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Clinical Trials

Date: 2018-11-27

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The Journal of the American Medical Directors Association

Company: Dyax (USA - MA), now Shire (UK - USA)

Product: DX-2930 - lanadelumab

Action mechanism:

  • monoclonal antibody. Lanadelumab - DX-2930 is a novel, fully human monoclonal antibody that specifically binds and inhibits plasma kallikrein, an enzyme which is uncontrolled in people with HAE, to help prevent attacks.
  • It is being developed as a subcutaneous injection with a half-life of approximately 14 days in patients with hereditary angioedema. 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 hereditary angioedema.
  • Lanadelumab is approved under the brand name Takhzyro™ in the U.S. and Canada

Disease: type 1 and type 2 hereditary angioedema (HAE)

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country: Canada, Germany, Italy, Jordan, Puerto Rico, UK, USA

Trial details:

  • The HELP study is a global, multi-center, randomized, double-blind placebo-controlled parallel group trial that evaluated the efficacy and safety of subcutaneously administered lanadelumab versus placebo over 26 weeks.  The study population comprised 125 patients age 12 or older with HAE Type I or II who were randomized to one of four groups: 150 mg of lanadelumab every four weeks (150 mg Q4W), 300 mg every four weeks (300 mg Q4W), 300 mg every two weeks (300 mg Q2W), or placebo. (NCT02586805)

Latest news:

