8-K
INSMED Inc (INSM)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of
The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 8, 2023
INSMED INCORPORATED
(Exact name of registrant as specified in its charter)
| Virginia | 000-30739 | 54-1972729 |
|---|---|---|
| (State or other jurisdiction of incorporation) | (Commission File Number) | (IRS Employer Identification No.) |
| 700 US Highway 202/206<br><br> <br>Bridgewater, New Jersey | 08807<br><br> <br>(Zip Code) | |
| --- | --- | |
| (Address of principal executive offices) |
Registrant’s telephone number, including area code: (908) 977-9900
Not Applicable
(Former name or former address, if changed since last report.)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
|---|---|
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
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| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| --- | --- |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
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Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbol(s) | Name of each exchange on which<br><br> <br>registered |
|---|---|---|
| Common Stock, par value $0.01 per share | INSM | Nasdaq Global Select Market |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (17 CFR 230.405) or Rule 12b-2 of the Securities Exchange Act of 1934 (17 CFR 240.12b-2).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
ITEM 7.01 – Regulation FD Disclosure.
As previously announced, Insmed Incorporated (the “Company”) will present today at an investor and analyst event titled “The Future of Rare at Insmed: Functional Genes, AI-Enhanced Proteins, Glowing Algae, and More”. A live webcast of the presentation will be accessible through the investor relations section of the Company’s website. In connection therewith, the Company issued a press release, a copy of which is attached hereto as Exhibit 99.1 and incorporated herein by reference. A copy of the slide presentation to be used during the presentation is attached hereto as Exhibit 99.2 and incorporated herein by reference.
The information contained herein, including the exhibits attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, except as shall be expressly set forth by specific reference in such a filing.
ITEM 9.01 - Financial Statements and Exhibits.
(d) Exhibits
| Exhibit<br><br> <br>No. | Description |
|---|---|
| 99.1 | Press release issued by Insmed Incorporated on May 8, 2023. |
| 99.2 | Insmed Incorporated May 8, 2023 Presentation. |
| 104 | Cover Page Interactive Date File (embedded within the Inline XBRL document). |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Dated: May 8, 2023 | INSMED INCORPORATED | |
|---|---|---|
| By: | /s/ Michael Smith | |
| Name: | Michael Smith | |
| Title: | General Counsel and Corporate Secretary |
Exhibit 99.1
Insmed Unveils New Research Platforms and Capabilities at Investor and Analyst Event, “The
Future of Rare at Insmed: Functional Genes, AI-Enhanced Proteins, Glowing Algae,
and More”
—Early-Stage Research Pillar Anticipated to Generate at Least Six Investigational New Drug (IND) Applications by End of 2025—
—Company Reveals Select Initial Disease Targets for Next-Generation Gene Therapies and Deimmunized Therapeutic Proteins, Including Duchenne Muscular Dystrophy (DMD) and Stargardt Disease—
—Gene Therapy Clinical Trial in DMD to be Initiated in 2023, with Data Expected First Half of 2024—
—Company Announces $500,000 Equity Investment from CureDuchenne Ventures to Support the Development of a Targeted Gene Therapy for DMD—
BRIDGEWATER, N.J., May 8, 2023 /PRNewswire/ -- Insmed Incorporated (Nasdaq: INSM), a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases, today announced progress across its early-stage research programs, which will be discussed in greater detail this morning at the Company’s investor and analyst event, The Future of Rare at Insmed: Functional Genes, AI-Enhanced Proteins, Glowing Algae, and More. The event will feature presentations from Insmed’s management team and scientific leaders as well as from John W. Day, M.D., Ph.D., Professor of Neurology, Pediatrics, and Pathology at Stanford University, and Michael G. Kelly, Ph.D., Chief Scientific Officer of CureDuchenne, a leading global nonprofit focused on finding and funding a cure for Duchenne muscular dystrophy (DMD).
“Our singular focus at Insmed has always been on patients – developing and delivering therapies that will make a transformational impact on their lives, regardless of modality or therapeutic area,” said Will Lewis, Chair and Chief Executive Officer of Insmed. “Across our first three pillars, this has been the standard against which we have measured success, and we have proven our ability to deliver on our promise to patients at every stage of drug development and commercialization. Today, I look forward to unveiling the unique platforms and capabilities that will fuel our next phase of growth and, together with our first three pillars, put us on the path to become one of the next great, sustainable biotechnology companies. Driven by our highly skilled, industry-leading research teams, we believe the technologies we are progressing can address the challenges facing today’s gene therapies and therapeutic proteins to deliver the next generation of first-in-class, first-in-disease, and potentially best-in-class medicines.”
Select Highlights from ‘The Future of Rare at Insmed’:
Gene Therapy with Targeted Delivery
Insmed has developed a targeted adeno-associated virus (AAV) delivery system to potentially address some of the key challenges associated with current gene therapies, including high dose requirements, inherent systemic toxicities, low efficacy, and off-target transduction. This targeted mode of delivery has the potential to reduce the needed dose 10- to 50-fold, which may in turn offer an enhanced safety profile without limiting efficacy. Key updates from this platform include:
| • | Insmed’s first gene therapy candidate using a targeted intrathecal delivery approach will be in DMD, a devastating genetic disorder characterized by progressive muscle degeneration<br> and weakness. |
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| • | The Company announced a $500,000 equity investment from CureDuchenne Ventures, the investment arm of CureDuchenne, to support the development of Insmed’s gene therapy program for<br> DMD. |
|---|---|
| • | Insmed plans to initiate a gene therapy clinical trial in DMD later this year, with muscle biopsy data expected in the first half of 2024. |
| --- | --- |
| • | Additional gene therapy targets have been identified and preclinical work is underway. |
| --- | --- |
| • | Insmed has created an end-to-end gene therapy manufacturing process designed to be scalable, reproducible, and able to meet commercial demand and quality standards. This includes<br> development of a 1,000-liter suspension-based bioreactor manufacturing process and in-house GMP quality control laboratory to disposition AAV drug product. |
| --- | --- |
“While exciting advances have led to clinical trials of gene replacement approaches for DMD, the current landscape is complicated by requiring high doses of viral vectors that raise safety and tolerability concerns, resulting in significant debate and lack of clarity on how best to manage patients with this devastating disease,” noted Dr. Day. “The possibility of a more targeted, lower-dose therapy that could reduce systemic toxicity and provide a safer option for patients is very promising. While the gene therapy approaches discussed today are still in development, I am confident the entire neurogenetic community will be watching closely to see what possibilities this research opens for individuals living with DMD or other genetic disorders.”
