Type of information: Granting of a Market Authorisation in the EU
Product name: Takhzyro® (lanadelumab - DX-2930 - SHP643)
Compound: monoclonal antibody inhibitor of plasma kallikrein - recombinant human IgG1 kappa light chain monoclonal antibody targeting plasma kallikrein
Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases
- monoclonal antibody. Takhzyro® is a novel, fully human monoclonal antibody inhibitor of plasma kallikrein (pKal) and is being developed by Dyax as a subcutaneous injection for the prevention of HAE attacks. Uncontrolled pKal activity leads to excessive generation of bradykinin, a vasodilator thought to be responsible for the localized swelling, inflammation and pain characteristically associated with HAE.
- This monoclonal antibody has been designed to recognise and attach to kallikrein proteins, and thereby block the activity of the kallikrein-kinin system and reduce the number of angioedema attacks.
- HAE affects an estimated 1 in 50,000 men and women. Type I is the most common, and accounts for 85 percent of cases. Symptoms of HAE typically begin in childhood and worsen following puberty. Some patients may have many attacks each month, while others will go months without an attack.
Company: Dyax (USA - MA), now Shire (UK - USA)
Disease: hereditary angioedema (HAE)
- • On November 22, 2018, the European Commission has granted Marketing Authorisation for Takhzyro® (lanadelumab) subcutaneous injection, for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older. The recommended starting dose is 300 mg lanadelumab every two weeks. In patients who are stably attack free on treatment, a dose reduction of 300 mg lanadelumab every four weeks may be considered, especially in patients with low weight. The Phase III HELP (Hereditary Angioedema Long-term Prophylaxis) Study™ supporting the approval was recently published in JAMA. Orphan Drug Designation has been maintained by the European Commission.
- • On October 18, 2018, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the granting of marketing authorisation of Takhzyro® (lanadelumab) injection for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older. If approved, lanadelumab will be a first-of-its-kind, fully human monoclonal antibody (mAb) available in the EU that inhibits the activity of plasma kallikrein, an enzyme which is uncontrolled in people with HAE, to help prevent attacks.
- Takhzyro® is administered subcutaneously every 2-4 weeks, offering an improvement in patient care compared to current alternative therapies which are administered either intravenously or more frequently via subcutaneous route.
- The positive opinion is supported by data from the Phase III HELP (Hereditary Angioedema Long-term Prophylaxis) Study™, the largest randomised controlled prevention study conducted to date in HAE, which evaluated the efficacy and safety of subcutaneously administered lanadelumab versus placebo over 26 weeks in 125 patients 12 years of age or older with HAE. In the pivotal study, patients taking lanadelumab 300 mg every 2 weeks had an 87% reduction in mean monthly attacks vs. placebo (adjusted P<0.001). Overall, each lanadelumab treatment arm demonstrated statistically significant attack rate reductions compared with placebo for all secondary efficacy endpoints (adjusted P<0.001 for all comparisons). Patients taking lanadelumab 300 mg every 2 weeks had 83% fewer moderate or severe attacks and 87% fewer attacks that needed on-demand treatment. A pre-specified, exploratory analysis showed that 44% of patients (n=27) receiving lanadelumab 300 mg every two weeks had zero attacks compared to placebo (2%, n=41) for the 26-week treatment period.1 Additionally, in a post hoc sensitivity analysis of the steady state period from Day 70 to Day 182, 77% of patients (n=26) treated with lanadelumab in the same dosage arm of the trial were attack-free compared to placebo (3%, n=37).
- • On September 18, 2018, following priority review, Health Canada has authorized Takhzyro® (lanadelumab injection) for routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults (12 years of age and older). Health Canada’s authorization of Takhzyro® for the routine prevention of HAE attacks in adolescents and adults is supported by results of the Phase III HELP study.
- • On August 23, 2018, the FDA approved Takhzyro® (lanadelumab), the first monoclonal antibody approved in the U.S. to treat patients 12 years and older with types I and II hereditary angioedema (HAE). The agency based its approval on data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 125 patients with HAE. The FDA granted this application Priority Review and Breakthrough Therapy designation.
- • On April 18, 2018, Shire announced that the Swiss Agency for Therapeutic Products (Swissmedic) has validated the marketing authorization application (MAA) for lanadelumab (SHP643). The validation of the MAA confirms that the lanadelumab MAA submission is complete and that the formal review process will begin.
