Phase 2 study to test the efficacy & safety of KPL 301 in GCA

• Research type

  Research Study

• Full title

  A Phase 2, randomized, double-blind placebo-controlled study to test the efficacy and safety of KPL-301 in giant cell arteritis

• IRAS ID

  247189

• Contact name

  Bhaskar Dasgupta

• Contact email

  bhaskar.dasgupta@southend.nhs.uk

• Sponsor organisation

  Kiniksa Pharmaceuticals, Ltd. (Hamilton, Bermuda) c/o Kiniksa Pharmaceuticals Corp.

• Eudract number

  2018-001003-36

• Duration of Study in the UK

  2 years, 6 months, 1 days

• Research summary

  Research Summary:
  iant cell arteritis (GCA) is an inflammatory disease of large and medium-sized arteries that causes headaches, ischemic visual loss, and jaw and other muscle claudication. If left untreated, GCA can lead to blindness, aortic aneurysm, myocardial infarction, and, rarely, stroke and death. GCA affects adults over 50 years of age, with a 3:1 imbalance of women to men. Glucocorticoids are the mainstay of treatment. While corticosteroids are effective for some patients, many times patients are unable to wean from corticosteroids because they continue to experience disease flares as the dose is reduced.

  This is a Phase 2 randomized, placebo-controlled Proof of Concept study to evaluate the efficacy and safety of KPL-301 co-administered with a 26-week corticosteroid taper in patients with GCA. The study will consist of a screening period (up to 6 weeks), a double-blind placebo-controlled period during which subjects will receive blinded KPL-301 or placebo, a 26-week corticosteroid taper, and will continue on double blind treatment until the last subject has reached the 26-week time point and the results from the 26-week time point have been analysed, and an Open-Label Extension (OLE) for an additional 26-week period. The study will include patients with both new-onset and relapsing disease, and randomization will be stratified according to this criterion.
  
  KPL-301 is a liquid product intended for subcutaneous administration. It is formulated at 150 mg/mL via prefilled syringe.
  60 patients, 50 -85 years of age will be randomised and approximately 36 subjects will be assigned to KPL-301 and approximately 24 subjects assigned to placebo. Of the study population, the aim is to have 50% with new-onset disease and 50% with relapsing disease. Study procedures will include safety and efficacy assessments and PK blood sampling, imaging and Patient Scales and Assessments. This study is sponsored by Kiniksa Pharmaceuticals

  Summary of Results:
  In KPL-301-C001 in GCA, KPL-301 was well-tolerated in 42 subjects with exposures up to 26 weeks. Compared to the placebo group (n=28), there were no substantive differences in incidence of Treatment Emergent Adverse Event (TEAEs) and Serious Adverse Event (SAEs) , vital signs, laboratory measures, electrocardiogram (ECG) findings, and pulmonary function tests, including the diffusing capacity for carbon monoxide (DLCO). There were no deaths in either cohort. The rate of SAEs and TEAEs was slightly lower in the KPL-301 cohort compared to placebo, and there were no related SAEs in the active cohort. The most common TEAEs in the KPL-301 cohort, in descending order of frequency >5% were headache, neck pain, carbon monoxide diffusing capacity decreased, back pain, muscle spasm, upper respiratory tract infection and constipation. Important potential risks thought to be related to immunoglobulin administration or associated with the mechanism of action of KPL-301 have not been identified to date. Although there was a higher frequency of TEAEs coded to DLCO decreased in the KPL-301 arm (4 events, 9.5%) compared to the placebo arm (1 event, 3.6%), review of the detailed individual data does not reveal a meaningful difference in DLCO between the active and placebo cohorts. In the KPL-301 arm, 3/4 events were considered mild and 1 was moderate; in the placebo arm, the 1 event was considered moderate. Further, only 1 of the 4 events of DLCO decreased in the KPL301 arm was considered related to study drug, and the 1 event in the placebo arm was also considered related to study drug. The Independent Pulmonary Evaluation Committee adjudicated (1) all reductions in the Pulmonary function tests (PFTs) Forced vital capacity (FVC) and Forced expiratory volume (FEV)1 that were at least 20% from any previous value, and (2) reductions in DLCO corrected for hemoglobin that were at least 20% from any previous value and confirmed by a repeat test. There were no cases of suspected or confirmed Pulmonary alveolar proteinosis (PAP) by Independent Pulmonary Evaluation Committee adjudication. Although the DLCO corrected for hemoglobin and the percent-predicted the DLCO were slightly lower in the KPL-301 group, the magnitude did not appear to be clinically meaningful. Currently, the evidence is insufficient to prove a causal relationship between KPL-301 treatment and PFT abnormalities and whether reductions in PFTs have meaningful clinical implications. Based upon these safety findings and the efficacy findings discussed earlier, the benefit-risk profile remains favorable, and supports proceeding to a phase 3 study.

• REC name

  London - London Bridge Research Ethics Committee

• REC reference

  18/LO/1542

• Date of REC Opinion

  27 Nov 2018

• REC opinion

  Further Information Favourable Opinion