RNA End-Joining (REJ) Technology
Insmed’s REJ technology has the potential to enable large-size gene delivery, overcoming the capacity challenges associated with traditional AAV vectors. This technology may make it possible to employ gene therapy for diseases caused by large genes that have historically not been viable targets for AAV gene therapy. Key updates from this platform include:
| • | Insmed plans to target Stargardt disease, a hereditary retinal disease that causes vision loss typically beginning in childhood, with its first REJ gene therapy candidate. Patients<br> with Stargardt disease currently have no approved therapies to treat their condition. |
|---|---|
| • | The Company expects to submit an IND for the treatment of Stargardt disease by the end of 2024. |
| --- | --- |
| • | Insmed is also exploring the potential of REJ to deliver larger dystrophin protein in DMD. |
| --- | --- |
| • | Evaluation of additional REJ targets is currently underway. |
| --- | --- |
Protein Deimmunization
Insmed’s proprietary protein deimmunization platform, Deimmunized by Design^®^ (DbD), offers a potential solution to the immunogenicity challenges associated with both gene therapies and protein therapeutics by using artificial intelligence to reengineer proteins to silence their immunogenic properties while maintaining their therapeutic activity. Using this platform, Insmed is actively deimmunizing several therapeutic proteins and viral vectors, including AAV capsids, which could unlock the potential for redosable gene therapy. Key updates from this platform include:
| • | Insmed is exploring the potential of redosable gene therapy using a deimmunized AAV capsid in the treatment of argininosuccinic aciduria (ASA), a rare, devastating urea cycle<br> disorder that typically presents in newborns, and expects to have preclinical data in 2024. |
|---|---|
| • | Insmed is also exploring the potential of a deimmunized variant of uricase, a therapeutic protein, in the treatment of chronic refractory gout, and expects to have preclinical data<br> in 2024. |
| --- | --- |
| • | Additional therapeutic proteins are currently under development. |
| --- | --- |
Proprietary Manufacturing
Insmed is advancing a proprietary manufacturing technique that leverages the unique properties of algae to potentially reduce the time, cost, and complexity of producing therapeutic proteins and viral vectors for gene therapy. This next-generation approach may offer potential benefits including rapid scalability, no plasmid transfection, low production costs, and ease of culturing and maintenance. Insmed expects to advance to full AAV capsid production using this manufacturing platform in 2024.
Live Webcast
‘The Future of Rare at Insmed’ will take place today from 8:00 a.m. to 12:00 p.m. ET in person and via webcast. The event and accompanying slides will be streamed live on the Investor Relations section of the Company’s website at www.insmed.com. A replay of the event will be accessible approximately 30 minutes after its completion. A copy of the presentation materials and webcast will be archived for 90 days under the Investor Relations section of the Company’s website at www.insmed.com.
About Insmed
Insmed Incorporated is a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases. Insmed's first commercial product is a first-in-disease therapy approved in the United States, Europe, and Japan to treat a chronic, debilitating lung disease. The Company is also progressing a robust pipeline of investigational therapies targeting areas of serious unmet need, including neutrophil-mediated inflammatory diseases and rare pulmonary disorders. Insmed is headquartered in Bridgewater, New Jersey, with a footprint across Europe and in Japan. For more information, visit www.insmed.com.
Forward-looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties. “Forward-looking statements,” as that term is defined in the Private Securities Litigation Reform Act of 1995, are statements that are not historical facts and involve a number of risks and uncertainties. Words herein such as “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “intends,” “potential,” “continues,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) may identify forward-looking statements.
The forward-looking statements in this press release are based upon the Company’s current expectations and beliefs, and involve known and unknown risks, uncertainties and other factors, which may cause the Company’s actual results, performance and achievements and the timing of certain events to differ materially from the results, performance, achievements or timings discussed, projected, anticipated or indicated in any forward-looking statements. Such risks, uncertainties and other factors include, among others, the following: failure to obtain, or delays in obtaining, regulatory approvals for ARIKAYCE outside the U.S., Europe or Japan, or for the Company’s product candidates in the U.S., Europe, Japan or other markets, including separate regulatory approval for the Lamira^®^ Nebulizer System in each market and for each usage; failure to successfully commercialize ARIKAYCE, the Company's only approved product, in the U.S., Europe or Japan (amikacin liposome inhalation suspension, Liposomal 590 mg Nebuliser Dispersion, and amikacin sulfate inhalation drug product, respectively), or to maintain U.S., European or Japanese approval for ARIKAYCE; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; impact of the COVID-19 pandemic and efforts to reduce its spread on the Company’s business, employees, including key personnel, patients, partners and suppliers; risk that brensocatib or TPIP does not prove to be effective or safe for patients in ongoing and future clinical studies, including, for brensocatib, the ASPEN study; uncertainties in the degree of market acceptance of ARIKAYCE by physicians, patients, third-party payors and others in the healthcare community; the Company’s inability to obtain full approval of ARIKAYCE from the U.S. Food and Drug Administration, including the risk that the Company will not successfully or in a timely manner complete the study to validate a patient reported outcome tool and the confirmatory post-marketing clinical trial required for full approval of ARIKAYCE; inability of the Company, PARI or the Company’s other third-party manufacturers to comply with regulatory requirements related to ARIKAYCE or the Lamira^®^ Nebulizer System; the Company’s inability to obtain adequate reimbursement from government or third-party payors for ARIKAYCE or acceptable prices for ARIKAYCE; development of unexpected safety or efficacy concerns related to ARIKAYCE, brensocatib, TPIP or the Company’s other product candidates; inaccuracies in the Company’s estimates of the size of the potential markets for ARIKAYCE, brensocatib, TPIP or the Company’s other product candidates or in data the Company has used to identify physicians, expected rates of patient uptake, duration of expected treatment, or expected patient adherence or discontinuation rates; the risks and uncertainties associated with, and the perceived benefits of, the Company’s secured senior loan with certain funds managed by Pharmakon Advisors, LP and the Company’s royalty financing with OrbiMed Royalty & Credit Opportunities IV, LP, including our ability to maintain compliance with the covenants in the