patients with acute hepatic porphyria who experience recurrent attacks. Alnylam remains on track to initiate the givosiran Phase 3 program in late 2017.
  • New results presented at ICPP include all available data from cohorts 1-3 in Part C of the Phase 1 trial (N=12) and cohorts 1 and 2 (N=8) of the OLE study as of the data cutoff date of April 21, 2017. Givosiran achieved potent silencing of the ALAS1 mRNA, which resulted in robust and durable lowering of aminolevulinic acid  and porphobilinogen, the toxic heme intermediates that mediate acute attacks and chronic porphyria symptoms. In the first three unblinded treatment cohorts from Part C, givosiran-treated patients (N=9) experienced a mean 63 percent reduction in the annualized number of all porphyria attacks relative to the run-in period attack rate, with consistent effects observed across a wide range of baseline attack rates. Evaluating only attacks that were treated at a healthcare facility or with hemin, givosiran administration was associated with a mean 73 percent reduction in annualized attack rate relative to placebo during the treatment period. In addition, a 73 percent mean decrease in annualized hemin doses relative to the run-in period was reported. Finally, in a new analysis, the observed reduction in annualized attack rate was found to be associated with the degree of ALA and PBG lowering.
  • Initial results from cohorts 1 and 2 (N=8) of the givosiran OLE study were also presented; to date, all eligible patients have rolled over from the Phase 1 study to the OLE study. Longer-term treatment with givosiran was associated with consistent reductions in the annualized porphyria attack rate. In addition, preliminary evidence was obtained suggesting the potential for further reductions in the attack rate with extended dosing. Specifically, for the six OLE patients randomized to receive givosiran in Phase 1, the mean annualized attack rate during the Phase 1 treatment period was nine and this was reduced further to five in the OLE study with a mean follow up of 111 days. Further, in the two OLE patients randomized to receive placebo in Phase 1, no attacks have occurred as of the data cut-off date following givosiran administration in the OLE study, with a mean follow up of 31 days. The Company expects to continue enrollment and dosing of patients in the OLE study, and plans on reporting results at least once annually.
  • As of the data cutoff date, givosiran administration was generally well tolerated in recurrent attack AIP patients in cohorts 1-3 in Part C of the Phase 1 study and in cohorts 1 and 2 of the ongoing OLE study, with a mean of 169 and 111 days on study, respectively, and up to 12 months on givosiran. In Part C there were no drug-related serious adverse events or discontinuations due to adverse events. Excluding porphyria attacks, three patients had four SAEs; none were assessed as related to study drug. As previously reported, one death occurred in a patient in cohort 3 in the givosiran arm due to hemorrhagic pancreatitis complicated by a pulmonary embolism and following a recent hospitalization for bacteremia; the death was considered to be unlikely related to study drug by the investigator and the study's Safety Review Committee. During the Phase 1 treatment period, all randomized patients reported at least one AE. The majority of AEs were assessed as mild or moderate in severity. Twenty-five percent of patients had severe AEs, assessed as unrelated to study drug. AEs in three or more patients included: abdominal pain, headache, nasopharyngitis, nausea and vomiting. Four patients were assessed as having AEs possibly related to study drug, including injection site reaction (mild and self-limiting), hypersensitivity, myalgia, headache, moderate renal impairment (in a patient with a history of moderate renal impairment) and erythema. There were no other clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters (including liver function tests and lipase tests), or physical examination. The overall safety experience in the ongoing OLE study was consistent with results from the Phase 1 study. No SAEs (excluding porphyria attacks) or discontinuations due to AEs have been reported in the OLE study.
  • • On December 3, 2016, Alnylam Pharmaceuticals announced initial results from Cohorts 1 and 2 of Part C of its Phase 1 study with givosiran, the International Nonproprietary Name for ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. These results were presented in a poster at the 58th Annual Meeting of the American Society of Hematology (ASH). Part C of the Phase 1 study is a randomized, double-blind, placebo-controlled study in patients with acute intermittent porphyria (AIP) experiencing recurrent attacks. Results demonstrated robust and durable lowering of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that are believed to mediate porphyria symptoms and acute attacks.
