Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive results from the 6-month primary analysis of the ILLUMINATE-B Phase 3 pediatric study of lumasiran, an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – in development for the treatment of adults and children with primary hyperoxaluria type 1 (PH1). Results were presented from ILLUMINATE-B, as well as new 12-month results from the ILLUMINATE-A pivotal Phase 3 study and the ongoing Phase 2 open-label extension (OLE) study, at the American Society of Nephrology (ASN) Kidney Week 2020 held as a virtual event on October 22-25.
Lumasiran is under review by the Food and Drug Administration (FDA) and received a Positive Opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on October 16, 2020. If approved, lumasiran will be marketed as OXLUMOTM.
“We are delighted to present these positive data from ILLUMINATE-B that reinforce previously reported clinical study findings for lumasiran and underscore its potential to be an important treatment option for patients of all ages with PH1, a devastating and potentially fatal disease with no approved pharmaceutical treatment options,” said Pritesh J. Gandhi, PharmD., Vice President and General Manager, Lumasiran Program at Alnylam. “Based on longer term follow-up from the ILLUMINATE-A and Phase 2 open-label extension studies, investigators presented data showing enduring reductions of urinary oxalate – the disease-causing metabolite in PH1. Moreover, we believe that newly presented results of exploratory endpoints provide preliminary evidence that reductions in urinary oxalate may lead to reduced rates of renal stone events and improve nephrocalcinosis in some patients.”
“Pathologic overproduction of oxalate by the liver is the root cause of morbidity and mortality associated with PH1. There is strong evidence in the literature to suggest that levels of urinary oxalate correlate with clinical outcomes in patients with this ultra-rare disease. With that in mind, I am pleased to see the reduction in urinary oxalate levels in response to lumasiran in all three studies presented at this year’s meeting. More broadly, I am encouraged by the promise that these findings hold for my patients living with this condition,” said Jeffrey M. Saland, M.D., Professor and Chief, Pediatric Nephrology and Hypertension, Jack and Lucy Clark Department of Pediatrics, Mount Sinai Kravis Children’s Hospital, New York City, and Investigator on the ILLUMINATE-A trial. “With the sustained reductions in urinary oxalate during long-term treatment and the exploratory renal stone and nephrocalcinosis data presented, I am hopeful about the potential of lumasiran to have a positive impact on the severe clinical manifestations that individuals with PH1 suffer.”
ILLUMINATE-B 6-Month Results
Alnylam presented positive efficacy and safety results from the 6-month primary analysis (N=18) of the ILLUMINATE-B Phase 3 study of lumasiran in infants and children under the age of 6, with the youngest patient enrolled at 3 months of age. The efficacy results and safety profile of lumasiran were found to be similar to those observed in adults and children 6 years or older in the ILLUMINATE-A study. Treatment with lumasiran in ILLUMINATE-B led to a 72 percent mean reduction in spot urinary oxalate:creatinine ratio from baseline to Month 6, averaged across months 3 to 6 – the primary endpoint of the study. Lumasiran also demonstrated positive results across secondary endpoints, including proportion of patients (9/18 or 50 percent) achieving urinary oxalate levels at or below 1.5 times ULNa.
Preliminary analysis of exploratory endpoints indicated improvements in nephrocalcinosis in 8 out of 18 patients (44 percent), while estimated glomerular filtration rates (eGFR) remained stable. At baseline, 14 of 18 patients had nephrocalcinosis. After 6 months of lumasiran treatment, no patients worsened, 10 remained stable, and eight showed bilateral (3 out of 8) or unilateral (5 out of 8) improvements in nephrocalcinosis. As expected, given the 6-month duration of the study, there was no change in the rate of renal stone events (RSEs)b .
Lumasiran had an acceptable safety profile in infants and young children under the age of six. There were no deaths, severe adverse events, discontinuations of treatment or withdrawals from the study. One patient had a serious adverse event (SAE) of viral infection that was considered not related to lumasiran by the study investigator. The most common drug-related adverse events (AEs) were mild and transient injection site reactions (ISRs) reported in 3 of 18 (17 percent) patients. No clinically relevant changes in laboratory measures (including liver function tests), vital signs, or electrocardiograms related to lumasiran were observed.
ILLUMINATE-A 12-Month Results
As of the data cut-off date of May 1, 2020, results from the extension period of the ILLUMINATE-A Phase 3 study showed that patients initially randomized to lumasiran in the 6-month double-blind (DB) period who continued treatment with lumasiran through Month 12 (“lumasiran/lumasiran”; N=24) maintained their reduction in 24-hour urinary oxalate excretion, with a 64 percent mean reduction relative to baseline. The majority (88 percent) of patients in this group reached normal or near-normal levels (at or below 1.5x ULN)a of urinary oxalate. In patients who were originally randomized to placebo in the DB period but crossed over to lumasiran (“placebo/lumasiran”; N=13), treatment with lumasiran led to a 57 percent mean reduction in 24-hour urinary oxalate excretion after six months of treatment; 77 percent of these patients reached urinary oxalate levels at or below 1.5 x ULN.
In an exploratory analysis, reductions in oxalate levels were associated with lower rates of RSEb in lumasiran treated patients in both lumasiran/lumasiran and placebo/lumasiran groups.
The safety profile of lumasiran remained consistent with ongoing dosing (233 doses) and 9.9 months of mean exposure (range 2.8-15.1 months). There were no deaths, SAEs, treatment interruptions or discontinuations related to lumasiran. One patient had an SAE of urosepsis that was not related to study drug. Mild ISRs were the most common drug-related AE reported in at least 10 percent of patients. Most common ISR symptoms included erythema, pain, pruritus, or swelling at the injection site. No clinically relevant changes in laboratory measures (including liver function tests), vital signs, and electrocardiograms related to lumasiran were observed.