agreements for the senior secured loan and royalty financing and the perceived impact of the restrictions on the Company’s operations under these agreements; the Company’s inability to create an effective direct sales and marketing infrastructure or to partner with third parties that offer such an infrastructure for distribution of ARIKAYCE or any of the Company’s product candidates that are approved in the future; failure to obtain regulatory approval to expand ARIKAYCE’s indication to a broader patient population; risk that the Company’s competitors may obtain orphan drug exclusivity for a product that is essentially the same as a product the Company is developing for a particular indication; failure to successfully predict the time and cost of development, regulatory approval and commercialization for novel gene therapy products; failure to successfully conduct future clinical trials for ARIKAYCE, brensocatib, TPIP and the Company’s other product candidates due to the Company’s limited experience in conducting preclinical development activities and clinical trials necessary for regulatory approval and its potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval, among other things; risks that the Company’s clinical studies will be delayed or that serious side effects will be identified during drug development; failure of third parties on which the Company is dependent to manufacture sufficient quantities of ARIKAYCE or the Company’s product candidates for commercial or clinical needs, to conduct the Company’s clinical trials, or to comply with the Company’s agreements or laws and regulations that impact the Company’s business or agreements with the Company; the Company’s inability to attract and retain key personnel or to effectively manage the Company’s growth; the Company’s inability to successfully integrate its recent acquisitions and appropriately manage the amount of management’s time and attention devoted to integration activities; risks that the Company’s acquired technologies, products and product candidates are not commercially successful; the Company’s inability to adapt to its highly competitive and changing environment; risk that the Company is unable to maintain its significant customers; risk that government healthcare reform materially increases the Company’s costs and damages its financial condition; deterioration in general economic conditions in the U.S., Europe, Japan and globally, including the effect of prolonged periods of inflation, affecting the Company, its suppliers, third-party service providers and potential partners; the Company’s inability to adequately protect its intellectual property rights or prevent disclosure of its trade secrets and other proprietary information and costs associated with litigation or other proceedings related to such matters; restrictions or other obligations imposed on the Company by agreements related to ARIKAYCE or the Company’s product candidates, including its license agreements with PARI and AstraZeneca AB, and failure of the Company to comply with its obligations under such agreements; the cost and potential reputational damage resulting from litigation to which the Company is or may become a party, including product liability claims; risk that the Company’s operations are subject to a material disruption in the event of a cybersecurity attack or issue; business disruptions or expenses related to the upgrade to the Company’s enterprise resource planning system; the Company’s limited experience operating internationally; changes in laws and regulations applicable to the Company’s business, including any pricing reform, and failure to comply with such laws and regulations; the Company’s history of operating losses, and the possibility that the Company may never achieve or maintain profitability; goodwill impairment charges affecting the Company’s results of operations and financial condition; inability to repay the Company’s existing indebtedness and uncertainties with respect to the Company’s ability to access future capital; and delays in the execution of plans to build out an additional third-party manufacturing facility approved by the appropriate regulatory authorities and unexpected expenses associated with those plans.
The Company may not actually achieve the results, plans, intentions or expectations indicated by the Company’s forward-looking statements because, by their nature, forward-looking statements involve risks and uncertainties because they relate to events and depend on circumstances that may or may not occur in the future. For additional information about the risks and uncertainties that may affect the Company’s business, please see the factors discussed in Item 1A, “Risk Factors,” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022 and any subsequent Company filings with the Securities and Exchange Commission (SEC).
The Company cautions readers not to place undue reliance on any such forward-looking statements, which speak only as of the date of this press release. The Company disclaims any obligation, except as specifically required by law and the rules of the SEC, to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements.
Contact:
Investors:
Bryan Dunn
Executive Director, Investor Relations
Insmed
(646) 812-4030
bryan.dunn@insmed.com
Eleanor Barisser
Associate Director, Investor Relations
Insmed
(718) 594-5332
eleanor.barisser@insmed.com
Media:
Mandy Fahey
Executive Director, Corporate Communications
Insmed
(732) 718-3621
amanda.fahey@insmed.com
Exhibit 99.2
The Future of Rare at Insmed: Functional Genes, AI-Enhanced Proteins, Glowing Algae, and More 6
Forward Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. “Forward-looking statements,” as that term is defined in the Private Securities Litigation Reform Act of 1995, are statements that are not historical facts and involve a number of risks and uncertainties. Words herein such as “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “intends,” “potential,” “continues,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) may identify forward-looking statements. The forward-looking statements in this presentation are based upon the Company’s current expectations and beliefs, and involve known and unknown risks, uncertainties and other factors, which may cause the Company’s actual results, performance and achievements and the timing of certain events to differ materially from the results, performance, achievements or timings discussed, projected, anticipated or indicated in any forward-looking statements. Such risks, uncertainties and other factors include, among others, the following: failure to obtain, or delays in obtaining, regulatory approvals for ARIKAYCE outside the U.S., Europe or Japan, or for the Company’s product candidates in the U.S., Europe, Japan or other markets, including separate regulatory approval for the Lamira® Nebulizer System in each market and for each usage; failure to successfully commercialize ARIKAYCE, the Company's only approved product, in the U.S., Europe or Japan (amikacin liposome inhalation suspension, Liposomal 590 mg Nebuliser Dispersion, and amikacin sulfate inhalation drug product, respectively), or to maintain U.S., European or Japanese approval for ARIKAYCE; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; impact of the COVID-19 pandemic and efforts to reduce its spread on the Company’s