Alnylam Reports Positive Initial Clinical Results for ALN-AS1, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1 (ALAS1) for the Treatment of Acute Hepatic Porphyrias

CAMBRIDGE, Mass.--()--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today 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. 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.

"The acute hepatic porphyrias are caused by mutations in heme synthesis enzymes that result in build up of ALA and PBG, the toxic intermediates that mediate porphyria attacks. Accordingly, we're very encouraged by these initial Phase 1 data, showing up to 82% lowering of ALA and up to 93% lowering of PBG in ASHE patients with AIP. We are also impressed by the durability of effect on these disease biomarkers following a single subcutaneous injection, which we believe to be supportive of a monthly or potentially once quarterly dosing regimen, and we've now transitioned to the multi-dose cohorts in the Phase 1 study to explore this potential. Importantly, ALN-AS1 has been generally well tolerated, with no clinically significant drug-related adverse events reported to date. We very much look forward to the continued advancement of ALN-AS1, which we believe has the potential to be a transformative therapy for patients with acute hepatic porphyrias, a group of ultra-rare orphan diseases with enormous unmet medical need," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. "It's also notable that this is now our fifth GalNAc-siRNA conjugate program to demonstrate robust clinical activity and excellent translation from non-human primate to human studies, providing further support that we've achieved what we believe to be a reproducible and modular platform for innovative medicines. Accordingly, our R&D efforts continue to create what we believe to be a significant opportunity for patient impact and value creation."

"Patients with AIP and other hepatic porphryias often present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, neuropathy, neuropsychiatric manifestations, and, in very severe cases, cardiovascular instability, paralysis and respiratory failure. Novel therapies are clearly needed for porphyria patients who suffer from recurrent attacks, as these patients experience enormous suffering and a very poor quality of life," said Eliane Sardh, M.D., Ph.D., Senior Physician at the Porphyria Centre Sweden and the Centre for Inherited Metabolic Diseases and Department of Endocrinology, Metabolism and Diabetes at Karolinska University Hospital in Stockholm, Sweden. "I am encouraged with these initial Phase 1 data with ALN-AS1, which I believe support the potential for an RNAi therapeutic to reduce disease burden in patients with AIP and other acute hepatic porphyrias. If proven to be safe and effective in more advanced studies, I believe a subcutaneously administered drug with an infrequent dosing regimen would be a very welcome therapeutic option for these patients and their caregivers."

ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that employs Alnylam's ESC-GalNAc delivery technology. 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.

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
















  3.4   1.1 ± 1.1   13.4   8.5 ± 3.1   25.6   11.7 ± 6.8

0.035 mg/kg

  23.4   15.9 ± 4.2   59.1   44.4 ± 7.5   62.5   45.3 ± 12.1

0.1 mg/kg

  42.2   33.7 ± 5.8**   78.8   65.5 ± 12.5*   89.3   70.5 ± 11.9*

0.35 mg/kg

  59.2   44.5 ± 8.2**   89.5   77.1 ± 6.9**   81.0   72.6 ± 5.5~

1.0 mg/kg

  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.

"Patients afflicted with acute hepatic porphyrias, such as AIP, can suffer from severe and recurrent attacks resulting in a markedly decreased ability to lead a normal functioning life," said Desiree Lyon, Co-Founder and Executive Director of the American Porphyria Foundation. "I am encouraged by the initial clinical data emerging from Alnylam's investigational porphyria program, as they suggest the potential for ALN-AS1 to have an impact on the cause of painful disease symptoms. Moreover, I am grateful for Alnylam's commitment and care for our community, and believe that their efforts could make a meaningful difference in the lives of our patients."