Phase 2 OLE Results
Additional positive data were also presented from the ongoing Phase 2 OLE study of lumasiran demonstrating the long-term efficacy and safety of lumasiran with up to 22 months of exposure (range: 11-22 months; median: 15 months). As of January 30, 2020, data cut-off date, patients continued to experience sustained reductions in urinary oxalate excretion, with similar responses across dosage regimens. Specifically, ongoing treatment with lumasiran resulted in 74 percent (range: 35.7–88.3 percent) mean maximal reduction in urinary oxalate relative to Phase 1/2 baseline (N=17), and 17/18 (94 percent) of patients achieved normal or near-normal levels of urinary oxalate. Mean eGFR levels remained stable over time.
Lumasiran had an acceptable safety profile. There were no deaths, severe AEs, or AEs leading to discontinuation of treatment. There were no drug-related SAEs. The most common drug-related AEs were mild ISRs. No clinically significant laboratory changes related to lumasiran were reported.
Post-hoc analysis of renal stones showed that long-term treatment with lumasiran resulted in a decline in the number of patients experiencing renal stones. In the 12 months prior to study entry, 6/20 patients (30 percent) reported renal stones. In the Phase 1/2 Part B study where renal stones were captured as AEs, 4/20 patients (20 percent) reported AEs of renal stones during the initial 5-month period, and no patients (0/20) reported AEs of renal stones during the Phase 2 OLE with up to 22 months of treatment.
Additional findings on real-world disease manifestations and healthcare resource use among patients with PH1 were also presented based on a retrospective multinational study of physician chart reviews.
To view all data presented by Alnylam at ASN Kidney Week, please visit www.alnylam.com/capella.
Lumasiran has received U.S. and EU Orphan Drug Designations, Breakthrough Therapy and Rare Pediatric Disease Designations from the FDA, and a Priority Medicines (PRIME) designation from the EMA. Alnylam has filed a New Drug Application (NDA) for lumasiran with the FDA, which has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act (PDUFA). Following the recent Positive Opinion from the CHMP, the Company plans to initiate commercialization of lumasiran in the EU under the tradename OXLUMO, upon marketing authorization from the European Commission.
The Company is also conducting ILLUMINATE-C – a global open-label Phase 3 study of lumasiran in PH1 patients of all ages with advanced renal disease, including patients on dialysis, with topline results expected in 2021.
a Upper limit of normal or ULN = 0.514 mmol/24 hr/1.73m2; 1.5 x ULN = 0.771 mmol/24 hr/1.73 m2
b A renal stone event (RSE) is defined as an event that includes at least one of the following: visit to healthcare provider because of a renal stone, medication for renal colic, stone passage, or macroscopic hematuria due to a renal stone
About ILLUMINATE-A Phase 3 Study
ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients, age six and older, with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly doses at 3 mg/kg. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo. Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening (≤1.7 or >1.7 mmol/24hr/1.73m2). Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety and tolerability.
About ILLUMINATE-B Phase 3 Study
ILLUMINATE-B (NCT03905694) is a single arm, open-label, multicenter Phase 3 trial to evaluate the efficacy and safety of lumasiran in 18 patients with PH1 under the age of six (range: 3-72 months), with an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2 or normal serum creatinine if less than 12 months old, at nine study sites, in five countries around the world. Lumasiran was administered according to a weight-based dosing regimen. The primary efficacy endpoint of the study was the percent change from baseline to Month 6 in spot urinary oxalate:creatinine ratio averaged across Months 3 to 6. At six months, relative to baseline, lumasiran demonstrated a clinically meaningful reduction in spot urinary oxalate:creatinine ratio. Reduction of urinary oxalate relative to baseline was consistent across all three body weight categories (less than 10 kg; 10 kg to less than 20 kg, and 20 kg or higher).
Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of primary hyperoxaluria type 1 (PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received both U.S. and EU Orphan Drug Designations, Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). Lumasiran is under review by the U.S. FDA and received a Positive Opinion from the Committee for Medicinal Products for Human Use (CHMP) of the EMA.
About Primary Hyperoxaluria Type 1 (PH1)
PH1 is an ultra-rare disease in which excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a small minority of patients respond to vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S, EU, and Brazil. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam 2020” strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam or on LinkedIn.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the safety and efficacy of lumasiran as demonstrated in the ILLUMINATE-B Phase 3 study in children under the age of six, including infants, as well as in the 12-Month extension period of the ILLUMINATE-A pivotal study and in results from the ongoing Phase 2 OLE study, the potential for lumasiran to have a favorable impact on PH1 disease manifestations and overall disease progression and management across all ages, Alnylam's expectations with respect to the review timelines for the lumasiran NDA by the FDA and expectations regarding EMA approval following the Positive Opinion from the CHMP, Alnylam’s plans, assuming favorable regulatory reviews, to bring lumasiran to patients with PH1 around the world under the tradename OXLUMO, expectations regarding the timing of topline results from ILLUMINATE-C, and expectations regarding the continued execution on its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam’s business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam’s ability to execute business continuity plans to address disruptions caused by the COVID-19 or any future pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates, including lumasiran, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam’s ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to establish and maintain strategic business alliances and new business initiatives; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.
Christine Regan Lindenboom
(Investors and Media)