RHYTHM PHARMACEUTICALS, INC.

This proxy statement (“Proxy Statement”) is furnished in connection with the solicitation by the Board of Directors (the “Board”) of Rhythm Pharmaceuticals, Inc., a Delaware corporation (“Rhythm,” “we,” “our,” “us” or the “Company”), of proxies in the accompanying form to be used at our annual meeting of stockholders to be held on June 24, 2026 at 2:00 p.m., Eastern Time, and any continuation, postponement or adjournment thereof (the “Annual Meeting”). The Annual Meeting will be a completely virtual meeting, which will be conducted via live webcast. You will be able to attend the Annual Meeting online and submit your questions during the meeting by visitingwww.meetnow.global/MQ27S2Z and entering your control number included in your Notice of Internet Availability of Proxy Materials (the “Internet Notice”), on any proxy card you received or on the instructions that accompanied your proxy materials.

Holders of record of shares of our common stock, $0.001 par value per share, (the “Common Stock”) and Series A Convertible Preferred Stock, $0.001 par value per share (“Convertible Preferred Stock”) at the close of business on April 27, 2026 (the “Record Date”), will be entitled to notice of the Annual Meeting and any continuation, postponement, or adjournment of the Annual Meeting. Stockholders of record of our Common Stock are entitled to vote at the Annual Meeting. Holders of our Convertible Preferred Stock are entitled to vote at the Annual Meeting, subject to the terms of the Convertible Preferred Stock as specified in the Amended and Restated Certificate of Designations for the Convertible Preferred Stock (the “Certificate of Designations”). For more information, see “Who can vote at the Annual Meeting?” below.

When are this Proxy Statement and the accompanying materials scheduled to be sent to stockholders?

This Proxy Statement and the Company’s Annual Report to Stockholders for the year ended December 31, 2025 (the “2025 Annual Report”) will be released on or about May 6, 2026 to our stockholders on the Record Date.

Notice of Internet Availability of Proxy Materials.

As permitted by Securities and Exchange Commission (“SEC”) rules, Rhythm is making this Proxy Statement and its 2025 Annual Report available to its stockholders electronically via the Internet. On or about May 6, 2026, we will mail to our stockholders a Notice of Internet Availability of Proxy Materials (the “Internet Notice”) containing instructions on how to access this Proxy Statement and our 2025 Annual Report and vote online. If you received an Internet Notice by mail, you will not receive a printed copy of the proxy materials in the mail unless you specifically request them, by following the instructions for requesting such materials contained on the Internet Notice.

The Internet Notice instructs you on how to access and review all of the important information contained in the Proxy Statement and 2025 Annual Report. The Internet Notice also instructs you on how you may submit your proxy over the Internet.

Who can vote at the Annual Meeting?

The Record Date for the Annual Meeting is April 27, 2026. You are entitled to vote at the Annual Meeting only if you were a stockholder of record at the close of business on that date, or if you hold a valid proxy for the Annual Meeting. Each share of Common Stock entitles the holder to one vote on each matter presented at the Annual Meeting. As of the close of business on the Record Date, we had 68,530,107 shares of Common Stock outstanding.

The voting rights of the Convertible Preferred Stock are subject to the terms of the Convertible Preferred Stock as specified in the Certificate of Designations. Each outstanding share of Convertible Preferred Stock entitles the holder thereof to a number of votes equal to 20.8333 shares of Common Stock per $1,000 liquidation preference of Convertible Preferred Stock.