business, employees, including key personnel, patients, partners and suppliers; risk that brensocatib or TPIP does not prove to be effective or safe for patients in ongoing and future clinical studies, including, for brensocatib, the ASPEN study; uncertainties in the degree of market acceptance of ARIKAYCE by physicians, patients, third-party payors and others in the healthcare community; the Company’s inability to obtain full approval of ARIKAYCE from the U.S. Food and Drug Administration, including the risk that the Company will not successfully or in a timely manner complete the study to validate a patient reported outcome tool and the confirmatory post-marketing clinical trial required for full approval of ARIKAYCE; inability of the Company, PARI or the Company’s other third-party manufacturers to comply with regulatory requirements related to ARIKAYCE or the Lamira® Nebulizer System; the Company’s inability to obtain adequate reimbursement from government or third-party payors for ARIKAYCE or acceptable prices for ARIKAYCE; development of unexpected safety or efficacy concerns related to ARIKAYCE, brensocatib, TPIP or the Company’s other product candidates; inaccuraciesin the Company’s estimates of the size of the potential markets for ARIKAYCE, brensocatib, TPIP or the Company’s other product candidates or in data the Company has used to identify physicians, expected rates of patient uptake, duration of expected treatment, or expected patient adherence or discontinuation rates; the risks and uncertainties associated with, and the perceived benefits of, the Company’s secured senior loan with certain funds managed by Pharmakon Advisors, LP and the Company’s royalty financing with OrbiMed Royalty & Credit Opportunities IV, LP, including our ability to maintain compliance with the covenants in the agreements forthe senior secured loan and royalty financing and the perceived impact of the restrictions on the Company’s operations under these agreements; the Company’s inability to create an effective direct sales and marketing infrastructure or to partner with third parties that offer such an infrastructure for distribution of ARIKAYCE or any of the Company’s product candidates that are approved in the future; failure to obtain regulatory approval to expand ARIKAYCE’s indication toa broader patient population; risk that the Company’s competitors may obtain orphan drug exclusivity for a product that is essentially the same as a product the Company is developing for a particular indication; failure to successfully predict the time and cost of development, regulatory approval and commercialization for novel gene therapy products; failure to successfully conduct future clinical trials for ARIKAYCE, brensocatib, TPIP and the Company’s other product candidates due to the Company’s limited experience in conducting preclinical development activities and clinical trials necessary for regulatory approval and its potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval, among other things; risks that the Company’s clinical studies will be delayed or that serious side effects will be identified during drug development; failure of third parties on which the Company is dependent to manufacture sufficient quantities of ARIKAYCE or the Company’s product candidates for commercial or clinical needs, to conduct the Company’s clinical trials, or to comply with the Company’s agreements or laws and regulations that impact the Company’s business or agreements with the Company; the Company’s inability to attract and retain key personnel or to effectively manage the Company’s growth; the Company’s inability to successfully integrate its recent acquisitions and appropriately manage the amount of management’s time and attention devoted to integration activities; risks that the Company’s acquired technologies, products and product candidates are not commercially successful; the Company’s inability to adapt to its highly competitive and changing environment; risk that the Company is unable to maintain its significant customers; risk that government healthcare reform materially increases the Company’s costsand damages its financial condition; deterioration in general economic conditions in the U.S., Europe, Japan and globally, including the effect of prolonged periods of inflation, affecting the Company, its suppliers, third-party service providers and potential partners; the Company’s inability to adequately protect its intellectual property rights or prevent disclosure of its trade secrets and other proprietary information and costs associated with litigation or other proceedings related to such matters; restrictions or other obligations imposed on the Company by agreements related to ARIKAYCE or the Company’s product candidates, including its license agreements with PARI and AstraZeneca AB, and failure of the Company to comply with its obligations under such agreements; the cost and potential reputational damage resulting from litigation to which the Company is or may become a party, including product liability claims; risk that the Company’s operations are subject to a material disruption in the event of a cybersecurity attack or issue; business disruptions or expenses related to the upgrade to the Company’s enterprise resource planning system; the Company’s limited experience operating internationally; changes in laws and regulations applicable to the Company’s business, including any pricing reform, and failure to comply with such laws and regulations; the Company’s history of operating losses, and the possibilitythat the Company may never achieve or maintain profitability; goodwill impairment charges affecting the Company’s results of operations and financial condition; inability to repay the Company’s existing indebtedness and uncertainties with respect to the Company’s ability to access future capital; and delays in the execution of plans to build out an additional third-party manufacturing facility approved by the appropriate regulatory authorities and unexpected expenses associated with those plans. The Company may not actually achieve the results, plans, intentions or expectations indicated by the Company’s forward-looking statements because, by their nature, forward-looking statements involve risks and uncertainties because they relate to events and depend on circumstances that may or may not occur in the future. For additional information about the risks and uncertainties that may affect the Company’s business, please see the factors discussed in Item 1A, “Risk Factors,” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022 and any subsequent Company filings with the Securities and Exchange Commission (SEC). The Company cautions readers not to place undue reliance on any such forward-looking statements, which speak only as of the date of this presentation. The Company disclaims any obligation, except as specifically required by law and the rules of the SEC, to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. 6
Will Lewis Chair and Chief Executive Officer 6
Insmed is Assembling the Key Pieces from Which All Successful Biotechnology Companies are Made Culture 6 Disciplined Business Development Research Engine Core Commercial Engine Commercial Engine: Global scale with ability to support business (Pillars 1 – 3) Research Engine: Technologies, platforms, and talent that work synergistically to yield impactful therapies (Pillar 4) Business Development: Disciplined and committed to clear criteria that maximize the likelihood for success Unifying Culture: Mission, Vision, Values