  • In the first unblinded treatment cohort, givosiran demonstrated initial evidence for clinical activity in AIP patients with meaningful reductions in the number and frequency of porphyria attacks. In addition, aggregated and currently blinded results from the second cohort provided further evidence for clinical activity. In the first two dose cohorts, givosiran was found to be generally well tolerated with no drug-related serious adverse events. In the third dose cohort, which remains blinded, one death was reported after the data transfer date due to acute pancreatitis complicated by a pulmonary embolism and following an earlier hospitalization for bacteremia; the death was considered to be unlikely related to givosiran or placebo by the investigator and the study's Safety Review Committee. The Company plans to initiate a Phase 3 study in late 2017, subject to successful global regulatory interactions. Clinical Activity Results: Initial results from Part C presented at ASH include all available data as of the data transfer date of November 7, 2016. Data presented include unblinded results for Cohort 1 (N=4, 2.5 mg/kg given once-quarterly) and aggregated, blinded results for Cohort 2 (N=4, 2.5 mg/kg given once-monthly) given that the patients in Cohort 2 are still in the treatment phase of the study. Consistent with results in ASHE patients, givosiran administration resulted in robust and durable lowering of ALA and PBG. In Cohort 1, givosiran administration resulted in meaningful reductions in the number and frequency of porphyria attacks. Specifically, as compared with the run-in phase, there was a 74 percent mean decrease in the annualized attack rate and a 75 percent mean reduction in annualized hemin administration. In addition, the maximum attack-free interval (i.e., the greatest period of time between porphyria attacks) was a mean of approximately 10.5 times that observed during the run-in phase. Favorable treatment effects in all three parameters were seen in each of the givosiran-treated patients. In contrast, the single placebo patient in Cohort 1 showed a generally similar number and frequency of porphyria attacks and a generally similar amount of hemin usage during the run-in and treatment phases. Finally, the aggregated blinded data for Cohort 2 patients, with approximately 3 months of treatment phase data, provided additional evidence of clinical activity. Specifically, as compared with the run-in phase, Cohort 2 patients receiving placebo or givosiran showed a 50 percent mean reduction in annualized attack rate and a 76 percent mean reduction in annualized hemin doses administered; the maximum attack-free interval was a mean of approximately 2.4 times that observed during the run-in phase. Results are provided in the table below. Safety Results: As of the data transfer on November 7, 2016 , there were no drug-related serious adverse events (SAEs) reported in Cohorts 1-4. In Cohort 3, which remains blinded, one death was reported after the data transfer date due to acute pancreatitis, with evidence of sludge in the gallbladder, complicated by a pulmonary embolism and following an earlier hospitalization for bacteremia; the death was considered to be unlikely related to givosiran or placebo by the investigator and the study's Safety Review Committee. Of note, increases in pancreatic enzymes and acute pancreatitis have been reported in the literature in patients with acute hepatic porphyria (Shen et al., Acta Neurol Taiwan, 2008;17:177-183; Shiraki et al., Nihon Rinsho, 1995;53:1479-1483). In Cohorts 1 and 2, there were no discontinuations due to adverse events (AEs). Possibly or definitely related AEs reported in two or more cases were injection site reactions and myalgia; all of these events were mild. There were no other clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters, or physical examination.