Also in an oral presentation at the ICPP, Alnylam presented initial results (from data in the database as of August 14, 2015) from the EXPLORE study, a multinational, prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks. This study aims to provide enhanced understanding of the natural history of hepatic porphyrias in patients with recurrent attacks, as well as to obtain information about the burden of disease, current management and unmet need. Initial data presented at ICPP were from 68 patients, who had a mean of 10.6 ± 11.0 attacks for the 12 months prior to study entry. In baseline questionnaires, the most common symptoms associated with past porphyria attacks were abdominal and back pain, tiredness, nausea, weakness, and change in urine color. Also, it was found that approximately 50% of patients experience chronic porphyria symptoms even when not having an acute attack. In their baseline evaluation, the patients reported a diminished quality of life, with an EQ-5D Index of 0.74, even while not in the midst of an acute attack. After enrollment in the study, a total of 101 porphyria attacks were documented, with 41/68 (60%) patients reporting at least one attack; the mean duration of attacks was 7.9 days. The majority of attacks were treated in the hospital setting with hematin and/or pain management. At baseline, liver ALAS1 mRNA was elevated by over 4-fold compared to healthy subjects, and this was found to significantly increase further during an acute attack (p less than 0.0001, repeated measures model). Similarly, in a group of patients (n=16) with paired samples from both asymptomatic and attack periods, urinary ALA and PBG levels increased above asymptomatic levels by 6.3- and 2.5-fold, respectively, during the acute attack period. These data suggest that elevated levels of ALAS1 mRNA, ALA, and PBG are associated with acute attacks in patients with acute hepatic porphyria, and that they may be useful biomarkers for disease activity. The EXPLORE study is ongoing, and the company plans to report additional data from this study in 2016.

Genzyme Alliance
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. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

Conference Call Information
Alnylam management will discuss these new Phase 1 results with ALN-AS1 in a webcast conference call on Tuesday, September 15 at 8:30 a.m. ET. A slide presentation will also be available on the Investors page of the company's website,, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 36798385. A replay of the call will be available beginning at 11:30 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 36798385.

About ALN-AS1
Alnylam is developing 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). AIP is an ultra-rare autosomal dominant disease caused by loss of function mutations in porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis pathway that can result in accumulation of toxic heme intermediates, including aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP can suffer from acute and/or recurrent life-threatening attacks characterized by severe abdominal pain, neuropathy (affecting the central, peripheral or autonomic nervous system), and neuropsychiatric manifestations. ALN-AS1 is an ESC-GalNAc-siRNA conjugate targeting ALAS1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the heme biosynthesis pathway. Inhibition of ALAS1 is known to reduce the accumulation of heme intermediates that cause the clinical manifestations of AIP. ALN-AS1 has the potential to be a prophylactic approach for the prevention of recurrent attacks, as well as for the treatment of acute porphyria attacks.

About Acute Hepatic Porphyrias
The porphyrias are a family of rare metabolic disorders with autosomal dominant inheritance predominately caused by a genetic mutation in one of the eight enzymes responsible for heme biosynthesis. Acute hepatic porphyrias constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria, and variegate porphyria. Exposure of acute hepatic porphyria patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinic acid synthase 1 (ALAS1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of heme intermediates that precipitate disease symptoms. Patients with one of the acute hepatic porphyrias can suffer from a range of symptoms that, depending on the specific type, can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and possibly death if untreated or if there are delays in treatment. The only approved treatment for acute attacks is hematin (Panhematin® or Normosang®), a preparation of heme derived from human blood. Hematin requires administration through a large vein or a central intravenous line and is associated with a number of complications including thrombophlebitis or coagulation abnormalities. While hematin is not approved for prophylactic use (i.e., the prevention of acute attacks), it is often used in this manner in patients who experience recurrent attacks. Chronic administration of hematin has been found to result in renal insufficiency, iron overload, systemic infections (due to the requirement for central venous access) and, in some instances, tachyphylaxis.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline programs, including programs in clinical development.

About RNAi
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs – including 4 in late stages of development – across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam's pipeline of investigational RNAi therapeutics, please visit

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 potential for RNAi therapeutics, including ALN-AS1 for the treatment of acute hepatic porphyrias and the potential clinical activity and durability of ALN-AS1, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 1 clinical trial of ALN-AS1 and the EXPLORE study, expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-AS1, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage operating expenses, Alnylam's ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, 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 to update any forward-looking statements.



Alnylam Pharmaceuticals, Inc.
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