Beur schreef op 2 maart 2015 17:51:
Highlights of Hereditary Angioedema (HAE) Data at the 2015 AAAAI MeetingThe excitement over hereditary angioedema (HAE) at the American Academy of Allergy, Asthma, & Immunology Annual Meeting (AAAAI) Annual Meeting this year mostly evolved around multiple medications, which were just approved or in development. Biocryst, CSL Behring, and Shire all presented data. Biocryst presented their results of the phase 2 trial of their oral kallikrein inhibitor. CSL presented on two new products in development to include preclinical data on their new Factor-12 inhibitor and data on the new subcutaneous C1-inhibitor for prophylaxis. They also presented data from their phase 4 post-marketing safety study. Lastly, Shire presented their data on the phase three study of C1-inhibitor and hyaluronidase combination for subcutaneous injection and data on the post marketing survey of icatibant.
Biocryst’s BCS4161Biocryst’s new therapy for prophylaxis is BCX4161, which is an oral therapy that inhibits kallekrein leading to decrease production of bradykinin. The trial was a double-blind, placebo-controlled, cross-over comparing 400 mg TID of BCX4161 to placebo in 24 patients. In those subjects with serum levels above 24ng/ml there was a reduction of 0.5 attacks per week compared to placebo. Adverse events were not reported.
These data suggest efficacy, but only in those that achieve adequate serum levels, which is complicated by the poor bioavailability of BXC4161. Dose ranging phase two studies have also been completed and phase three studies are presently underway. (1)
CSL Behring’s Berinert and New F12 AntibodyCSL Behring presented two sets of data from their post-marketing study on intravenous C1-inhibitor (Berinert). The first was on 48 patients and 4111 infusions. From this cohort
82 adverse events (AE) were reported from 16 patients.
Only 3 of the AE were thought to be secondary to Berinert. These included non-cardiac chest pain, post infusion headache and deep vein thrombosis (DVT). (2) The latter was in a patient with a central indwelling port, which has been demonstrated to predispose to DVT. (3) A second poster presented data on 14,819 infusions in 318 patients. 95% of the patients self-infused at home. Adverse event profile is similar to the cohort presented above. (4)
One of the most exciting posters included data on a new CSL product that is a monoclonal antibody against Factor 12. The monoclonal, anti-FXIIa mAb 3F7, specifically targets F12, with high affinity, and inhibits its proteolytic function, which prevents the activation of the contact system. 3F7 was effective at preventing edema in a murine model in this preclinical study.
The importance of these data are that this drug may be a specific medication for prophylaxis of HAE with deficient C1-inhibitor and HAE with dysfunctional C1-inhibitor, but also for those with HAE and normal C1-inhibitor, previously called HAE type 3. Shire’s Combination TherapyShire presented their data on the use of C1-inhibitor (Cinryze) combined with recombinant Human Hyaluronidase (rHuPH20) for subcutaneous injection to prevent attacks (prophylaxis). The study was a double-blind, dose-ranging, cross-over study comparing 1000 units C1-inhibitor combined with 24,000 units of rHuPH20 to 2000 units C1-inhibitor combined with 48,000 units of rHuPH20 given subcutaneous every 3 to 4 days. The higher dose appeared to yield 2 fold higher levels of C1-inhibitor function, which would be expected to improve efficacy. Unfortunately the study was terminated due to antibody production against rHuPH20.
It appears that Shire will abandon this product and instead focus on using a more concentrated solution to reduce the needed volume for subcutaneous injection. (6)
Shire also presented their post marketing data from their “Icatibant Outcome Survey”. The outcome survey included 353 patients with a total of 1716 treated attacks. 81% of injections were self-administered. Most initiated therapy within 1 hour of start of attack. Symptom resolution occurred on average in 4.9 hours.
No significant adverse events were reported. (7)
Other HighlightsMultiple other oral and poster presentations were presented on HAE at the 2015 AAAAI; however, the ones noted above seem to suggest this disease space, which already has 5 specific drugs approved, will have a few new ones in the next few years. Present therapies include androgens, fresh frozen plasma, ecallantide, icatibant, c1-inhibitor (Berinert and Cinryze) and the newly approved recombinant C1-inhibitor called Ruconest, but this list will soon grow.
I was surprised very little was presented on Ruconest despite the recent approval for treatment of acute HAE attacks. As noted above 5 drugs are presently being investigated. Subcutaneous Cinryze study has been terminated. Dyax’s monoclonal in in phase 2 studies. CSL Behring’s subcutaneous Berinert is in phase three studies. Biocryst has an on going phase three study with their oral kallikrein inhibitor. Lastly, CSL Behring’s preclinical research on a monoclonal that targets Factor-12 may advance into phase 1 trials soon.
HAE is a rare disease that affects 1 in 20,000-50,000 patients and accounts for 5000 to 15000 patients in the USA; however,
may soon have more therapies than can be counted on 2 hands. www.raredr.com/articles/Highlights--H...