Hereditary Angioedema: Novel Molecules for Treatment of Acute Attacks and Long-Term Prophylaxis

Round 1

Reviewer 1 Report

The patent for FIRAZYR^® (icatibant injection) expired on July 15, 2019. Generic versions of icatibant are available.

Author Response

We thank the Reviewer for the annotation on Firazyr patent expiration. We have added a caption in table 1 for icatibant/Firazyr reporting that "Patent expired in 2019, generic icatibant is now available".

Reviewer 2 Report

This is an extensive and well-prepared review. and I want to congratulate the authors for their work.

Line 73 that may mimic and acute abdomen

Line 83-84  in some cases with increased and some cases a reduction of frequency/severity -please reformulate

Line 141 Is there any method recommended to certify the  stabilization of the therapeutic response?

Line 275 other sc -explain sc

High quality of English

Author Response

We thank the Reviewer for the kind appreciation of our work. 

According to his/her suggestions:

• line 73: "that may mimic and acute abdomen" has been changed in "that may mimic an acute abdomen"
• line 83-84: " in some cases with increased and some cases a reduction of frequency/severity" has been rewritten as: "in some cases there is an increase and in some other cases there is a reduction of frequency/severity".
• Line 141: Is there any method recommended to certify the  stabilization of the therapeutic response?  This is an important observation.  In the real life most patients starting Lanadelumab will show a significant and early reduction of attack rate; yet there is not a shared consensus on what should be considered a stabilization of the disease, induced by long-term prophylaxis. According to the drug label, lanadelumab can be administered every 28 days if the patient has attained an attack-free period of at least 6 months. We have therefore added a short final statement to corroborate the decision of prolonging the administration interval to 28 days that sounds like: "or after 6 months if the patient is attack-free".

• Line 275 other sc -explain sc: sc was intended for subcutaneous; we have amended into: ...subcutaneously administered medications...

Reviewer 3 Report

I congratulate the authors with their manuscript, providing a comprehensive overview of existing treatments and novel developments in the treatment of acute HAE attacks and long-term prophylaxis. 

The outline of the paper is clear and the major advancements and future perspectives with regards to HAE treatment are well described. The overview/summary of novel molecules for treatment seems complete. 

Some minor items that, in my opinion, need to be addressed: 

- Abstract (lines 8-10): as currently stated, it is suggested that HAE can only be due to genetic alterations in the SERPING1 gene. Please acknowledge that different genes (e.g. genes coding for Factor XII, angio-poietin-1 or plasminogen) might also be involved in HAE. 

- Lines 279-280: "ATN-249 (Attune Pharmaceuticals) represents an innovative and potent plasma kallikrein inhibitor, under study for oral prophylactic treatment for HAE". Please add that ATN-249 is considered a small molecule plasma kallikrein inhibitor.

There are multiple grammar and punctation inconsistencies/errors that require attention to improve readability. Some examples include: 

Line 11: "Nowadays there are effective drugs for both 1. Treating acute attacks and 2. Preventing 11 attacks with a long-term prophylaxis'' (Please do not use captital letters here).

Lines 34-40: "This latter vasoactive peptide, binds specifically to B2 receptors, G-protein coupled receptors that are constitutively expressed on endothelial cells, and induce intracellular transduction mechanisms that, through steric rearrangement and destruction of VE-cadherin, produce an increased permeability of the endothelial layer to plasma fluids and the ultimate translocation of liquid from the intravascular space to the subcutaneous site of derma where the original trigger has activated the swelling mechanism." Very long sentence, which impairs readability. (Please chop up into separate sentences). 

Lines 62-63: "probably for a mechanism of" (Please convert into "probably due to")

Line 76: "because may cause asphyxiation" (Please insert the wordt 'it' between 'because' and 'may')

Lines 84-85: "Delivery can be also carried out by vaginal" (Please convert to 'vaginally' of 'by vaginal route')

Lines 121-123: "The effect of danazol in preventing HAE attacks is not completely understood, probably consist of a combination of stimulation of C1 inhibitor synthesis" (Please convert into 'but probably consists')

Line 208: "deucrictibant at variable dosage of 10, 20, 30 mg" (Please change to '10, 20 and 30 mg') 

Lines 211-213: "deucrictibant resulted significantly more efficacious than placebo in reducing VAS-3 after 4 hours of onset; also, patients treated had a less need of rescue medications compared to placebo" (Please convert 'resulted' to 'proved' and remove the word 'a'). 