Accelerating the Transformation of Insmed 3 1 2 4 6 TPIP ARIKACE® Brensocatib Early-Stage Research
Near-term readouts for ARIKAYCE and brensocatib potentially unlock the commercial value of these assets, steer the company towards profitability, and fund early-stage research Potential Addressable Patient Populations: Pillars 1 & 2 Refractory MAC lung disease All MAC Lung Disease + All Bronchiectasis + Additional Indications Refractory + All Other MAC Lung Disease + Bronchiectasis at Launch BRENSOCATIB CRSsNP CF Additional BE BE ARIKAYCE All Other MAC Refractory MAC 2023 Revenue guidance of $285M to $300M for Refractory MAC lung disease Number of Patients 6
Few Have Accomplished Our Proven Success at Each Stage of Drug Development Research Clinical Regulatory Commercial ARIKAYCE developed in our labs TPIP developed in our labs Brensocatib diligence by research team Advanced ARIKAYCE through all stages Advanced brensocatib into pivotal Phase 3 Advanced TPIP into multiple Phase 2s ARIKAYCE – approved in US, EU and JP Brensocatib – PRIME & BTD ARIKAYCE top 10 rare disease launches (US) Commercial infrastructure in US, EU and Japan 6
8 Our Drug Development is Focused on Having the Highest Impact to Patients Refractory MAC Lung Disease (Ref MAC) All MAC Lung Disease (All MAC) First-In- Disease First-In- Class Best-In- Class** Non-CF Bronchiectasis (NCFBE) Chronic Rhinosinusitis without Nasal Polyps (CRSsNP) Cystic Fibrosis (CF) Hidradenitis Suppurativa (HS) Pulmonary Hypertension associated with Interstitial Lung Disease (PH-ILD) Pulmonary Arterial Hypertension (PAH) Brensocatib* TPIP* 2 3 1 ARIKAYCE Core Respiratory/Inflammation Commercial Engine * Potentially, if approved. Brensocatib and TPIP are investigational products that have not been approved for sale by the FDA or any international regulatory agency. ** Best-in-class indicates a profile that could be considered more attractive than other treatment options in the class. Head-to-head clinical trials are not anticipated. Core Commercial Engine
9 Pillar 4 Aims to Bring ‘First-in-Class’ & ‘Best-in-Class’ Gene Therapies and Therapeutic Proteins to Patients* First-In- Disease First-In- Class Best-In- Class** Duchenne Muscular Dystrophy1 (DMD) Stargardt Disease1 (STGD) Chronic Refractory Gout2 (CRG) Argininosuccinic Aciduria1 (ASA) Early-Stage Research 4 Scientific Technology, Platforms, and Talent * Potentially, if approved. All of our early-stage research candidates are in preclinical development and have not been approved for sale by the FDA or any international regulatory agency. ** Best-in-class indicates a profile that could be considered more attractive than other treatment options in the class. Head-to-head clinical trials are not anticipated. 1 Next Generation Gene Therapies 2 Deimmunized Therapeutic Protein Research Engine
Our Principles for Business Development Have Guided How We Built our Pillar 4 Potential for First- or Best-in-Class Therapies & Technologies Asymmetric Return Potential Low Up-Front Cost Success-Driven Milestones Consensus on the Final Decision Disciplined Business Development 10
Acquired DbD Platform Acquired RNA End Joining (REJ) Technology Recent Acquisitions Potentially Position Us to Bring Gene Therapies and Therapeutic Proteins to Market Faster and Cheaper 2022 2023 AlgaeneX Vertuis Deimmunized by Design (DbD) Began AI-protein engineering Acquired Next Generation Gene Therapies with Targeted Delivery 2013 2019 2020 2021 Work began Acquired New Proprietary Manufacturing Work began First experiments Motus 10
Our Next-generation Gene Therapies Could Leapfrog Current Approaches Inconsistency between batches and dose measurements Cannot target genes >4kbs 10 to 50-fold dose reduction Insmed’s Next Generation Gene Therapies CHALLENGES High doses – linked to adverse safety outcomes P O T E N T I A L B E N E F I T S Large size gene delivery Every batch can be precisely controlled for dose strength Immunogenicity against viral capsids Repeat dosing Difficult and expensive to manufacture AAV in 1/3rd the time, at fraction of the cost Our proprietary technologies Internally developed assays & manufacturing processes Targeted Delivery (e.g. intrathecal) RNA End Joining (REJ) Deimmunized by Design (DbD) AlgaeneX 10
Deimmunized Therapeutic Proteins Could Overcome Immunogenicity and Cost Challenges Facing Biologics Reduced efficacy (49% of drugs) and safety (60%) due to Immunogencity1 Difficult and expensive to manufacture Innovative drugs with low immunogenicity Insmed’s Deimmunized Therapeutic Proteins 1 Wang YM, Wang J, Hon YY, Zhou L, Fang L, & Ahn HY. (2016). Evaluating and reporting the immunogenicity impacts for biological products-A clinical pharmacology perspective. The AAPS Journal, 18(2), 395–403 Immunogenicity constrains drug development for many proteins with known therapeutic potential Significantly lower cost of goods Our proprietary technologies Deimmunized by Design (DbD) Deimmunized by Design (DbD) AlgaeneX Bio-better version of biologics with known immunogenicity issues CHALLENGES P O T E N T I A L B E N E F I T S 10
Brian Kaspar, PhD Chief Scientific Officer 10
Next-Generation Gene Therapy 10 World-leading expertise and differentiated approach in GTx
Gene Therapy Can Have a Truly Transformational Impact on Patients, as Past Success Has Shown Spinal muscular atrophy (SMA): genetic neuromuscular disease affecting children Children born with SMA rarely reach the age of 2 Evelyn’s story: Now 7 ½ years post- treatment with gene therapy Evelyn, shown here at 3 years of age. 10
70+ Years of Biotech Experience T H E I N S M E D S A N D I E G O F O U N D I N G T E A M Former CEO and Co Founder of Celenex (acquired by Amicus) Investor & Board member of Advanced Cell Technology (ACTC) (acquired by Astellas) Investor & Board member of Cynvenio Founder and Managing Director - Troy Capital & Quid Capital, VC/PE firms with $1.2B AUM Co-Founder & former Chief Scientist at AveXis (acquired by Novartis), Celenex (acquired by Amicus), and Milo Biotechnology Formerly Endowed Chair in Pediatrics and Professor at The Center for Gene Therapy at NCH & OSU’s College of Medicine Ph.D. from UCSD – over 110 scientific articles published Former SVP and Chief Regulatory Officer at AveXis(acquired by Novartis). Former SVP of Regulatory at Intermune. Multiple global successes on submitted NDA including Zolgensma for Spinal Muscular Atrophy PhD in Biology from Boston University. James L’Italien SVP, Regulatory Affairs Principal Scientist at Pfizer Significant Experience in Manufacturing Science & Technology Ph.D. in Immunology from Stanford with post- doctoral training at the Burnham Institute Allan Kaspar VP, Research & Gene Therapy 1st scientist hired at AveXis (acquired by Novartis) – served as SVP of Research and Development Former Principal Scientist, AveXis, Inc. (acquired by Novartis) focused on bringing AAV-based gene therapies to clinical setting Former Assistant Professor, Regenerative Medicine Institute Cedars-Sinai Medical Center PhD in Neuroscience from UCLA, Postdoctoral training at Cedars-Sinai Medical Center Gretchen Thomsen Executive Director, Gene Therapy Samit Varma SVP, Gene Therapy 10 Brian Kaspar Chief Scientific Officer