  • * On September 7, 2016, Alnylam Pharmaceuticals announced interim data from its ongoing Phase 1 study with ALN-AS1 for the treatment of acute hepatic porphyrias. These results were presented during an oral presentation at the 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, being held from September 6 - 9, 2016 in Rome, Italy . The new data were from Parts A and B of the ongoing Phase 1 study, which were conducted in asymptomatic "high excreter" (ASHE) subjects. ASHE subjects have a mutation in the porphobilinogen deaminase (PBGD) gene as found in acute intermittent porphyria (AIP) and have elevated levels of upstream toxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG) that mediate porphyria attacks. Results demonstrated that single and once-monthly, subcutaneous administration of ALN-AS1 achieved rapid, dose-dependent, and durable lowering of ALA and PBG. Further, ALN-AS1 was found to be generally well tolerated. Alnylam is currently conducting Part C of the Phase 1 study in symptomatic AIP patients with recurrent porphyria attacks. Consistent with previous guidance, the Company plans to present initial porphyria biomarker data from Part C in late 2016, with potential clinical efficacy data on the frequency and severity of recurrent attacks expected in 2017. New results include all available data as of the data transfer date of June 28, 2016. In Part A (N=20), subjects were enrolled in five single ascending dose (SAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving ALN-AS1 at doses from 0.035 to 2.5 mg/kg. In Part B (N=8), subjects were enrolled in two multiple ascending dose (MAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving two monthly subcutaneous doses of ALN-AS1 at 0.35 or 1.0 mg/kg. In both Parts A and B, ALN-AS1 administration resulted in rapid, dose-dependent, and durable silencing of liver ALAS1 mRNA. In addition, ALN-AS1 resulted in rapid and dose-dependent lowering of ALA and PBG of up to 95%. Reductions in ALA and PBG were highly durable, with effects lasting for over ten months after a single dose. As of the data transfer date, ALN-AS1 continued to be generally well tolerated in ASHE subjects following single and multiple doses. There were three serious adverse events (SAEs) that were all deemed to be unlikely related to study drug. A total of 78 adverse events (AEs) were reported in both the SAD and MAD cohorts, of which 62 were determined to be not related or unlikely related to ALN-AS1 administration. With the exception of one AE, not related to study drug, that was severe, all other AEs were mild or moderate in severity, and most commonly included abdominal pain, diarrhea, hypoesthesia, nasopharyngitis, pruritis, and rash. Two mild and transient injection site reactions (ISRs) were reported. There were no clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters, or physical examination.
  • * On September 15, 2015, Alnylam Pharmaceuticals announced initial positive results from its ongoing Phase 1 clinical trial with ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. The Phase 1 study is being performed in asymptomatic "high excreter" (ASHE) patients, who carry the genetic mutation of acute intermittent porphyria (AIP) and have elevated levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that mediate porphyria attacks. Study results showed that single subcutaneous doses of ALN-AS1 resulted in an up to 82% lowering of ALA and an up to 93% lowering of PBG, providing human proof-of-concept for this investigational RNAi therapeutic as a potential therapy for AIP and other acute hepatic porphyrias. In addition, through analysis of exosomal mRNA preparations from serum and urine, it was demonstrated that ALN-AS1 treatment resulted in potent, dose-dependent, and durable silencing of ALAS1 mRNA in liver. Further, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events to date.
  • Initial Phase 1 study results were presented in an oral presentation at the 2015 International Congress of Porphyrins and Porphyrias (ICPP) held September 14 - 16 in Dusseldorf, Germany . All results are based on data in the database as of September 2, 2015 . A total of 16 ASHE patients were enrolled in four single ascending dose (SAD) cohorts (N=4 per group), with subjects receiving 0.035, 0.1, 0.35, or 1.0 mg/kg doses of ALN-AS1. In all dose cohorts, the volume of injection was less than 1.0 mL. The 0.035 mg/kg cohort was added to explore a lower dose after initial results were obtained from the 0.1 and 0.35 mg/kg cohorts. The multi-dose Part B of the study has now been initiated with monthly subcutaneous doses of 0.35 mg/kg. Alnylam expects to report initial data from this part of the study in 2016.