The holders of the Convertible Preferred Stock are affiliates of Baker Bros. Advisors L.P. (“Baker Brothers”) and entities affiliated with Perceptive Advisors LLC (“Perceptive”). Inclusive of the Common Stock issuable upon conversion of their respective shares of Convertible Preferred Stock, Baker Brothers beneficially held 8.2% of our Common Stock and Perceptive beneficially held 6.5% of our Common Stock as of the close of business on the Record Date. However, based on certain restrictions on the conversion of the Convertible Preferred Stock specified in the Certificate of Designations, a holder of Convertible Preferred Stock is not entitled to effect a conversion of any portion of its shares of Convertible Preferred Stock, or to vote in its capacity as a holder of shares of Convertible Preferred Stock with respect to matters submitted to holders of the Common Stock if, after giving effect to such conversion, that holder would beneficially own in excess of 4.99%, in the case of Baker Brothers, or 9.99%, in the case of Perceptive, of the number of shares of Common Stock outstanding immediately after giving effect to such exercise. As a result, of the 115,000 shares of Convertible Preferred Stock outstanding as of the close of business on the Record Date, of which Perceptive beneficially held 55,000 shares and Baker Brothers beneficially held 60,000 shares, Perceptive is entitled to 1,145,831 votes in respect of its Convertible Preferred Stock and Baker Brothers is not entitled to any votes in respect of its Convertible Preferred Stock at the Annual Meeting. For more information, see “Investment Agreement” in the section titled Certain Relationships and Related Party Transactions, and “Beneficial Ownership of Capital Stock.”

There is no cumulative voting.

Who can attend the Annual Meeting?

The Annual Meeting will be held entirely online this year. You may attend the Annual Meeting online only if you are a stockholder who is entitled to vote at the Annual Meeting, or if you hold a valid proxy for the Annual Meeting. You may attend and participate in the Annual Meeting by visiting the following website: www.meetnow.global/MQ27S2Z. To attend and participate in the Annual Meeting, you will need the control number included in your Internet Notice, on any proxy card you received or on the instructions that accompanied your proxy materials. If you lose your control number, you may join the Annual Meeting as a “Guest” but you will not be able to vote, ask questions or access the list of stockholders as of the Record Date.

If your shares are held in “street name,” as described below, you must register in advance to attend the Annual Meeting online or attend the Annual Meeting online using the control number provided by your bank or broker by following the instructions found under the caption “How do I vote?” below. You will need to obtain your own Internet access if you choose to attend the Annual Meeting online and/or vote over the Internet.

The meeting webcast will begin promptly at 2:00 p.m. Eastern Time. We encourage you to access the meeting prior to the start time, leaving ample time for check-in procedures.

What is the difference between a stockholder of record and beneficial owner of shares held in “street name”?

Stockholder of Record. If your shares are registered directly in your name with our transfer agent, Computershare Trust Company, N.A. (“Computershare”), you are considered the stockholder of record with respect to those shares, and the Notice of Annual Meeting and Proxy Statement were sent directly to you by the Company.

Beneficial Owner of Shares Held in “Street Name.” If your shares are held in an account at a brokerage firm, bank, broker-dealer, nominee, or other similar organization, then you are the beneficial owner of shares held in “street name,” and the Notice and Proxy Statement were forwarded to you by that organization. The organization holding your account is considered the stockholder of record for purposes of voting at the Annual Meeting. As a beneficial owner, you have the right to direct that organization on how to vote the shares held in your account.

How do I vote?

Stockholders of Record. If you are a stockholder of record, you may vote:

•By Internet before the Annual Meeting. You may vote by proxy via the Internet atwww.investorvote.com/RYTM by following the instructions provided on the Internet Notice or any proxy card you received.

•By Telephone before the Annual Meeting. If you live in the United States or Canada, you may vote by proxy by calling toll-free 1-800-652-8683 and by following the instructions provided on the Internet Notice or any proxy card you received. You must have the control number that is included on the Internet Notice or proxy card when voting.

•By Mail before the Annual Meeting. Complete and mail any proxy card you may have received in the accompanying postage prepaid envelope, and return the proxy card to Computershare Proxy Services, PO Box 43101, Providence, RI 02040-3101. Your proxy will be voted in accordance with your instructions. If you have received printed copies of these proxy materials and sign and return the enclosed proxy card but do not otherwise specify how you want your shares voted, they will be voted “FOR” the election of the Class III director nominees named herein to the Board, “FOR” the ratification of the selection of Ernst & Young LLP as Rhythm’s independent registered public accounting firm for the fiscal year ending December 31, 2026, and “FOR” the approval, on an advisory basis, of the compensation of our named executive officers (the “Say-on-Pay Vote”), and will be voted according to the discretion of the proxy holder named in the proxy card upon any other business that may properly be brought before the meeting and at all continuations, adjournments and postponements thereof.