- • On February 27, 2018, Shire announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted an accelerated assessment for lanadelumab (SHP643). Shire is on track to submit its EU Marketing Authorization Application (MAA) in the coming weeks. Accelerated assessments by the CHMP of a marketing authorization filed under the centralized European procedure, reduces the amount of evaluation days required, from 210 to 150. The EMA will grant, upon request, accelerated assessment of an EU MAA if they deem the product to be of major interest for public health and therapeutic innovation
- The clinical development program for Shire's investigational HAE treatment includes data from four clinical trials, including HELP™, the pivotal Phase 3 efficacy and safety study, along with interim data from its extension study. HELP, the largest prevention study in HAE conducted to date, enrolled a total of 125 patients aged 12 years and over with type I/II HAE. The HELP study demonstrated that subcutaneous administration of 300 mg lanadelumab once every two weeks resulted in an 87% reduction in the mean frequency of HAE attacks. In addition, an exploratory endpoint, which will require further confirmatory studies, showed that during the steady state stage of the trial (day 70-182) a 91% attack reduction was achieved with 8 out of 10 patients reaching an attack free state. In this study, no treatment-related serious adverse events or deaths were reported. The most common adverse event was injection site pain (29.3% placebo vs. 42.9% combined lanadelumab arms).
- • On February 23, 2018, Shire announced the FDA accepted the Biologics License Application (BLA) and granted priority review for lanadelumab (SHP643). The BLA for Shire's investigational HAE treatment is supported by data from four clinical trials, including HELP™, the pivotal Phase 3 efficacy and safety study, along with interim data from its extension study. The FDA is expected to provide a decision on lanadelumab by August 26, 2018, based on the Prescription Drug User Fee Act V action date.
- • On September 1-3, 2015, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for recombinant human IgG1 kappa light chain monoclonal antibody targeting plasma kallikrein for treatment of hereditary angioedema.
- • On August 12, 2015, Dyax provided an update regarding its ongoing manufacturing initiatives for DX-2930. Dyax's manufacturing partner, Rentschler Biotechnologie GmbH (Rentschler), is responsible for providing cGMP (Current Good Manufacturing Practice) drug substance for certain future clinical trials and commercial supply. In preparation for commercial-scale production, Rentschler has commenced characterization and validation of the DX-2930 manufacturing processes. In addition, Rentschler will also support Dyax in the preparation of its submissions to regulatory authorities for marketing approval of the product. If DX-2930 is approved, Rentschler will be responsible for producing commercial supply. Dyax and Rentschler entered into a definitive manufacturing services agreement in 2014. Dyax looks forward to initiating the Phase 3 trial for DX-2930 in HAE patients during the latter part of this year.
- • On July 7, 2015, Dyax announced that the FDA granted Breakthrough Therapy designation for the investigation of DX-2930 for hereditary angioedema (HAE). Dyax is developing DX-2930, an investigational fully human monoclonal antibody inhibitor of plasma kallikrein (pKal), as a subcutaneous injection for prevention of HAE attacks. The designation is supported by the interim results of Dyax's Phase 1b clinical trial of DX-2930 in HAE patients. The Phase 1b study met all objectives assessing safety, tolerability and pharmacokinetics of multiple subcutaneous administrations of DX-2930. Additionally, in a pre-specified proof-of-concept efficacy analysis, DX-2930 demonstrated statistically significant reductions in attack rate compared to placebo.
- • On March 31, 2015, Dyax announced positive safety, pharmacokinetic, biomarker, and efficacy results from the Phase 1b clinical study of DX-2930. The company also announced receipt of Fast Track designation from the FDA for the investigation of DX-2930 for HAE.
- • On December 5, 2013, Dyax Corp. has announced that the FDA has granted orphan drug designation to its drug candidate DX-2930, its fully human monoclonal antibody inhibitor of plasma kallikrein, for use in the treatment of hereditary angioedema (HAE). Dyax is developing DX-2930 to be a long-acting, prophylactic agent that prevents HAE attacks. Development plans include a dosage formulation that will permit infrequent self-administration by small volume, subcutaneous injection. DX-2930 is currently being studied in a placebo-controlled, dose-escalation Phase 1 trial in normal individuals. Results from this study are expected in the first quarter of 2014.
- • On September 15, 2014, Dyax announced that the U.S. Patent and Trademark Office (USPTO) has issued two new patents related to DX-2930. One patent, assigned U.S. Patent No. 8,816,055, contains claims covering the specific sequence of DX-2930, and the other, assigned U.S. Patent No. 8,822,653, contains claims covering monoclonal antibodies that bind to the active form of human plasma kallikrein and do not bind human pre-kallikrein. Both patents are expected to provide coverage for DX-2930 until at least 2032. Dyax is currently developing DX-2930 as a subcutaneous injection for the prevention of HAE attacks and expects to report data from a Phase 1b trial early in 2015.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2018-08-23
UE authorization: 2018-11-22
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2013-12-05
Orphan status UE: 2015-10-09
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On November 15, 2018 , the Institute for Clinical and Economic Review (ICER) released a Final Evidence Report and Report-at-a-Glance assessing the comparative clinical effectiveness and value of therapies for long-term prophylaxis against hereditary angioedema (HAE) attacks.
