Type of information: Granting of a Market Authorisation in the EU
Product name: Onpattro™ (ALN-TTR02)
Compound: patisiran (ALN-TTR02)
Therapeutic area: Rare diseases - Genetic diseases
- RNAi/siRNA. Patisiran is an investigational RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it is made. This may help to enable the clearance of TTR amyloid deposits in peripheral tissues and potentially restore function to these tissues.
- In January 2014, Alnylam and Sanofi Genzyme formed an alliance to accelerate the advancement of RNAi therapeutics as a potential new class of innovative medicines for patients around the world with rare genetic diseases.
Company: Alnylam Pharmaceuticals (USA - MA) Sanofi (France)
- transthyretin (TTR)-familial amyloid polyneuropathy (FAP)
- hereditary transthyretin-mediated amyloidosis (hATTR)
• On August 27, 2018, the European Commission has granted marketing authorization for Onpattro™ (patisiran) for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adults with stage 1 or stage 2 polyneuropathy. Onpattro™ is based on Nobel Prize-winning science and is the first-ever RNA interference (RNAi) therapeutic to be approved in the European Union. The EC decision was based on the evaluation of the effects of patisiran in hATTR amyloidosis patients with polyneuropathy and its safety profile as demonstrated in the APOLLO Phase 3 study. Results from the APOLLO study were published in the July 5, 2018, issue of The New England Journal of Medicine.
In APOLLO, the safety and efficacy of patisiran were evaluated in a diverse, global population of hATTR amyloidosis patients in 19 countries, with a total of 39 TTR mutations. Patients were randomized in a 2:1 ratio to receive intravenous patisiran (0.3 mg per kg of body weight) or placebo once every 3 weeks for 18 months. The study showed that patisiran improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms relative to placebo in adult patients with hATTR amyloidosis with polyneuropathy. The primary endpoint of the APOLLO study was the modified Neuropathy Impairment Score +7 (mNIS+7), which assesses motor strength, reflexes, sensation, nerve conduction and postural blood pressure.
• On August 10, 2018, the FDA approved Onpattro™ (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.
- Patients treated with patisiran had a mean 6.0-point decrease (improvement) in mNIS+7 score from baseline compared to a mean 28.0-point increase (worsening) for patients in the placebo group, resulting in a mean 34.0-point difference relative to placebo, after 18 months of treatment.
- While nearly all patisiran-treated patients experienced a treatment benefit relative to placebo, 56 percent of patisiran-treated patients at 18 months of treatment experienced improvement of neuropathy impairment (as assessed by mNIS+7 score) relative to their own baseline, compared to four percent of patients who received placebo.
- Patients treated with patisiran had a mean 6.7-point decrease (improvement) in Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) score from baseline compared to a mean 14.4-point increase (worsening) for patients in the placebo group, resulting in a mean 21.1-point difference relative to placebo, after 18 months of treatment.
- As measured by Norfolk QoL-DN, 51 percent of patients treated with patisiran experienced improvement in quality of life at 18 months relative to their own baseline, compared to 10 percent of the placebo-treated patients.
- Over 18 months of treatment, patients treated with patisiran experienced significant benefit vs. placebo for all other secondary efficacy endpoints, including measures of activities of daily living, walking ability, nutritional status, and autonomic symptoms.
- Patisiran was associated with favorable effects on exploratory endpoints related to cardiac structure and function in the prespecified subpopulation of patients with cardiac involvement.
- The incidence and severity of adverse events were similar in patients receiving patisiran and placebo. The most common adverse events that occurred more frequently with patisiran than with placebo were peripheral oedema and infusion-related reactions. To reduce the risk of infusion-related reactions, patients received premedications prior to infusion.
- The efficacy of Onpattro™ was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro™ infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro™ had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.
- The most common adverse reactions reported by patients treated with Onpattro™ are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro™ leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
- • On July 27, 2018, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending marketing authorization of patisiran for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adults with stage 1 or stage 2 polyneuropathy. If approved by the European Commission (EC), the medicine will be commercialized under the brand name Onpattro™.
- The CHMP positive opinion is based on the evaluation of the effects of patisiran in patients with hATTR amyloidosis and its safety profile as demonstrated in the APOLLO Phase 3 study. The SmPC recommended by the CHMP includes data from APOLLO primary and secondary endpoints, as well as exploratory cardiac endpoints. The results of the APOLLO study were published July 5, 2018 in The New England Journal of Medicine (NEJM).