Lines 399-400: "will restitutes a condition similar" (Please correct to 'restitute')

Lines 419-420: "that once included in the genome, will' (please add a comma between 'that' and 'once')

Author Response

We thank the Reviewer for the appreciation of our work and the useful suggestions that will improve pur manuscript.

• Abstract (lines 8-10): as currently stated, it is suggested that HAE can only be due to genetic alterations in the SERPING1 gene. Please acknowledge that different genes (e.g. genes coding for Factor XII, angio-poietin-1 or plasminogen) might also be involved in HAE. 
• We acknowledge that other genes may be less frequently involved in hereditary forms of angioedema. These forms are also known as angioedema with normal C1 inhibitor. We have focused our review on HAE type I and II with low or dysfunctional C1 inhibitor, due to a genetic defect of the SERPING1 gene; the intended use of approved medications and drugs under development is for these type of HAE. As a matter of fact there are not approved medications for HAE with normal C1 inhibitor. We would like therefore to avoid potential confusion in the not specialized readers about this point. Perhaps, the possible involvement of others genes has been recalled in lines 59-62 (Introduction).
•  Lines 279-280: "ATN-249 (Attune Pharmaceuticals) represents an innovative and potent plasma kallikrein inhibitor, under study for oral prophylactic treatment for HAE". Please add that ATN-249 is considered a small molecule plasma kallikrein inhibitor. 
• We have added small molecule as attribute of ATN-249.
• Line 11: "Nowadays there are effective drugs for both 1. Treating acute attacks and 2. Preventing 11 attacks with a long-term prophylaxis'' (Please do not use captital letters here).
• We have eliminated the capital letters.
• Lines 34-40: "This latter vasoactive peptide, binds specifically to B2 receptors, G-protein coupled receptors that are constitutively expressed on endothelial cells, and induce intracellular transduction mechanisms that, through steric rearrangement and destruction of VE-cadherin, produce an increased permeability of the endothelial layer to plasma fluids and the ultimate translocation of liquid from the intravascular space to the subcutaneous site of derma where the original trigger has activated the swelling mechanism." Very long sentence, which impairs readability. (Please chop up into separate sentences). 
• All the paragraph has been modified as following: This latter vasoactive peptide, binds specifically to B2 receptors, G-protein coupled receptors that are constitutively expressed on endothelial cells. B2 receptors induce intracellular transduction mechanisms that, through steric rearrangement and destruction of VE-cadherin, produce an increased permeability of the endothelial layer to plasma fluids and the ultimate translocation of liquid from the intravascular space to the subcutaneous site of derma. 
• Lines 62-63: "probably for a mechanism of" (Please convert into "probably due to").
• The correction has been made.
• Line 76: "because may cause asphyxiation" (Please insert the wordt 'it' between 'because' and 'may').
• The correction has been made.
• Lines 84-85: "Delivery can be also carried out by vaginal" (Please convert to 'vaginally' of 'by vaginal route').
• The sentence has been converted in ... "by vaginal route"...

• Lines 121-123: "The effect of danazol in preventing HAE attacks is not completely understood, probably consist of a combination of stimulation of C1 inhibitor synthesis" (Please convert into 'but probably consists').

• The correction has been made.
• Line 208: "deucrictibant at variable dosage of 10, 20, 30 mg" (Please change to '10, 20 and 30 mg').
• The correction has been made.
• Lines 211-213: "deucrictibant resulted significantly more efficacious than placebo in reducing VAS-3 after 4 hours of onset; also, patients treated had a less need of rescue medications compared to placebo" (Please convert 'resulted' to 'proved' and remove the word 'a'). 
• The correction has been made.
• Lines 399-400: "will restitutes a condition similar" (Please correct to 'restitute').
• The correction has been made
• Lines 419-420: "that once included in the genome, will' (please add a comma between 'that' and 'once').
• The correction has been made.

Round 2

Reviewer 1 Report

Well-collected information on HAE. The work is a review, it does not bring anything new to a person dealing with HAE patients, but I hope that it will be a source of knowledge for other specialists.