Insmed Is Uniquely Positioned To Address Challenges In GTx Landscape With Game Changing, Novel, Proprietary Technologies Rare and debilitating genetic disorders with no effective treatment options Gap in expertise and experience bringing GTx programs to market Challenges in manufacturing at scale with robust quality and analytical capabilities High doses, inherent systemic toxicities, low efficacy, and off-target transduction Inability to treat diseases requiring delivery of large genes High production costs with low yields Immunogenicity and inability to target diseases requiring redosing 10
Insmed’s Targeted Up-Front Investment And Focus On CMC, Quality, And Analytics Designed to Ensure A Locked Commercial Process To Supply The Market with Control And Understanding Of The Product In House GMP QC Lab with 25 state-of-the-art assays to ensure quality and robust analytical understanding of manufactured Gene Therapy Products At-scale 1000L manufacturing process defined prior to IND submission to ensure locked commercial process to supply market 10
Insmed is Uniquely Positioned to Address Challenges in GT x Landscape with Game-Changing, Novel, Proprietary Technologies transduction requiring redosing Next Generation Gene Therapies HWighitDhosTesa, irngheeretnetd systemDicetolixviceitireys, low efficacy, and off-target Enhanced safety profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) RNA End Joining Technology Inability to(RtreEaJt )diseases requiring delivery of large genes Unlocks new GTx market opportunities with no competition Large size gene delivery through traditional AAVs Deimmunized by Design (ImDmbuDno)gpenlaictitfyoanrdm inability to target diseases Redosable viral vectors Deimmunized biobetters & derisked innovator drugs Repeat dosing of gene therapies and overcoming immunogenicity AlgaeneX New, Proprietary MHaignhupfraodcutuctriionng costs with low yields Lowest cost of goods for Insmed’s gene therapy portfolio Opportunity to license technology Significant reduction in AAV manufacturing time and cost 10
Duchenne Muscular Dystrophy 10 John W. Day, M.D., PhD Professor of Neurology, Pediatrics, and Pathology Stanford University
Duchenne Muscular Dystrophy (DMD) 10 Duchenne is caused by a genetic mutation that prevents the body from producing dystrophin, a protein that muscles need to work properly. Without dystrophin, muscle cells become damaged and weaken. Duchenne muscular dystrophy is inherited in an X-linked recessive pattern. Modern treatment for Duchenne muscular dystrophy is primarily aimed at the symptoms. Aggressive management of dilated cardiomyopathy with anticongestive medications is used, including cardiac transplantation in severe cases. In Europe and North America, the prevalence of DMD is approximately 1 out of every 3,600 male births. DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively.
Insmed Has Developed A Targeted Delivery System To Circumvent Challenges Within The DMD Landscape Competitor High doses Inherent systemic toxicities Low efficacy Off-target transduction 10
[Placeholder Slide for Dr. Day] 10
Brian Kaspar, PhD Chief Scientific Officer 10
Insmed Has Developed A Targeted Delivery System To Circumvent Challenges Within The DMD Landscape High doses Inherent systemic toxicities Low efficacy Off-target transduction Next Generation Gene Therapies With Targeted Delivery 10 Enhanced safety profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) Insmed Value Proposition & Solution
Robust expression & tactical targeting Minimal expression & limited targeting No dose NovaRed immunostaining for GFP expression (Vector® HRP substrate) *Doses are expressed as total vector genomes administered per animal Intravenous (IV) Delivery Intrathecal (IT) Delivery 10 Insmed’s IT-Delivery of AAV9-GFP Shows Greatly Improved Muscle Targeting When Compared To Systemic (IV) Dosing O N E - T I M E I N T R A T H E C A L D E L I V E R Y P L A T F O R M : A A V 9 - G F P I N N H P
Insmed’s IT Delivery Shows Enhanced Targeting Of Skeletal And Cardiac Muscles With Lower Liver Expression Relative To Systemic (IV) Delivery NovaRed immunostaining for GFP expression (Vector® HRP substrate) *Doses are expressed as total vector genomes administered per animal Intravenous (IV) Delivery Intrathecal (IT) Delivery 10 O N E - T I M E I N T R A T H E C A L D E L I V E R Y P L A T F O R M : A A V 9 - G F P I N N H P
Insmed’s IT-Delivery Shows Efficient DNA Biodistribution in Skeletal And Cardiac Muscles O N E - T I M E I N T R A T H E C A L D E L I V E R Y P L A T F O R M : N H P A A V 9 - G F P d d P C R 10
Treatment involves a one-time administration of AAV9-Micro- Dystrophin in human DMD patients to replace missing dystrophin protein and promote muscle function Recombinant AAV9 Capsid Shell scAAV ITR shRNA SOD1 H1 Stuffer Sequence scAAV ITR The constructs contain unique promoter, enhancer, intron, and micro-dystrophin elements packaged in the AAV9 Capsid The mdx mouse, lacking functional dystrophin, is the most commonly used model to study DMD micro-dystrophin gene MHCK7 promoter 5’ ITR SV40 intron SV40 pol 3’ 10 y (A) signal ITR Innovative Gene Construct (INS1201) Specifically Designed for DMD
Preclinical Proof of Concept Study Intracerebroventricular (ICV) Injections of INS1201 ICV injection of INS1201 at P28 (postnatal day 28) in mdx mice Tissue analyzed for dystrophin expression and correction of histopathological DMD features at various time points The goal of this study is to evaluate a dose response of INS1201 on protein expression and efficacy in the mdx mouse model using a GMP produced engineering lot of INS1201 10
INS1201-Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner (Muscle: Gastrocnemius) 10
Reduced Fibrosis and Increased Fiber Size 10 Dystrophin Expression in up to 84% of cells INS1201-Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner (Muscle: Gastrocnemius)
INS1201 Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner (Muscle: Tibialis Anterior) 10
Reduced Fibrosis and Increased Fiber Size Dystrophin Expression in up to 89% of cells INS1201-Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner 10 (Muscle: Tibialis Anterior)
INS1201 Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner (Muscle: Diaphragm) 10
Reduced Fibrosis and Increased Fiber Size Dystrophin Expression in up to 81% of cells INS1201-Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a 10 Dose-Dependent Manner (Muscle: Diaphragm)
INS1201 Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose- Dependent Manner (Muscle: EDL) 10
Reduced Fibrosis and Increased Fiber Size Dystrophin Expression in up to 74% of cells INS1201-Treated mdx Mice Demonstrate Substantial Improvement of Dystrophic Pathology in a Dose-Dependent Manner 10 (Muscle: EDL)
40 Consistent Functional & Histopathological Effects Observed Following Intrathecal Administration Of INS1201 With 10 To 50-fold Reduction In Dose Compared To Systemic Delivery In mdx Mouse High Dose Low Dose Relative Dose in mdx mouse (in Total vg) Mid Dose INS1201 Intrathecal Administration Sarepta IV/Systemic Administration Doses with Consistent Functional & Histopathological Effects Observed 10-50x Lower Doses with Intrathecal administration vs competitors 1.2e13 6e12 2e12 8e11 4e11 2e11 8e9 No claim of comparative safety or effectiveness relative to INS1201 is made or implied. INS1201 has not yet been studied in clinical trials.
