Alnylam Provides Pipeline Update on Fitusiran and Givosiran Investigational RNAi Therapeutic Programs
- Company Suspends Fitusiran Dosing due to Thrombotic Event and Aims to Resume Dosing as Soon as Possible upon Agreement with Global Regulatory Authorities -
- Company Achieves Alignment with
- New Givosiran Phase 3 Plan Enables Potential for NDA Filing of Interim Analysis Results at or Around Year-End 2018 -
- Company to Host Conference Call Today at
Fitusiran Program Update
"We are deeply saddened to learn of this patient's death, and we extend
our sympathies to his family," said
Fitusiran clinical studies include the ongoing Phase 2 OLE study of
hemophilia A and B patients with and without inhibitors and the ATLAS
Phase 3 program, which has recently been initiated but in which patient
dosing has yet to begin. Alnylam recently became aware of a fatal
serious adverse event (SAE) that occurred in a patient with hemophilia A
who was receiving fitusiran in the Phase 2 OLE study. Approximately nine
days prior to hospital admission, he developed exercise-induced right
hip pain that was treated with a total of three doses of factor VIII
concentrate (31-46 IU/kg) on three separate days. Four days prior to
admission, when the patient received his third dose of factor, he
developed a severe headache. While he was initially suspected of having
viral meningitis, the patient was diagnosed with subarachnoid hemorrhage
on the basis of CT imaging, and treated with factor VIII concentrate
administered two to three times daily. Over a 14-day hospitalization,
his medical condition worsened despite the administration of factor and
the patient died from subsequent cerebral edema. The initial diagnosis
of subarachnoid hemorrhage was reported by the investigator as not
related to fitusiran. For a more complete understanding, the Company
initiated further investigation of the SAE, including review of the
patient's CT scans by three independent neuro-radiologists, who all
Based on today's program update, Alnylam will postpone its fitusiran
RNAi Roundtable webinar previously scheduled for
Givosiran Program Update
"We believe that givosiran has shown very promising results as an
innovative approach to potentially preventing debilitating and painful
attacks in patients with acute hepatic porphyrias, a family of
ultra-rare orphan diseases with enormous symptomatic burden and unmet
need. Based on our ongoing clinical study results, we are very pleased
with the support from global regulatory authorities who share our
commitment to evaluate and establish the efficacy and safety of
givosiran as a therapeutic option for patients as rapidly as possible,"
In interim Phase 1 study
results presented at the 2017
As previously scheduled, Alnylam will discuss the givosiran program,
including the Phase 3 study and interim analysis design, at an RNAi
Roundtable event today at
Conference Call Details
Management will discuss these updates via conference call today, Thursday, September 7, 2017, at 8:00 a.m. ET. A slide presentation will also be available on the Investors page of the Company's website, www.alnylam.com, 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 81805520. A replay of the call will be available beginning at 11:00 a.m. ET on September 7, 2017. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 81805520.
Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding. Fitusiran utilizes Alnylam's ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability. The clinical significance of this technology is under investigation.
The safety and efficacy of fitusiran have not been evaluated by the
Hemophilia is a hereditary bleeding disorder characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective clotting, thereby resulting in recurrent bleeds into joints, muscles, and major internal organs. There are approximately 200,000 persons diagnosed worldwide with hemophilia A and hemophilia B.
Standard treatment for persons with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or "on-demand" therapy, which can lead to a temporary restoration of thrombin generation capacity. However, as many as one third of people with severe hemophilia A will develop a neutralizing antibody to their replacement factor - a very serious complication; individuals with these ‘inhibitors' become refractory to standard replacement factor therapy. Inhibitors may also develop in severe Hemophilia B patients, albeit at a lower rate.
Alnylam is developing givosiran (formerly known as ALN-AS1), a
subcutaneously administered, investigational RNAi therapeutic targeting
ALAS1 for the treatment of AHP, including AIP. AIP is the most common of
the porphyrias, 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 ALA and PBG. Givosiran 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. Givosiran
has the potential to be a novel treatment approach for the prevention of
recurrent attacks. Givosiran has been granted the following regulatory
designations: PRIME by
The safety and efficacy of givosiran have not been evaluated by the
About Acute Hepatic Porphyrias
The porphyrias are a family of rare metabolic disorders with mostly autosomal dominant inheritance predominantly caused by a genetic mutation in one of the eight enzymes responsible for heme biosynthesis. Acute hepatic porphyrias (AHP) constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP) and ALAD-deficiency porphyria (ADP). Exposure of AHP 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 neurotoxic heme intermediates that precipitate disease symptoms. Patients with AHP 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 paralysis and death if untreated or if there are delays in treatment. There are no approved treatments for the prevention of attacks; the only approved treatment for acute attacks is hemin for injection (Panhematin® or Normosang®), a preparation of heme derived from human blood. Hemin requires administration through a large vein or a central intravenous line and is associated with a number of complications including thrombophlebitis or coagulation abnormalities. Chronic administration of hemin may result in renal insufficiency, iron overload, systemic infections (due to the requirement for central venous access) and, in some instances, tachyphylaxis.
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding protein synthesis 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, with the goal of preventing disease-causing proteins from being made.
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 patients who have limited or inadequate treatment options. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform and deep pipeline of investigational medicines, including three product candidates that are in late-stage development or will be in 2017. Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam.
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 planned interactions with regulatory authorities and the expected resumption of dosing in its fitusiran clinical studies, the potential for fitusiran for the treatment of patients with hemophilia A and B, with or without inhibitors, the potential for givosiran for the treatment of hepatic porphyrias, expectations regarding the initiation of a Phase 3 clinical study for givosiran and the possibility of an interim analysis in such study, the anticipated filing date of an NDA for givosiran, and expectations regarding 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, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its product 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 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, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its intellectual property rights against third parties and defend its patent portfolio against challenges from third parties, obtaining and maintaining regulatory approval, pricing and reimbursement for products, progress in establishing a commercial and ex-United States infrastructure, 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, 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 and distribution of products, 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.
Fitusiran and givosiran have not been approved by the U.S. Food and Drug Administration, European Medicines Agency, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of these investigational therapeutics.
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