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Emgality and CCH - bummer trial results


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I guess we kind of knew this, but it's still sad to me to see it confirmed.  https://www.docguide.com/phase-3-randomized-placebo-controlled-study-galcanezumab-patients-chronic-cluster-headache-results-3?tsid=5

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment; Dodick D, Goadsby P, Lucas C, Jensen R, Bardos J, Martinez J, Zhou C, Aurora S, Yang J, Conley R, Oakes T; Cephalalgia 333102420905321 (Feb 2020)

  • OBJECTIVE To report efficacy and safety of galcanezumab in adults with chronic cluster headache.

BACKGROUND Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity.

METHODS This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported.

RESULTS A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was -4.6 placebo versus -5.4 galcanezumab ( p  = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema.

CONCLUSION Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine.

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For 2019, the 30-day efficacy jumped to over 90% of CHers starting this regimen experiencing a significant reduction in CH frequency from a mean of 21 CH/week down to a mean of 4 CH/week.  Better yet, over 65% of CHers starting this regimen experienced a lasting cessation of CH in the first 30 days. 

I attribute this increase in efficacy to the switch to the Bio-Tech D3-50 50,000 IU water soluble vitamin D3.  That's the only thing that's changed since July of 2018.

I know the medical evidence purists will say an open label observational study rates a low level of medical evidence.  To that I say, this is not your every-day average observational study.  It's been running for over 8 years with over 320 participants and the year-over-year 30-day efficacy has remained constant at ≥80% for a favorable response and ≥50% for a lasting complete cessation of CH in the first 30 days.  Moreover the generalizability of these results is very good as participants have come from 35 different countries around the world.

That's not to mention all the health benefits made possible by the anti-inflammatory regimen at a cost of ~ 50 cents/day or $15/month USD.  The Emgality cost is $550/month and it carries some onerous adverse side effects.

Bottom line...  The Anti-CGRP mAbs are never going to work as they cannot pass through the blood brain barrier to reach the site of action in neuronal nuclei within the trigeminal ganglia where CGRP is expressed.  At best all the Anti-CGRP mAbs can do in lower the CGRP serum concentration.  Here's the math and molecular biology behind this statement.  These mAbs have a molecular mass of 150 kDa (150,000 Daltons) but the fenestration (windows) through the BBB have a maximum aperture of 400 Da.  That makes the monoclonal antibodies 375 time too big to pass through the BBB windows.

A molecule of vitamin D3 has a molecular mass of 385 Da so it passes readily through the BBB and into neuronal nuclei to do its thing through genetic expression to down-regulate (decrease) the expression of CGRP, SP, VIP and PACAP.  The Anti-CGRP mAbs only react to CGRP. 


Edited by Batch
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