Date: 2016-09-24
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 17th Congress of the International Pediatric Nephrology Association (IPNA)
Company: Alnylam Pharmaceuticals (USA - MA)
Product: ALN-GO1
Action
mechanism: RNAi. ALN-GO1 is an investigational RNAi therapeutic targeting the enzyme glycolate oxidase (GO). PH1 is an autosomal recessive disorder of glyoxylate metabolism, where hepatic detoxification of glyoxylate is impaired due to mutation of the AGXT gene – which encodes the liver peroxisomal alanine-glyoxylate aminotransferase (AGT) enzyme – resulting in excessive oxalate production. Excess oxalate in PH1 patients is unable to be fully excreted by the kidneys leading to the formation of recurrent kidney stones and the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium deposition in the kidneys, and renal obstruction by calcium stones. Compromised kidney function exacerbates the disease as oxalate is released into systemic circulation potentially resulting in subsequent accumulation and crystallization in bones, eyes, skin, heart, and central nervous system, leading to severe illness and death. About 50% of patients will have kidney failure by age 15, and about 80% will have end stage renal disease by age 30. Current treatment options are very limited and although combined organ transplantation of liver and kidneys has been successful, it is a risky procedure and limited due to organ availability. The enzyme GO works upstream of AGT to oxidize glycolate to glyoxylate. Human genetics show that a loss of function mutation in the production of GO results in a 20-fold increase in the amount of glycolate in urine, with normal oxalate levels and normal kidney function. Co-inheritance of GO deficiency in mice with the AGXT mutation that causes PH1 completely prevents disease. These human and mouse genetic data strongly suggest that knockdown of GO through silencing of the HAO1 mRNA may starve the disrupted pathway of glyoxylate and safely reduce the oxalate burden in patients with PH1. ALN-GO1 has been granted Orphan Drug Designation from the European Medicines Agency (EMA) and the FDA in 2016. In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, 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 Sanofi Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-GO1, in the rest of the world (ROW) through the end of 2019, together with certain broader co-development/co-commercialization rights and global product rights for certain products, including ALN-GO1.
Disease: primary hyperoxaluria type 1 (PH1)
Therapeutic area: Rare diseases - Genetic diseases
Country: UK
Trial
details: The Phase 1/2 trial of ALN-GO1 is a randomized, single-blind, placebo-controlled study being conducted in two parts. Part A is a single-dose study designed to enroll up to a total of 40 normal healthy volunteers (NHV). Part B will be a multi-dose study designed to enroll up to a total of 20 patients with PH1. The primary objective of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-GO1. Secondary objectives include evaluation of pharmacokinetics and clinical activity for ALN-GO1 as measured by its effects on serum glycolate and urinary oxalate levels in NHV and PH1 patients, respectively.
