Exhibit 4.1

AMENDMENT to letter agreement
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This Amendment to Letter Agreement (this “Amendment”) is effective as of May 24, 2021, by and between Bicycle Therapeutics plc, a public limited company incorporated under the laws of England and Wales (the “Company”), and Citibank, N.A., a national banking association organized and existing under the laws of the United States of America (“Citibank” and, together with the Company, the “Parties” and each a “Party”). All capitalized terms used but not defined herein shall have the meanings assigned to such terms in the Letter Agreement (as defined below).
Recitals
A.The Parties previously entered in that certain Letter Agreement, dated as of July 1, 2020, and as amended on October 27, 2020 (the “Letter Agreement”), pursuant to which the Parties agreed, inter alia, to certain terms and conditions with respect to the Deposit Agreement, the Sales Agreement, and Program Sales.
B.Section 6(e) of the Letter Agreement provides that the Letter Agreement may not be modified or amended except by a writing signed by each of the Company and Citibank.
C.Each of the Company and Citibank now desires to amend the Letter Agreement as set forth herein. 
Agreement
In consideration of the foregoing and for other good and valuable consideration, the receipt and adequacy of which is hereby acknowledged by each Party, the Parties agree as follows:
1.Amendment of the Letter Agreement. 
(a)The first sentence of the second full paragraph of the Letter Agreement is hereby amended and replaced in its entirety with the following: 
“The Company has, upon the terms set forth in the Sales Agreement, dated as of June 5, 2020 (the “Sales Agreement”), by and among the Company, Cantor Fitzgerald & Co. (“Cantor”) and Oppenheimer & Co. Inc. (“Oppenheimer” and together with Cantor, the “Agents”), agreed to issue and sell through the Agents, each acting as agent and/or principal, ADSs (the “Program ADSs”), each Program ADS representing one (1) fully paid Share, with such Program ADSs having an aggregate offering price of up to U.S. $225,000,000 (the “Program Offer”).”
(b)The relevant portion of clause (i) of Section 4 of the Letter Agreement shall be amended to read as follows:
“(i) at the time of execution of this Letter Agreement, on October 27, 2020, and on May 24, 2021” 
 (c)The first sentence of the first full paragraph of Exhibit A to the Letter Agreement is hereby amended and replaced in its entirety with the following: 



“Reference is made to (i) the Deposit Agreement, dated as of May 28, 2019, as amended and supplemented from time to time (the “Deposit Agreement”), by and among Bicycle Therapeutics plc, a public limited company incorporated under the laws of England and Wales and its successors (the “Company”), Citibank, N.A., a national banking association (“Citibank”) organized and existing under the laws of the United States of America, as Depositary (the “Depositary”), and all Holders and Beneficial Owners of American Depositary Shares (the “ADSs”) issued thereunder, and (ii) the Letter Agreement, dated as of July 1, 2020, as amended on October 27, 2020, and on May 24, 2021 (the “Letter Agreement”), by and between the Company and the Depositary.”
2.Miscellaneous.
(a)This Amendment may be executed in counterparts, each of which shall be deemed an original, but all of which together shall constitute one and the same instrument. Counterparts may be delivered via facsimile, electronic mail (including pdf or any electronic signature complying with the U.S. federal ESIGN Act of 2000, Uniform Electronic Transactions Act or other applicable law) or other transmission method and any counterpart so delivered shall be deemed to have been duly and validly delivered and be valid and effective for all purposes.
(b)Except as expressly modified by this Amendment, the Letter Agreement shall remain unmodified and in full force and effect.
(c)Section 9 (Miscellaneous) of the Letter Agreement shall apply to this Amendment mutatis mutandis.
(d)This Amendment, together with the Letter Agreement (to the extent not amended hereby) and all exhibits thereto, constitutes the entire agreement of the Parties relating to the matters contemplated herein and shall supersede any and all previous oral or written contracts, arrangements or understandings between the Parties with respect to the subject matter herein.
(e)This Amendment may not be altered, amended or modified in any way except by written consent of each of the Company and Citibank.  Waiver of any term or provision of this Amendment or forbearance to enforce any term or provision by any party shall not constitute a waiver as to any subsequent breach or failure of the same term or provision or a waiver of any other term or provision of this Amendment.
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2.
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Exhibit 4.1

In Witness Whereof, the parties hereto have executed this Amendment to Letter Agreement as of the date set forth in the first paragraph above.
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	COMPANY:

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	Bicycle Therapeutics plc

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	By:
	/s/ Kevin Lee

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	Name:
	Kevin Lee

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	Title:
	Director and Chief Executive Officer



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In Witness Whereof, the parties hereto have executed this Amendment to Letter Agreement as of the date set forth in the first paragraph above.
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	DEPOSITARY
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	CITIBANK, N.A.
By: /s/ Leslie DeLuca​ ​

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	Name: Leslie DeLuca
Title: Attorney-in-Fact
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