  • Measurement of ALAS1 mRNA levels employed a method previously described by Alnylam scientists known as circulating extracellular mRNA detection (cERD) (Sehgal et al., RNA, 20:1-7(2014)), and was performed using serial serum and urine samples. At baseline, ASHE patients enrolled in the study were found to have substantially higher levels of liver ALAS1 mRNA detected in serum and urine relative to normal healthy volunteers. Specifically, there was an approximate 3-fold increase in liver ALAS1 mRNA (p less than 0.001, unpaired t test) relative to levels observed in healthy subjects. ALN-AS1 administration resulted in potent, dose-dependent, and durable silencing of liver ALAS1 mRNA. An up to 59% maximal and 44 ± 8% mean maximum (p less than 0.01, relative to placebo) silencing of liver ALAS1 mRNA was observed in the 0.35 mg/kg dose cohort; as of the data cut-off date, mRNA silencing data are pending for the top 1.0 mg/kg dose. Nadir silencing was achieved at approximately day 21, and effects were highly durable lasting over 42 days after a single dose. While it has been speculated that ASHE patients have increased liver ALAS1 mRNA levels compared to that of healthy subjects, these data represent the first definitive evidence that this is in fact the case in humans. In addition, to the company's knowledge, these mRNA silencing and time course data are the first to ever be presented from any human study with RNAi therapeutics, marking another milestone in Alnylam's efforts to advance this potential new class of medicines to patients.
  • In AIP, loss-of-function mutations in PBGD can result in excessive accumulation of ALA and PBG, the toxic heme synthesis intermediates that mediate porphyria attacks. ASHE patients are asymptomatic, but have increased ALA and PBG levels that, while lower than those seen in AIP patients during an acute attack, are still significantly higher than normal reference values. In the Phase 1 ASHE patient study, mean baseline urinary levels of ALA and PBG were 11.0 and 21.7 mmol/mol creatinine, respectively. Compared to normal, these levels were elevated by approximately 3-fold for ALA and 14-fold for PBG. A single subcutaneous dose of ALN-AS1 resulted in potent, dose-dependent, and highly durable lowering of ALA of up to 82% and PBG of up to 93%. An up to 77 ± 7% and 73 ± 6% mean maximum lowering of urinary ALA and PBG, respectively, was achieved in the 0.35 mg/kg cohort (p less than 0.01 for ALA and p equal to 0.06 for PBG, both relative to placebo). A greater mean maximum lowering of ALA and PBG is expected to be achieved at the 1.0 mg/kg dose, but current data are limited to 2 subjects through day 14. Even at the lowest dose of 0.035 mg/kg, an approximately 33% lowering of ALA and PBG was observed. As with ALAS1 mRNA silencing, nadir effects on ALA and PBG were observed on day 21. Further, reductions in ALA and PBG were highly durable, with effects lasting over 42 days after a single dose. The durability of ALN-AS1 clinical activity is supportive of a once monthly and possibly a once quarterly, low volume subcutaneous dose regimen. There was a close correlation of liver ALAS1 mRNA silencing with ALA and PBG lowering (r2=0.82, p less than 10-15 for both ALA and PBG). Of note, a higher degree of ALA and PBG reduction was achieved at relatively lower levels of ALAS1 mRNA silencing, consistent with similar observations from pre-clinical studies. These data suggest that a substantial reduction in heme synthesis intermediate accumulation can be achieved with moderate levels of ALAS1 mRNA silencing, essentially where mRNA levels are more comparable to those seen in normal individuals. The initial clinical activity results are summarized in the table below.Initial ALN-AS1 Phase 1 Clinical Activity Results
SAD Cohort
Maximum % ALAS1 mRNA Silencing
Mean Maximum % ALAS1 mRNA Silencing#
Maximum % ALA Lowering
Mean Maximum % ALA Lowering#
Maximum % PBG
Lowering
Mean Maximum % PBG Lowering#
Placebo (N=4)
3.4
1.1
± 1.1
13.4
8.5
± 3.1
25.6
11.7
± 6.8
0.035
mg/kg (N=3)
23.4
15.9
± 4.2
59.1
44.4
± 7.5
62.5
45.3
± 12.1
0.1
mg/kg (N=3)
42.2
33.7
± 5.8**
78.8
65.5
± 12.5*
89.3
70.5
± 11.9*
0.35
mg/kg (N=3)
59.2
44.5
± 8.2**
89.5
77.1
± 6.9**
81.0
72.6
± 5.5~
1.0
mg/kg (N=3)^
Pending
Pending
81.7
Pending
93.0
Pending
  • #For mean maximum silencing/lowering relative to baseline, p values from pairwise comparisons vs. placebo using ANCOVA model ^For 1.0 mg/kg group, all ALAS-1 mRNA data are pending; for ALA and PBG data, N=2 at day 14 and N=1 for days 21 and 28 ~ p equal to 0.06 *p less than 0.05 **p less than 0.01
  • In the ongoing study, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events to date. There was one serious adverse event (SAE) of acute abdominal pain, which was deemed to be unlikely related to study drug. There were no study discontinuations. An additional 28 mild to moderate adverse events (AEs) were reported, of which 26 were determined to be not related or unlikely related to ALN-AS1 administration; these occurred with similar incidence in placebo and ALN-AS1 patients, with no dose-dependent trends. One patient in the 1.0 mg/kg cohort experienced a mild, localized injection site reaction (ISR), consisting of transient erythema. There were no other clinically significant, drug-related abnormalities in any laboratory or hematologic assessment, vital signs, electrocardiograms, or physical examinations.