Latest
news: * On September 24, 2016, Alnylam Pharmaceuticals announced initial data from its ongoing Phase 1/2 study with ALN-GO1, an investigational RNAi therapeutic targeting glycolate oxidase for the treatment of Primary Hyperoxaluria Type 1 (PH1). Initial clinical results were presented during an oral presentation at the 17th Congress of the International Pediatric Nephrology Association (IPNA), being held September 20 - 24, 2016 in Iguaçu, Brazil . These data were from Part A of the ongoing phase 1/2 study, which is being conducted in healthy adult volunteers. Results showed that single, subcutaneous doses of ALN-GO1 achieved dose-dependent increases in plasma and urine glycolate. Glycolate is the substrate used by the GO enzyme to produce excessive oxalate in patients with PH1; thus, increases in plasma and urine glycolate in normal volunteers confirm effective GO knockdown and provide preliminary human proof of concept for ALN-GO1. Further, ALN-GO1 was found to be generally well tolerated, with no serious adverse events (SAEs) reported through the safety data transfer date. The Company plans to soon transition to Part B of the Phase 1/2 study, which will evaluate multiple doses of ALN-GO1 in patients with PH1. * On December 21, 2015, Alnylam Pharmaceuticals announced that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) for ALN-GO1, a subcutaneously administered investigational RNAi therapeutic for the treatment of Primary Hyperoxaluria Type 1 (PH1). Upon approval of the CTA, the Company plans to initiate a Phase 1 study with ALN-GO1 in early 2016 and expects to report initial clinical data from the trial in late 2016. * On September 8, 2015, Alnylam Pharmaceuticals announced that it has selected a development candidate (DC) for ALN-GO1, an investigational RNAi therapeutic targeting the enzyme glycolate oxidase (GO), also referred to as hydroxyacid oxidase 1 (HAO1), for the treatment of primary hyperoxaluria type 1 (PH1). New pre-clinical data with the ALN-GO1 DC were presented at the 48th European Society of Paediatric Nephrology (ESPN) Annual meeting – held September 3 – 5, 2015, in Brussels – showing up to 99% silencing of the HAO1 mRNA and up to 98% mean reduction of urinary oxalate in animal models of PH1. Based on these data and the significant unmet need in PH1, the company is accelerating its development timelines for ALN-GO1 and now plans to file a CTA in late 2015 and to initiate a Phase 1 study in early 2016. The ALN-GO1 DC employs Alnylam’s proprietary enhanced stabilization chemistry (ESC)-GalNAc-siRNA conjugate platform, a clinically validated approach for RNAi therapeutics that enables subcutaneous dose administration with potent and highly durable effects and a wide therapeutic index. New preclinical study results for ALN-GO1 were presented at the ESPN meeting showing potent, dose-dependent, and durable silencing of the HAO1 mRNA in mice, rats, and non-human primates (NHP). In wild-type animals, HAO1 silencing resulted in dose-dependent increases in serum glycolate. In mouse and rat models of PH1, ALN-GO1 administration resulted in profound lowering of urinary oxalate, with an essentially one-to-one correlation between oxalate lowering and mRNA silencing. Administration of ALN-GO1 resulted in a mean reduction in urinary oxalate of up to 98% in a rat PH1 model with weekly subcutaneous doses. In an ongoing NHP study, ALN-GO1 demonstrated an up to 99% silencing of HAO1 mRNA and showed corresponding increases in serum glycolate levels of up to 4 fold. In NHP, a single subcutaneous dose of ALN-GO1 showed durable efficacy supporting the potential for a once monthly, and possibly a once quarterly, low volume subcutaneous dose profile in human studies. * On October 14, 2014, Alnylam announced that it presented new data from multiple clinical and pre-clinical studies at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 12 - 15, 2014 in San Diego. Among multiple presentations, the company announced a pre-clinical data from the new program, ALN-GO1, in development for the treatment of primary hyperoxaluria type 1 (PH1). PH1 is an autosomal recessive disorder of glyoxylate metabolism, where hepatic detoxification of glyoxylate is impaired due to mutation of the AGXT gene, which encodes the liver peroxisomal alanine-glyoxylate aminotransferase (AGT) enzyme, resulting in excessive oxylate production. Excess oxalate in PH1 patients is unable to be fully excreted by the kidneys leading to the formation of recurrent kidney stones and the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, nephrocalcinosis, and renal obstruction by stones. About 50% of patients will have kidney failure by age 15, and about 80% will have end stage renal disease by age 30. The prevalence of PH1 reported in Europe ranges from 1 to 9 per million. Higher values are reported in specific populations with a high rate of consanguinity. Many patients are diagnosed under the age of 10 years. Current treatment options are very limited and although combined organ transplantation of liver and kidneys has been successful, this is risky and limited due to organ availability. The enzyme glycolate oxidase (GO) works upstream of AGT to oxidize glycolate to glyoxylate. Human genetics show that a loss of function mutation in the production of GO results in a 20-fold increase in the amount of glycolate in urine, but no other clinical symptoms, suggesting that knockdown of GO may starve the disrupted pathway of glyoxylate and thereby reduce the oxalate burden in patients with PH1. A panel of ESC-GalNAc-siRNA conjugates targeting GO were screened in vitro for their ability to silence the GO mRNA. The most potent of these were further evaluated in vivo with subcutaneous dosing, and an ESC-GalNAc-siRNA targeting GO was identified that yielded a single-dose ED50 of 1.25 mg/kg and a multi-dose ED50 of 0.3 mg/kg. In addition, this compound demonstrated therapeutic efficacy in rodent models of PH1, as indicated by a significant decrease in levels of urinary oxalate of up to 79%. As noted above, Alnylam plans to select a Development Candidate for ALN-GO1 by mid-2015 and to file an investigational new drug (IND) application in 2016.