  •  • On November 27, 2018, Shire announced the Journal of the American Medical Association (JAMA) publication of complete results from the Phase 3 HELP Study™, a randomised, placebo-controlled trial evaluating the efficacy and safety of subcutaneously administered lanadelumab versus placebo over 26 weeks in 125 patients 12 years of age or older with hereditary angioedema (HAE). The HELP Study™ is the largest randomised controlled prevention study ever conducted to date in HAE.
  • The study met all primary and secondary endpoints, with all three lanadelumab treatment regimens demonstrating statistically significant reductions in the mean monthly HAE attack rate compared to placebo. All three of the lanadelumab treatment dosages were better than placebo in reducing the number of attacks. During the study period, the lanadelumab treatment groups averaged from 0.26 to 0.53 attacks over 26 weeks, compared with an average of 1.97 attacks among the placebo group. Significantly more participants receiving lanadelumab than those in the placebo group were attack free throughout the period - 31 to 44 percent compared with 2.4 percent - and reductions were seen in the numbers of moderate attacks, severe attacks and attacks requiring acute treatment. Participants receiving the active drug also reported significant improvements in their quality of life.
  • At 300 mg every two weeks, lanadelumab reduced the number of mean monthly HAE attacks by 87% relative to placebo (adjusted P<0.001). Patients receiving lanadelumab 300 mg every two weeks had 83% fewer moderate to severe attacks (vs. placebo), 87% fewer attacks that needed on-demand treatment (vs. placebo) and an 89% attack rate reduction (vs. placebo) from day 14 to 182.
  • A pre-specified, exploratory analysis showed that over the entire 26-week study period, 44% of patients receiving lanadelumab 300 mg every two weeks (n=12/27) were attack-free vs. 2% of patients receiving placebo (n=1/41). Additionally, in a post-hoc sensitivity analysis of the steady-state period of the last 16 weeks of the study, 77% of patients (n=20/26) receiving lanadelumab 300 mg every two weeks were attack-free vs. 3% of patients on placebo (n=1/37).
  • A clinically meaningful improvement was also observed in 81% of patients treated with lanadelumab 300 mg every two weeks based on the Angioedema Quality of Life Questionnaire (AE-QoL) compared to 37% of patients in the placebo group. The AE-QoL measures the impact of angioedema over a four-week period across four domains: fear/shame, functioning, fatigue/mood, and nutrition.
  • The most commonly reported treatment-emergent adverse events (excluding HAE attacks) in patients treated with lanadelumab during the entire treatment period were injection site pain (42.9%), viral upper respiratory tract infection (23.8%), headache (20.2%), injection site erythema (9.5%), injection site bruising (7.1%), and dizziness (6.0%). Most treatment-emergent adverse events (98.5%) were mild to moderate in severity. The most commonly reported treatment-emergent adverse events in patients treated with lanadelumab that were considered related to treatment were injection site pain (41.7%), injection site erythema (9.5%), injection site bruising (6.0%), and headache (7.1%). There were no deaths or related serious treatment-emergent adverse events.
  • • On November 16, 2018, Shire announced additional data from the Phase 3 HELP (Hereditary Angioedema Long-term Prophylaxis) Study™, evaluating the efficacy and safety of subcutaneously administered lanadelumab in HAE, will be presented at the American College of Allergy, Asthma & Immunology (ACAAI) 2018 Annual Scientific Meeting.
  • Data showed that patients treated with lanadelumab 300 mg every two weeks experienced significantly fewer HAE attacks, were less likely to have moderate or severe attacks or use rescue medication (primary and secondary endpoints), and were more likely to be HAE attack-free than those treated with placebo. These results were noted during the entire 26-week treatment period and, according to a post hoc sensitivity analysis, were greatest for patients during the 16-week steady state period (days 70-182). Interim results from the HELP Study open-label extension found treatment with lanadelumab was generally well-tolerated and consistent with the previously observed safety profile. At the time of interim analysis, patients had been exposed to lanadelumab for a mean (SD) of 8.21 (2.17) months and continued to experience a reduction in HAE attacks.
  • • On March 3, 2018, Shire announced  new Phase 3 results from the HELP Study™ will be highlighted in three poster presentation discussions at the 2018 American Academy of Allergy, Asthma & Immunology (AAAAI) and World Allergy Organization (WAO) Joint Congress.Poster Presentation 151: Consistent Lanadelumab Treatment Effect in Patients with HAE Regardless of Baseline Attack Frequency in the Phase 3 HELP Study
  • Lanadelumab consistently achieved reductions in monthly attack rates compared to placebo, regardless of baseline attack rate and the dosing regimen. In this analysis, patients were categorized by baseline attack rate, 38 of the 125 patients in the trial had a baseline attack rate of 1 to ? 2 attacks per month. Compared to placebo (n=12), patients taking 150 mg every four weeks (n=10) had a 51% reduction in attacks, patients taking 300 mg every four weeks (n=9) had an 80.4% reduction, and patients taking 300 mg every two weeks (n=7) had a 92.8% reduction.
  • Twenty-two patients had a baseline attack rate of 2 to < 3 per month. Compared with placebo (n=8), these patients had a 90.6% reduction in attack rates using 150 mg every four weeks (n=3), 77% with 300 mg every four weeks (n=5) and 88.2% with 300 mg every two weeks (n=6).
  • For patients with a baseline attack rate of ? 3 attacks per months (n=16), patients taking 150 mg every four weeks had a 78.8% reduction in attacks (n=15). Patients receiving 300 mg every four weeks experienced a 70.8% reduction (n=15). Patients receiving 300 mg every two weeks had an 85.9% reduction compared to placebo (n=21).
  • Poster Presentation 150: Lanadelumab in Patients Switching from Long-Term Prophylaxis with C1-Inhibitor (C1-INH)
  • This analysis of the HELP Study evaluated the efficacy of lanadelumab in patients who were previously using a C1-INH for long-term prophylaxis (LTP) and found that all lanadelumab dosing regimens significantly reduced attack rates versus placebo; the reductions were similar in magnitude to those who did not receive prior LTP. Patients 18 years of age and older who were previously on LTP underwent a two-week washout prior to entering the study.
  • Poster Presentation 152: Lanadelumab Markedly Improves Health-Related Quality of Life in HAE Patients
  • Health-related quality-of-life (HRQoL) was assessed as part of the HELP study using the Angioedema Quality-of-Life (AE-QoL) questionnaire, a validated, angioedema-specific instrument to measure impairment in HRQoL. The AE-QoL questionnaire was administered monthly; total and domain (functioning, fatigue/mood, fear/shame, and nutrition) scores were calculated. Responder rates were determined by use of the AE-QoL’s minimal clinically important difference (MCID=6).
  • The pooled lanadelumab group, which included patients across all dosing regimens, demonstrated a significantly greater reduction in total and domain AE-QoL scores, relative to placebo. The largest decrease in AE-QoL score (decrease indicates improvement) was observed in the functioning domain with a mean change of -29.28 for the pooled lanadelumab group compared to -5.41 for placebo. Items in the functioning domain included impairments in work, physical activity, spare time activities or social relations.
  • There was no evidence of a treatment effect for the EQ-5D-5L questionnaire, a non-validated, non-disease specific QoL tool. In addition, a significantly higher proportion of patients in the pooled lanadelumab group achieved an MCID in total AE-QoL scores (70% versus 37% for placebo).
  • • On May 18, 2017, Shire announced positive topline Phase 3 results for the HELP™ study, a global, multi-center, randomized, double-blind placebo-controlled parallel group trial that evaluated the efficacy and safety of subcutaneously administered lanadelumab versus placebo over 26 weeks in patients 12 years of age or older with Hereditary Angioedema (HAE). The study met its primary endpoint and all secondary endpoints with statistically significant and clinically meaningful results for all three lanadelumab treatment arms compared to placebo. The 300 mg dose administered once every two weeks resulted in a statistically significant reduction in mean HAE attack frequency of 87% compared to placebo. Results were consistent regardless of baseline attack rate. Notably for each of the three lanadelumab regimens studied, whether administered biweekly or monthly, a significantly higher proportion of patients—compared to placebo—were attack free throughout the entire 26 week study period.
  • This study was representative of the full HAE disease spectrum. Overall, 52% of patients experienced three or more attacks per month at baseline, 65% of patients reported a history of laryngeal attacks and 56% were on long-term prophylaxis (LTP). Ninety percent of patients completed the study. Ninety-six percent of those who completed the study chose to roll-over into the ongoing long-term safety study (HELP™ Study Extension).
  • Shire plans to submit a biologics license application (BLA) for evaluation by the FDA by late 2017 or early 2018.
   

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