  • The company has now transitioned to Part B of the Phase 1 study, in which subjects are receiving monthly subcutaneous dosing, and the company expects to initiate Part C in AIP patients suffering from recurrent attacks in early 2016. In addition, Alnylam presented initial data from the EXPLORE trial, a multinational, prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks.
  • * On May 26, 2015, Alnylam Pharmaceuticals announced that it has initiated a Phase 1 clinical trial with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias, including acute intermittent porphyria (AIP). The Phase 1 trial of ALN-AS1 will be conducted initially in AIP patients who are asymptomatic "high excreters" (ASHE). These ASHE subjects have a defined mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), but do not have a current history of porphyria attacks or disease activity. Subsequently, the trial is designed to enroll AIP patients who experience recurrent porphyria attacks. The company expects to present initial clinical data from this trial in early 2016. As per the filed CTA, the Phase 1 trial of ALN-AS1 will be conducted in three parts. Parts A and B will be randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE subjects. The primary objective of Part A and Part B is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urinary levels of ALA and PBG. Part C will be an open-label, multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, PK/PD, and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks and other disease symptoms, use of hematin and pain medications, number and duration of hospitalizations, and quality of life.
  • In addition to the Phase 1 trial, Alnylam and clinicians from the American Porphyria Consortium and The European Porphyria Network are currently enrolling patients in the EXPLORE trial, a prospective observational study of patients with acute hepatic porphyrias - including AIP, variegate porphyria, and hereditary coproporphyria - suffering from recurrent attacks. With this study, Alnylam and clinical investigators aim to learn more about the clinical course, management, and disease burden of patients with acute hepatic porphyrias that suffer from recurrent attacks.
  • * On January 5, 2015, Alnylam Pharmaceuticals announced that it has filed a Clinical Trial Application (CTA) with the Swedish Medical Products Agency (MPA) to initiate a Phase 1 clinical trial with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). Per the filed CTA, the Phase 1 trial of ALN-AS1 will be performed first in AIP patients who are asymptomatic "high excreters" (ASHE) - patients with a mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, but no recent symptoms of a porphyria attack - and then in AIP patients who experience recurrent porphyria attacks. Following approval of the CTA, the company expects to initiate the Phase 1 study in mid-2015, with initial data expected to be reported in early 2016. ALN-AS1 now becomes the company's fifth clinical stage program in its Genetic Medicine Strategic Therapeutic Area (STAr) and the sixth clinical pipeline program overall. "ALN-AS1 now becomes our fifth RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter a clinical development stage, and the fourth that utilizes our optimized Enhanced Stabilization Chemistry GalNAc technology. We very much look forward to the continued advancement of ALN-AS1, including the start of our Phase 1 trial in mid-2015, with data expected in early 2016"said Akshay Vaishnaw , M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam.
  • As per the filed CTA, the Phase 1 trial of ALN-AS1 will be conducted in three parts. Parts A and B will be randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE patients. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urine levels of ALA and PBG. Part C will be an open-label, multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, PK/PD, and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks, hematin and pain medication use, and number and duration of hospitalizations.

Is general: Yes