Initial results include all available data as of the data transfer dates on August 17, 2016 (for safety) and September 2, 2016 (for pharmacodynamic activity). Subjects in Part A (N=32) were enrolled in four single ascending dose cohorts (N=8 per group, randomized 3:1 drug:placebo), with subjects receiving ALN-GO1 at doses ranging from 0.3 to 6.0 mg/kg. ALN-GO1 administration resulted in dose-dependent and statistically significant (nominal two-sided p values less than 0.05) increases from baseline in plasma and urinary glycolate as compared to placebo, with up to an 8-fold increase in plasma glycolate in the highest dose cohort. Based on extrapolation from pre-clinical studies, the observed level of glycolate increase would correlate with an estimated greater than 80% silencing of the HAO1 mRNA, the transcript of the GO enzyme. The effects of ALN-GO1 were highly durable, with levels sustained through 85 days at the highest dose, supportive of a once-monthly and possibly once-quarterly subcutaneous dose regimen.
Single doses of ALN-GO1 were shown to be generally well tolerated in healthy adult volunteers. There were no SAEs reported. Adverse events (AEs) were reported in 88% (N=21) of ALN-GO1 treated subjects and 63% (N=5) of placebo treated subjects. Common AEs occurring in greater than 10% of ALN-GO1 treated subjects included nasopharyngitis (N=6), headache (N=5), and transient injection site pain (N=4). All AEs were mild to moderate with the exception of one subject in the lowest dose cohort who had transient, asymptomatic CPK elevation which was unrelated to study drug.
* On March 9, 2016, Alnylam Pharmaceuticals announced that it has initiated a Phase 1/2 clinical trial with ALN-GO1, a subcutaneously administered investigational RNAi therapeutic for the treatment of Primary Hyperoxaluria Type 1 (PH1). The Phase 1/2 trial will be conducted initially in normal healthy volunteers, and, then, in patients with PH1. Initiation of this trial is based on encouraging pre-clinical data presented last year. The Company has guided that it expects to report initial clinical activity data from this trial in late 2016. preclinical data were presented at the 48th European Society of Paediatric Nephrology (ESPN) Annual meeting, held September 3 - 5, 2015 in Brussels. ALN-GO1 demonstrated potent and durable silencing (up to 99 percent) of HAO1 mRNA (the gene for glycolate oxidase) across species and robust lowering of urinary oxalate (up to 98 percent) in animal models of PH1.
In addition, pre-clinical durability data support a once-monthly, and potentially once-quarterly, subcutaneous dose regimen with ALN-GO1.
Pre-clinical data were presented at the 48th European Society of Paediatric Nephrology (ESPN) Annual meeting, held September 3 - 5, 2015 in Brussels , showing that: ALN-GO1 demonstrated potent and durable silencing (up to 99%) of HAO1 mRNA (the mRNA encoding glycolate oxidase) across pre-clinical species and profound lowering of urinary oxalate (up to 98%) in animal models of PH1. In addition, pre-clinical durability data supports monthly, and potentially quarterly, subcutaneous dosing with ALN-GO1.