•By Internet during the Annual Meeting. If you attend the meeting online, you will need the control number included in your Internet Notice or any proxy card you received or on the instructions that accompanied your proxy materials to vote electronically during the meeting.

Whether or not you expect to attend the Annual Meeting electronically, we urge you to vote your shares as promptly as possible to ensure your representation and the presence of a quorum at the Annual Meeting.

If you submit your proxy in advance, you may still decide to attend the Annual Meeting and vote your shares or change your vote via the Internet during the Annual Meeting.

Beneficial Owners of Shares Held in “Street Name.” If your shares are held in a brokerage account, by a bank, by a trustee, or by another nominee (also referred to as held in “street name”), you may:

•Vote in Advance. You may vote in advance of the Annual Meeting by following the voting instructions provided by your broker or other nominee and, if desired, attend the Annual Meeting webcast as a “Guest.” Most brokers or other nominees permit their customers to vote by telephone or by Internet, in addition to voting by signing, dating and returning the voting instruction form provided by the broker or other nominee.

•Register to Attend the Annual Meeting in Advance. You may register to attend the Annual Meeting webcast as a stockholder in advance (allowing you to both vote and ask questions during the Annual Meeting). To register to attend the Annual Meeting online in advance, you must submit proof of your proxy power (legal proxy) reflecting your holdings in the Company along with your name and email address to Computershare. Requests for registration must be labeled as “Legal Proxy” and be received no later than 5:00 p.m., Eastern Time, on June 19, 2026. You will receive a confirmation of your registration by email after Computershare receives your registration materials. Requests for registration should be directed to Computershare in the following manner: (1) by email: Forward the email from your broker, or attach an image of your legal proxy, to legalproxy@computershare.com; or (2) by mail: Computershare, Rhythm Pharmaceuticals, Inc. Legal Proxy, P.O. Box 43001, Providence, RI 02940-3001.

•Attend the Annual Meeting Using a Control Number. We expect that the vast majority of beneficial holders will be able to attend and participate in the Annual Meeting by logging into the Annual Meeting using the control number received with the voting instruction form provided by your broker or other nominee. However, some beneficial holders may need to request a legal proxy and register in advance of the Annual Meeting pursuant to the instructions above under “Register to Attend the Annual Meeting in Advance.” Please contact your broker or other nominee to confirm whether your control number will allow you to access the Annual Meeting or whether you will need to obtain a legal proxy and register in advance.

You will need to obtain your own Internet access if you choose to attend the Annual Meeting online and/or vote online.

What are the Board’s recommendations on how to vote my shares?

The Board recommends a vote:

•Proposal 1: “FOR” the election of each of David W. J. McGirr and David P. Meeker, M.D. as Class III directors.

•Proposal 2: “FOR” the ratification of the selection of Ernst & Young LLP as Rhythm’s independent registered public accounting firm for the fiscal year ending December 31, 2026.

•Proposal 3: “FOR” the approval, on an advisory basis, of the Say-on-Pay Vote.

Who pays the cost for soliciting proxies?

Rhythm will bear the cost of solicitation of proxies. This includes the charges and expenses of brokerage firms and others for forwarding solicitation material to beneficial owners of our outstanding stock. Rhythm may solicit proxies by mail, personal interview, telephone or via the Internet through its officers, directors and other employees, who will receive no additional compensation for their services. We will also request that brokers, nominees, custodians and other fiduciaries forward soliciting materials to the beneficial owners of shares held by the brokers, nominees, custodians and other fiduciaries. We will reimburse these persons for their reasonable expenses in connection with these activities. Georgeson LLC, New York, New York, has been retained to assist us in the solicitation of proxies at a fee estimated not to exceed $16,000.

