Mar 06, 2019 Press Release for Alnylam
Alnylam Reports Positive Topline Results from ENVISION Phase 3 Study of Givosiran in Acute Hepatic Porphyria
Mar 06, 2019
− Givosiran Meets Primary and Majority of Secondary Endpoints, with Significant Reduction in Annualized Rate of Composite Porphyria Attacks Relative to Placebo –
− Alnylam Intends to Complete Filing of New Drug Application (NDA) and Marketing Authorisation Application (MAA) in mid-2019 –
− Full Results to be Presented at the
− Alnylam to Host Conference Call Today at
“Patients living with AHP experience debilitating and sometimes life-threatening neurovisceral attacks as well as chronic disease manifestations which negatively impact their quality of life. We believe the ENVISION results demonstrate a robust therapeutic benefit of givosiran treatment on the debilitating aspects of this disease. Based on these results, we believe givosiran has the potential, if approved, to be a transformative medicine for AHP patients and their families,” said Akshay Vaishnaw, M.D., Ph.D., President, R&D at Alnylam. “We extend our profound thanks to all the patients, investigators, and study staff who participated in the ENVISION study.”
“These positive ENVISION results represent another landmark event in
Alnylam’s pioneering efforts to advance RNAi therapeutics as a whole new
class of medicines. Notably, givosiran is the first GalNAc-conjugate
siRNA to achieve positive Phase 3 results, and the second example of
Alnylam’s R&D strategy bearing fruit due to our focus on genetically
validated targets for the advancement of potential high impact
medicines,” said
Givosiran has received Breakthrough Therapy and Prime designation by the
ENVISION Study Results
ENVISION, a randomized, double-blind, placebo-controlled trial, enrolled 94 patients with AHP (including 89 with genetically-confirmed acute intermittent porphyria [AIP], the most common subtype of AHP), at 36 study sites in 18 countries around the world, and is the largest ever interventional study conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. The primary endpoint for the study was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with AIP over six months.
At six months, givosiran met the primary endpoint in patients with AIP (p less than 0.00000001). All the components of the composite primary endpoint and all subgroup analyses for the primary endpoint favored givosiran. Secondary endpoints listed below also demonstrated statistically significant favorable differences in the givosiran arm compared to placebo (p less than 0.0001):
- Urinary ALA levels at three months in AIP patients;
- Urinary ALA levels at six months in AIP patients;
- Urinary PBG levels at six months in AIP patients;
- Annualized days of administered hemin doses in AIP patients; and
- Annualized attack rate in patients with AHP (including AIP).
The remaining four secondary endpoints did not meet the hierarchical threshold for significance and included: daily worst pain (p equal to 0.053), daily worst fatigue (p equal to 0.29), daily worst nausea (p equal to 0.25), and the physical component summary of the SF-12 health survey in AIP patients (p equal to 0.022).
Adverse events (AEs) were reported in 43/48 (89.6 percent) of givosiran and 37/46 (80.4 percent) of placebo patients and serious adverse events (SAEs) were reported in 10/48 (20.8 percent) of givosiran and 4/46 (8.7 percent) of placebo patients. There were no deaths in the study. One patient, described below, in the givosiran arm (2.1 percent) discontinued treatment due to an AE. AEs reported in greater than 10 percent of givosiran patients and seen more frequently compared to placebo were: nausea, injection site reactions, chronic kidney disease and fatigue; those reported in greater than 10 percent of placebo patients and seen more frequently than in givosiran-treated patients were headache, urinary tract infection, vomiting and pyrexia. The AEs of chronic kidney disease were reported in five givosiran-treated patients (10.4 percent) and no placebo patients; these events were all in patients with renal dysfunction at baseline and patients continued dosing throughout the study. Liver transaminase increases greater than three times upper limit of normal (ULN) were observed in 7/48 (14.6 percent) patients on givosiran and 1/46 (2.2 percent) patients on placebo; all had evidence of iron overload or liver disease at baseline. As previously reported and as noted above, one patient on givosiran discontinued treatment due to an increase in alanine aminotransferase (ALT) levels greater than 8 times ULN, a protocol-defined stopping rule; this elevation did not meet Hy’s Law and subsequently resolved. Peak ALT levels in the other six givosiran-treated patients ranged from 3.0-5.4 times ULN and were not accompanied by bilirubin increases. The patients were asymptomatic, and all events resolved with continued dosing (n=5) or after a brief pause in dosing (n=1).
Upon completion of dosing in the ENVISION double-blind period, all eligible patients (93/94 or 99 percent) enrolled in the ENVISION open-label extension (OLE) study, receiving monthly givosiran administration. In addition, patients continue dosing in the Phase 1/2 OLE study with over two years of exposure to givosiran.
Conference Call Information
Management will discuss these results via conference call on
About Acute Hepatic Porphyria
AHP refers to a family of rare, genetic diseases characterized by potentially life-threatening attacks and for some patients chronic debilitating symptoms that negatively impact daily functioning and quality of life. AHP is comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: AIP, hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD-deficiency porphyria (ADP). These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks. Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis, and consequently, patients afflicted by AHP often remain without a proper diagnosis for up to 15 years. In addition, long-term complications of AHP and its treatment can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease, including iron overload, fibrosis, cirrhosis and hepatocellular carcinoma. Currently, there are no treatments approved to prevent debilitating attacks or to treat the chronic manifestations of the disease.
About Givosiran
Givosiran is an investigational, subcutaneously administered RNAi
therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in
development for the treatment of AHP. Monthly administration of
givosiran has the potential to significantly lower induced liver ALAS1
levels in a sustained manner and thereby decrease neurotoxic heme
intermediates, aminolevulinic acid ALA and PBG, to near normal levels.
By reducing accumulation of these intermediates, givosiran has the
potential to prevent or reduce the occurrence of severe and
life-threatening attacks, control chronic symptoms, and decrease the
burden of the disease. Givosiran utilizes Alnylam’s Enhanced
Stabilization Chemistry ESC-GalNAc conjugate technology, which enables
subcutaneous dosing with increased potency and durability and a wide
therapeutic index. The safety and efficacy of givosiran were evaluated
in the ENVISION Phase 3 trial with positive results; these results have
not been evaluated by the
About RNAi
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 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.
About
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 discovery platform. Alnylam’s
first U.S.
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 benefits of givosiran, its
plans to complete an NDA submission and file an MAA in mid-2019, the
expected timing for the report of full results from the ENVISION study,
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-
1 Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM,
Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D,
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Source:
Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom
(Investors
and Media)
617-682-4340
Josh Brodsky
(Investors)
617-551-8276
For Media Inquiries, please contact:
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