41 Intracerebroventricular (ICV) Injections of INS1201 ICV injection of INS1201 at P28 (postnatal day 28) in wild type (C57BL/6J) mice Protocol Group Dosing Group Dose (total vg) Group 1 vehicle 0.0E+00 Group 2 Dose 1 8.0E+11 Group 3 Dose 2 4.0E+11 Group 4 Dose 3 2.0E+11 Group 5 Naïve/untreated 0.0E+00 Timing Cohort n 12-week 72 6-week 60 3-week 60 Total Animals: 192 N = 15 total per each injected group, 12 naïve untreated included in 12-week cohort The overall goal of this GLP study is to evaluate toxicologyand biodistributionof GMP produced engineering lot of INS1201 in wild type mice Brief Study Design
42 INS1201 Mouse GLP Toxicology Study Shows Clean Safety Profile With No Off-Target Transduction Normal Body Weight Gain Normal Clinical Observations No Concerning Histopathology Associated With INS1201 Delivery Observed mono-nuclear cell infiltrates around blood vessels in the brain, associated with virus delivery, not dose-dependent and appears to resolve over time Normal Blood Chemistry/Hematology No Unexpected Deaths In Any Treatment Groups 1 unexpected death in the vehicle control group The NOAEL* was 8.0+E11 vg, which was the highest dose tested in the study *No Observed Adverse Effect Level
Muscle Biodistribution of INS1201 Demonstrates a Dose Response and Robust Muscle Targeting in 3-week GLP Toxicology Study in Wild Type Mice 43
Muscle Biodistribution of INS1201 Demonstrates a Dose Response and Robust Muscle Targeting in 6-week GLP Toxicology Study in Wild Type Mice 43
Muscle Biodistribution of INS1201 Demonstrates a Dose Response and Robust Muscle Targeting in 12-week GLP Toxicology Study in Wild Type Mice 43
Muscle Biodistribution of INS1201 Demonstrates Durability Throughout Twelve Weeks and Effective Targeting of the Heart 43
Brief Study Design Intrathecal (IT) Injections of INS1201 IT injection of INS1201 in 10 NHP between 2-3 years Tissue analyzed at 21 days post treatment The overall goal of this study is to evaluate the Biodistribution of INS1201 in Non-Human Primates (NHP) Using GMP Produced Engineering Lot of INS1201 43
Muscle Biodistribution of INS1201 Demonstrates a Dose Response and Robust Muscle Targeting in Non- Human Primates Normal Body Weight Gain Normal Clinical Observations No mortality or moribundity in any NHPs dosed with INS1201 Normal Blood Chemistry/Hematology 43
Brief Study Design Intracerebroventricular (ICV) Injections of INS1201 ICV injection of INS1201 at P1 (postnatal day 1) in mdx mice EDL muscle analyzed by physiology The overall goal of this study is to evaluate INS1201 efficacy in newborn mdx mice 43
WT e9 0 1 le 15 e1 e1 ic 00 15 1.5 h Ve X+ 00 01 + MD X+ 0 X MD X+ MD MD 0 20 40 60 80 ) 1 C E / 0 1 C E ( s s e r t s C E f o % %EC Post/Pre ✱ 40 60 80 100 Eccentric Contraction Profile Contraction e s a e r c e D e c r o F % WT MDX + Vehicle MDX+001 1.5e11 MDX+001 5e10 MDX+001 5e9 Substantial Improvement in Muscle Physiology by Early Intervention in P1 mdx Mice Treated with INS1201 A B Eccentric Contraction Profile 1 2 3 4 5 6 7 8 9 10 Contraction % Force Decrease P1 9e10 P1 2.7e11 mdx + Vehicle WT P1 9e9 %EC Post/Pre P1 9e10 P1 2.7e11 mdx + Vehicle WT P1 9e9 Insmed Is Well-Positioned To Initiate An Early Intervention Study Once Newborn Screening Is Available 43 E X T E N S O R D I G I T O R U M L O N G U S ( E D L ) M U S C L E
Recombinant AAV9 Capsid Shell scAAV ITR shRNA SOD1 H1 Stuffer Sequence scAAV ITR micro-dystrophin gene MHCK7 promoter 5’ ITR SV40 intron SV40 pol 3’ 43 y (A) signal ITR Insmed Plans to Initiate a Clinical Trial for INS1201 in 2H2023
52 Insmed Will Initiate A Phase 1, Multicenter, Open-Label, Study to Investigate the Safety and Biodistribution of INS1201 in Male Toddlers for the Treatment of Duchenne Muscular Dystrophy Muscle Biopsy and Biomarker Data Expected To Be Available 1H2024 Screening Safety, Proof Of Concept Study (up to 6pts) Dose Selection Optimized Dose 3 pts Step Down Dose* 3 pts 30-day safety period between each patient *(Cohort to be opened based on safety data from optimized dose cohort) Optimized Dose (Expansion) 3 pts Decision for Optimized Dose Single dose; Intrathecal administration Concerns No Concerns IDMC (Independent Data Monitoring Committee)
Jessica Eisner, M.D. has over 20 years of leadership experience in regulated medical product development in both industry and the government. She has worked in multiple therapeutic areas including rare diseases, infectious diseases, cardiology, and oncology. Dr. Eisner’s previous positions include Senior Medical Officer at the FDA (both CDER & CDRH) where she was the primary medical reviewer for over 150 industry product submissions (e.g. INDs/ 510(k)s/PMAs and NDAs). She also previously held the position of Deputy Director of the Military Infectious Disease Research Program for the US Department of Defense and medical leadership positions at Takeda and Abbott Laboratories. Dr. Eisner was a member of the Board of Trustees for Group Health in the Pacific Northwest where she provided strategic and financial oversight for this HMO with over 500,000 members and $2.5 billion dollars revenue. She is currently a medical expert for International Standard Organization (ISO) drug delivery device standards committees. Dr. Eisner received her BA from Cornell College in Iowa. She earned her medical degree from the University of California, San Diego and completed her residency at the University of Washington in Seattle. Insmed Gene Therapy Welcomes Its Executive Medical Director For Clinical Development & Safety 53 Jessica Eisner, M.D.