Can I change or revoke my vote?

If you are a holder of record, you may revoke your proxy at any time before it is voted by notifying the Secretary of Rhythm in writing at our principal executive offices, by returning a signed proxy with a later date, by transmitting a subsequent vote over the Internet or by telephone prior to the close of the Internet voting facility or the telephone voting facility, or by attending and voting at the Annual Meeting.

If your stock is held in street name, you must contact your broker or nominee for instructions as to how to change or revoke your vote.

How is a quorum reached?

The presence, online or by proxy, of holders of at least a majority of the issued and outstanding stock entitled to vote on the Record Date (with the Convertible Preferred Stock entitled to vote pursuant to the terms of the Certificate of Designations counted on an as-converted basis) is necessary to constitute a quorum for the transaction of business at the Annual Meeting. Abstentions and “broker non-votes,” if any, will be counted as present and entitled to vote for purposes of determining whether a quorum is present for the transaction of business at the meeting.

What are broker non-votes?

“Broker non-votes” are shares represented at the Annual Meeting held by brokers, banks or other nominees (i.e., in “street name”) which do not vote on a particular proposal because the nominee does not have discretionary voting power with respect to that item and has not received instructions from the beneficial owner. Generally, nominees may vote to ratify the selection of independent auditors (Proposal No. 2) and on other “discretionary” or “routine” items. In contrast, nominees may not vote to elect directors (Proposal No. 1), or to approve on an advisory (non-binding) basis the compensation of our named executive officers (Proposal No. 3), because those proposals are considered “non-discretionary” items. Accordingly, if you do not instruct your broker, bank or other nominee how to vote your shares on “non-discretionary” matters, your broker, bank or other nominee will not be permitted to vote your shares on these matters. This is a “broker non-vote.”

What vote is required to approve each item?

Election of Directors (Proposal No. 1). Directors will be elected by a plurality of the votes cast (with the Convertible Preferred Stock entitled to vote pursuant to the terms of the Certificate of Designations voting, on an as-converted basis, together with the Common Stock as a single class). This means that the two individuals receiving the highest number of “FOR” votes will be elected as directors. Votes withheld and broker non-votes will not be treated as votes cast for this purpose and, therefore, will not affect the outcome of the election.

Ratification of the Selection of Independent Registered Public Accounting Firm (Proposal No. 2). The affirmative vote of a majority of shares of our Common Stock and Convertible Preferred Stock (entitled to vote pursuant to the terms of the Certificate of Designations, voting on an as-converted basis), voting together as a single class, present or represented by proxy at the Annual Meeting and entitled to vote on the proposal, is required to ratify the selection of our independent auditors. An abstention is treated as present and entitled to vote and, therefore, has the effect of a vote “against” the proposal. Because the ratification of the selection of the independent auditors is a routine matter, a nominee holding shares in street name may vote on this proposal in the absence of instructions from the beneficial owner and, therefore, we do not expect any broker non-votes on this proposal.

Approval, on an Advisory (Non-Binding) Basis, of the Compensation of Our Named Executive Officers (“Say-on-Pay Vote”) (Proposal No. 3). The affirmative vote of a majority of shares of our Common Stock and Convertible Preferred Stock (entitled to vote pursuant to the terms of the Certificate of Designations, voting on an as-converted basis), voting together as a single class, present or represented by proxy at the Annual Meeting and entitled to vote on the proposal, is required to approve the compensation of our named executive officers. An abstention is treated as present and entitled to vote and, therefore, has the effect of a vote “against” the proposal. Broker non-votes will have no effect on the outcome of the vote on this proposal.

If the Annual Meeting is adjourned or postponed for any purpose, at any subsequent reconvening of the meeting, your proxy will be voted in the same manner as it would have been voted at the original convening of the Annual Meeting unless you withdraw or revoke your proxy.

What if a quorum is not present at the Annual Meeting?

If a quorum is not present or represented at the scheduled time of the Annual Meeting, the presiding officer of the Annual Meeting may adjourn the Annual Meeting without notice other than announcement at the meeting.