- In its report, ICER assessed three therapies for the prevention of HAE attacks: lanadelumab (Takhzyro™, Shire), and two C1 inhibitors (Haegarda®, CSL Behring ; and Cinryze®, Shire). ICER's report was reviewed at an October 2018 public meeting of the California Technology Assessment Forum (CTAF), one of ICER's three independent evidence appraisal committees. During the meeting, CTAF found that the evidence demonstrated a net health benefit for using the C1 inhibitors as long-term prophylaxis, but that the evidence was insufficient to distinguish between Cinryze and Haegarda. Because of concerns about risks with a new therapy, the committee also found that current evidence was not adequate to determine whether long-term prophylaxis with lanadelumab is superior to on-demand therapy alone.
- Decision makers often give special considerations to therapies for ultra-rare diseases such as HAE, which may lead to coverage and funding decisions at higher thresholds for cost-effectiveness. During their deliberation, CTAF members underscored how HAE represents a particularly high lifetime burden of illness, and that all three prophylactic treatments may significantly improve both patients' and caregivers' ability to return to work or school. The panel recognized that Haegarda and lanadelumab offer simpler administration - subcutaneous injection - which may achieve better patient outcomes over a treatment like Cinryze, which is administered intravenously.
- CTAF voted that both Cinryze and lanadelumab represent a low long-term value for money when compared to on-demand therapy. When evaluating the long-term value for money of Haegarda, the panel's majority vote was split evenly between low and intermediate value. All three prophylactic treatments, at current pricing, exceed commonly cited thresholds for cost-effectiveness. Following the voting session, a policy roundtable of experts - including a patient advocate, physician, drugmaker, and payer representative - convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:
- -Payers seeking to negotiate better prices may consider giving all market share to the two injectable treatments, Haegarda and lanadelumab, due to these therapies' simpler administration compared to intravenous drugs.
- -Prior authorization criteria should be based on clinical evidence with input from clinical experts and patient groups. Insurers crafting coverage policy may seek to confirm HAE through lab tests or physician attestation, determine the appropriateness of long-term prophylaxis based on the frequency and severity of attacks, and use a patient's weight to more precisely manage dosing of weight-based treatments. Specific options are described in greater detail within the full report.
- There are currently no consensus criteria on when to consider starting long-term prophylaxis for patients with HAE. Specialists involved in the care of patients with HAE should convene and work with patients to develop a consensus statement to guide policymakers and payers on the appropriate use of long-term prophylaxis for patients with Type 1 or 2 HAE.
- • On,October 11, 2018, the Institute for Clinical and Economic Review (ICER) released an Evidence Report assessing the comparative clinical effectiveness and value of therapies for long-term prophylaxis against hereditary angioedema (HAE) attacks. The report reviews three therapies for the prevention of HAE attacks: lanadelumab (Takhzyro™, Shire Plc), and two C1 inhibitors (Haegarda®, CSL Behring ; and Cinryze®, Shire). ICER's earlier draft report also included an additional C1 inhibitor, Ruconest® (Pharming Healthcare,), which has since been removed from the assessment because the treatment is no longer under consideration for FDA approval for long-term prophylaxis.
- All three drugs reviewed reduced the number and severity of HAE attacks compared with no long-term prophylaxis, and available data suggest few harms. Haegarda and lanadelumab have the additional benefit of being subcutaneously administered, which may decrease the burden and complexity of administration and avoid complications due to repeated intravenous infusions. Evidence provides high certainty that Haegarda and Cinryze provide a substantial net benefit compared with no prophylaxis. Evidence on lanadelumab was considered promising but inconclusive because of concerns about long-term safety with a new therapy that was only studied in short-term trials and small numbers of patients. Evidence was insufficient to compare the net health benefits among the three treatments.
- Economic analyses assessing long-term cost-effectiveness found that all three treatments far exceed commonly cited thresholds of $50,000-$150,000 per quality-adjusted life year (QALY) gained, with $243,000 per QALY for Haegarda, $5,870,000 per QALY for Cinryze, and $1,020,000 per QALY for lanadelumab. To align costs with the added benefits for patients, discounts off the list price would need to be approximately 59% for Cinryze, 27% for Haegarda, and 33% for lanadelumab.
- However, because the overall cost-effectiveness of prophylactic treatment balances the high treatment cost of prophylaxis with the avoided high costs associated with on-demand treatment of acute attacks, the economic modeling results are highly sensitive to assumptions made about variables such as the baseline rate of acute attacks and the likelihood that patients will switch dosing schedules over time for prophylactic therapy.