- • On December 18, 2017, Alnylam Pharmaceutical and Sanofi Genzyme announced the submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of adults with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). Patisiran was previously granted accelerated assessment by the EMA, potentially reducing the Agency’s evaluation time from 210 to 150 days. Sanofi Genzyme is currently preparing regulatory filings for patisiran in Japan, Brazil and other countries, with submissions expected to begin in the first half of 2018
- The APOLLO Phase 3 study (N=225) was a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. The study was completed in August 2017 and detailed study results were presented at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors on November 2, 2017. All patients completing the APOLLO Phase 3 study are eligible to screen for the Global OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
- • On December 12, 2017, Alnylam Pharmaceuticals announced he completion of the rolling submission of a New Drug Application (NDA) to the FDA for patisiran for the treatment of adults with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). The rolling submission began on November 15, 2017 with the nonclinical and chemistry, manufacturing and controls components submitted, and now submission of the clinical data completes the filing. Alnylam has requested priority review for the application which, if granted, could result in a six-month review process.
- • On December 11, 2017, Alnylam Pharmaceuticals announced the FD has granted a request to amend the orphan drug designation for patisiran to the treatment of transthyretin-mediated amyloidosis (ATTR amyloidosis). This is an expansion to patisiran’s prior designation which was for the treatment of familial amyloidotic polyneuropathy. As reported previously, Alnylam initiated the rolling submission of a New Drug Application (NDA) to the FDA for patisiran, which previously received Fast Track and Breakthrough Therapy designations. The company intends to complete the NDA submission by year-end.
- • On November 11, 2013, Alnylam Pharmaceuticals has announced that the FDA has granted Fast Track designation to patisiran (ALN-TTR02) for the treatment of transthyretin (TTR)-familial amyloid polyneuropathy (FAP). According to the FDA, Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Alnylam is developing patisiran for the treatment of ATTR patients with FAP. The company recently announced positive Phase II data, which showed that multiple doses of patisiran led to robust and statistically significant knockdown of serum TTR protein levels of up to 96%, with mean levels of TTR knockdown exceeding 85%. Knockdown of TTR was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally safe and well tolerated in this study. The company has recently initiated an open label extension (“OLE”) study for patients that participated in the Phase II study; the study includes a number of clinical endpoints, and initial data are expected to be reported in 2014. The company also recently initiated the APOLLO Phase III trial of patisiran in ATTR patients with FAP, with the study now open for enrollment.
Submission of marketing authorization application USA : 2017-12-12
Submission of marketing authorization application UE: 2017-12-18
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2018-08-10
UE authorization: 2018-08-27
Favourable opinion UE: 2018-07-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On October 4, 2018, the Institute for Clinical and Economic Review (ICER) released a Final Evidence Report and Report-at-a-Glance on inotersen (Akcea Therapeutics) and patisiran (Onpattro™, Alnylam Pharmaceuticals) for the treatment of hereditary transthyretin amyloidosis (hATTR).
- ICER's report was reviewed at a September 2018 public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), one of ICER's three independent evidence appraisal committees. During the meeting, the Council found that both inotersen and patisiran provide a substantial net health benefit when compared to best supportive care alone, but evidence is insufficient to distinguish between the two treatments. However, current pricing far exceeds commonly cited thresholds for cost effectiveness.
- The Council unanimously recognized that the novel mechanism of action was an important other benefit for treating individuals with such a high lifetime burden of illness. A majority also recognized that the new treatments may reduce family and caregiver burden and may improve a patient's ability to return to work. These Council members emphasized that the burden that a hereditary disease places on families cannot be understated, and that these new treatments may also have a positive psychological effect on multiple generations of a family.
- The Council voted unanimously that, despite the net health benefit, both inotersen and patisiran represent a low long-term value for money. The votes were influenced heavily by the $450,000 annual list price of patisiran, and the assumption that inotersen would be priced similarly.
- Following the voting session, a policy roundtable of experts - including patient advocates, physicians, and payers - convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:
- Given that newly approved treatments for hATTR have new mechanisms of action, lack long-term safety and efficacy data, and are very expensive, it is reasonable for insurers and other payers to develop prior authorization criteria to ensure prudent use of these treatments.
- Manufacturers should bring the price for innovative treatments for hATTR down to a level that aligns fairly with the added benefits for patients.
- Patient organizations that have a leading role in funding, organizing, and promoting innovative research on new treatments should demand commitments from manufacturers for reasonable value-based pricing of the products patients helped bring to the market.
- Future research should address the durability of improvements in neurological function, longer-term safety, and cardiac outcomes provided by treatments for hATTR.