Could other matters be decided at the Annual Meeting?

Stockholders at an annual meeting will only be able to consider proposals or nominations specified in the Notice of Annual Meeting or brought before the meeting by or at the direction of our Board or by a stockholder of record on the Record Date for the meeting who is entitled to vote at the meeting and who has delivered timely written notice in proper form to our Corporate Secretary of the stockholder’s intention to bring such business before the meeting. As of the date of this Proxy Statement, Rhythm does not know of any other matters that may be presented for action at the Annual Meeting. Should any other business properly come before the meeting, the persons named on the enclosed proxy will have discretionary authority to vote the shares represented by such proxies in accordance with their best judgment to the same extent as the person signing the proxy would be entitled to vote. If you hold your shares through a broker, bank or other nominee as described above, the broker, bank or other nominee will not be able to vote your shares on any other business that comes before the Annual Meeting unless they receive instructions from you with respect to such matter.

Why hold a virtual meeting?

We believe that hosting a virtual meeting is in the best interest of the Company and its stockholders. A virtual meeting enables increased stockholder attendance and participation because stockholders can participate from any location around the world. You will be able to attend the Annual Meeting online and submit your questions by visitingwww.meetnow.global/MQ27S2Z. You also will be able to vote your shares electronically at the Annual Meeting by following the instructions above.

What if during the check-in time or during the Annual Meeting I have technical difficulties or trouble accessing the virtual meeting website?

We will have technicians ready to assist you with any technical difficulties you may have accessing the virtual meeting website. Please call 888-724-2416 (local) or +1 781-575-2748 (international) for assistance.

Will there be a question and answer session during the Annual Meeting?

As part of the Annual Meeting, we will hold a live Q&A session, during which we intend to answer questions submitted online during the meeting that are pertinent to the Company and the meeting matters, as time permits. Only stockholders that have accessed the Annual Meeting as a stockholder (rather than a “Guest”) by following the procedures outlined above in “Who can attend the Annual Meeting?” will be permitted to submit questions during the Annual Meeting.

Each stockholder is limited to no more than two questions. Questions should be succinct and only cover a single topic. We will not address questions that are, among other things:

•irrelevant to the business of the Company or to the business of the Annual Meeting;

•related to material non-public information of the Company, including the status or results of our business since our last Quarterly Report on Form 10-Q;

•related to any pending, threatened or ongoing litigation;

•related to personal grievances;

•derogatory references to individuals or that are otherwise in bad taste;

•substantially repetitious of questions already made by another stockholder;

•in excess of the two question limit;

•in furtherance of the stockholder’s personal or business interests; or

•out of order or not otherwise suitable for the conduct of the Annual Meeting as determined by the Chair or Secretary in their reasonable judgment.

Additional information regarding the Q&A session will be available in the “Rules of Conduct” available on the Annual Meeting webpage for stockholders that have accessed the Annual Meeting as a stockholder (rather than a “Guest”) by following the procedures outlined above in “Who can attend the Annual Meeting?”.

What happens if the meeting is continued, postponed or adjourned?

Your proxy may be voted at the continued, postponed or adjourned meeting. You will still be able to change your proxy until it is voted.

What does it mean if I receive more than one Internet Notice, proxy card or voting instruction form?

It means that you have multiple accounts at the transfer agent or with brokers. Please complete and return all proxy cards or voting instruction forms to ensure that all of your shares are voted.

Where can I find the voting results of the meeting?

The preliminary voting results will be announced at the Annual Meeting. The final results will be disclosed in a Current Report on Form 8-K within four business days after the Annual Meeting date.

IMPORTANT NOTICE REGARDING THE AVAILABILITY OF PROXY MATERIALS FOR THE

2026 ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON June 24, 2026

The Notice of Annual Meeting of Stockholders, this Proxy Statement and our Annual Report to securityholders are available free of charge atwww.edocumentview.com/RYTM orwww.rhythmtx.com under “Investors & Media” at “SEC Filings.”