Alnylam Announces Approval of GIVLAARI™ (givosiran) by the U.S. Food and Drug Administration (FDA)
− GIVLAARI Approved for the Treatment of Adults with Acute Hepatic Porphyria (AHP) Based on ENVISION Phase 3 Study Results Showing Significant Reduction in the Rate of Porphyria Attacks in Patients with AHP –
− FDA Approval Received in Less Than Four Months after New Drug Application (NDA) Filing Acceptance –
− GIVLAARI Becomes Second RNAi Therapeutic from Alnylam Approved by
− Alnylam to Host Conference Call Today at
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GIVLAARI™ (givosiran) packaging and product vial (Photo: Business Wire)
“We believe the approval of GIVLAARI represents a landmark event for the advancement of precision genetic medicines, providing new hope for patients and their caregivers living with the debilitating manifestations of AHP and unpredictable nature of AHP attacks, as well as for the doctors who diagnose and treat these patients. We are grateful to the investigators, patients and families who have helped make this new treatment option a reality for the AHP community. We also commend the
In the pivotal ENVISION study, the most common adverse reactions (reported in at least 20% of patients) with GIVLAARI were nausea (27%) and injection site reactions (25%). Other adverse reactions seen in patients treated with GIVLAARI (occurring over 5% more frequently than placebo) include rash, serum creatinine increase, transaminase elevations and fatigue. As previously reported, one patient in the GIVLAARI clinical development program experienced an anaphylactic reaction which resolved with medical management.
“Adults with AHP now have a new treatment option that has demonstrated the ability to reduce the frequency of porphyria attacks by specifically addressing factors associated with attacks and other disease manifestations of AHP,” said
“The FDA approval of GIVLAARI is an important milestone for our community, as we now have a new treatment option for adults living with acute hepatic porphyria,” said
Alnylam is committed to helping people access the medicines they are prescribed and will be offering comprehensive support services for people prescribed GIVLAARI through Alnylam Assist®. Visit AlnylamAssist.com for more information or call 1-833-256-2748.
GIVLAARI is expected to be available for shipment to healthcare providers in the U.S. by year-end. HCPs can initiate the process now by visiting www.AlnylamAssist.com and completing and submitting a Start Form.
In August, Alnylam announced a U.S. gastrointestinal (GI) disease education and promotional agreement for GIVLAARI with
GIVLAARI was reviewed by the
Conference Call Information
Alnylam management will discuss the
IMPORTANT SAFETY INFORMATION
GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.
Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.
Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.
Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.
Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.
Injection Site Reactions
Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.
Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.
The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).
For additional information about GIVLAARI, please see full Prescribing Information.
About GIVLAARI™ (givosiran)
GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of adults with acute hepatic porphyria (AHP). In the pivotal study, GIVLAARI was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or IV hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially-available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of aminolevulinic acid synthase 1 (ALAS1) messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, visit GIVLAARI.com.
Acute hepatic porphyria (AHP) refers to a family of ultra-rare, genetic diseases characterized by potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four types: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase-deficiency porphyria (ADP). Each type of AHP results from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. AHP disproportionately impacts women of working and childbearing age, and symptoms of the disease vary widely. Severe, unexplained abdominal pain is the most common symptom, which can be accompanied by limb, back, or chest pain, nausea, vomiting, confusion, anxiety, seizures, weak limbs, constipation, diarrhea, or dark or reddish urine. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as viral gastroenteritis, irritable bowel syndrome (IBS), addiction withdrawal and appendicitis. Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease or liver disease including hepatocellular carcinoma.
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.
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 approval of GIVLAARI™ (givosiran) injection for subcutaneous use, and the implications of such approval for patients and their caregivers, the results of the ENVISION Phase 3 clinical trial for givosiran, expectations concerning when GIVLAARI will be available for shipment to healthcare providers in the U.S., its plan to offer comprehensive support services for people prescribed GIVLAARI through Alnylam Assist®, its plans to leverage Ironwood’s capabilities in GI to help raise awareness of AHP among U.S. healthcare practitioners and assist in GIVLAARI promotional efforts, expectations regarding the review of GIVLAARI’s MAA under accelerated assessment by the EMA for the treatment of patients with AHP, 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, including GIVLAARI, progress in establishing a commercial and ex-
Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom
(Investors and Media)