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies transduction High production costs with low yields Immunogenicity and inability to target diseases requiring redosing Next Generation Gene Therapies HWighitDhosTesa, irngheeretnetd systemDicetolixviceitireys, low efficacy, and off-target Enhanced safety profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) RNA End Joining Technology Inability to(RtreEaJt )diseases requiring delivery of large genes Unlocks new GTx market opportunities with no competition 53 Large size gene delivery through traditional AAVs
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Insmed Value Proposition & Solution RNA End Joining Technology (REJ) Unlocks new GTx market opportunities with no competition Large size gene delivery through traditional AAVs Inability to treat diseases requiring delivery of large genes 53
I N T R A M U S C U L A R D E L I V E R Y O F A A V 8 - R E J - M I D - D Y S T R O P H I N Novel RNA End Joining Technology Enables Treatment With Larger Mid- Dystrophin Variants AAV8-REJ-mid-dystrophin An ~8kb/253kDa truncated dystrophin; improved efficacy/functionality, particularly for cardiac function Wild Type Control Dystrophic (d2.mdx) healthy untreated REJ-AAV8 mid-Dystrophin250kDa Treated healthy Dystrophin / nuclei 53 A Natural (Full Dystrophin (439) kD Mid-dystrophin (253) kDA
Intrathecal Dual REJ-AAV9 Mid-Dystrophin250kDa Results in Widespread Gene Replacement N E X T - G E N E R A T I O N D Y S T R O P H I N R E P L A C E M E N T Approach: Combination of two of Insmed’s key inventions: (1) Intrathecal AAV administration for widespread distribution and (2) RNA-end joining for expanded AAV capacity. Result: Intrathecal injection of dual REJ- AAV9 mid-Dystrophin250kDa results in widespread Dystrophin replacement with an expanded 250kDa mid-gene. Dystrophin expression in key muscle tissues including skeletal muscle (e.g. Tibialis anterior), the diaphragm and the heart. Dystrophin Laminin Tibialis anterior Diaphragm Heart 53
Full-Length Dystrophin Replacement With Triple REJ-AAV Approach T R I P L E R E J - A A V A P P R O A C H F O R U L T R A - L A R G E G E N E R E P L A C E M E N T Reconstitution of full length YFP from three vectors using REJ technology Three vector approach allows for ~12kb CDS 53
Full-Length Dystrophin Replacement With Triple REJ-AAV Approach T R I P L E R E J - A A V A P P R O A C H F O R U L T R A - L A R G E G E N E R E P L A C E M E N T Reconstitution of full length Dystrophin from three vectors using REJ technology Three vector approach allows for ~12kb CDS 53
Cure Duchenne 53 Michael G. Kelly, PhD Chief Scientific Officer CureDuchenne
CureDuchenne Ventures was established to find, fund and de-risk innovative research programs, advance them to the clinic to accelerate the approval of life-changing treatments for all Duchenne/Becker patients. Early funder, substantial due diligence and de-risk projects to attract further investments. Cultivate long-term strategic relationships providing deep domain expertise, insight and support. Our investments have attracted approximately $3B in follow-on funding for DMD from VC firms and public markets. Seventeen CureDuchenne-funded projects have advanced to clinical trials. 87 CureDuchenne Ventures
Supporting Innovation - Growing a Pipeline of Therapeutic Opportunities Our investments are targeted and impactful: We invest with an emphasis on treatments that restore dystrophin in addition to approaches that provide a “stand-alone” benefit for Duchenne and Becker muscular dystrophy patients. “Combination therapy” is expected to become the standard-of-care as new drugs are approved. The pipeline has evolved to target the disease from multiple angles: Our investments have supported DNA editing, RNA modulation, gene therapy, new muscle targeted AAV’s, solutions for nAb’s and AAV redosing, non-viral gene delivery, muscle and bone sparing agents, and novel anti-inflammatories etc. RNA Targeting/Exon Skipping AAV Gene Therapy Exosomes & Non-Viral Delivery Anti-inflamm, Muscle & Bone Preserving Gene Editing 87
Activating Private Capital & Public Markets We've invested alongside many VC and biotech funds to drive innovation. New technologies targeting DNA/RNA have emerged that will dramatically impact many monogenetic diseases. The “next-generation” cell-penetrating muscle-targeted exon-skipping approach's have entered the clinic. Approval of the first gene therapy products are anticipated. But significant challenges remain to more effectively treat DMD 87
We Still Need Breakthroughs To Get Closer To Our Goal Gaps and opportunities exist within the current gene therapy pipeline. Delivery & cost: improved muscle targeting for AAV and non-viral approaches. Lower AAV dose - reduce manufacturing burden & cost of goods and improve safety Gene size: larger dystrophin transcripts will be needed for more effective treatment. Larger “mid-length” BMD transcripts associated with mild/asymptomatic phenotypes. Full-length dystrophin protein is our ultimate goal. Treatment needs to begin at diagnosis. Newborn screening. Redosing - solutions needed for nAb’s. 87
CureDuchenne Ventures/Insmed 87 CD Ventures held separate meetings over the past few years with Motus Bio & Vertuis Bio. Vertuis Bio: utilized RNA end joining technology to deliver larger dystrophin transcripts - efficiently produced mid-length (ca. 8kb, 253 kDa) BMD constructs and full-length dystrophin protein (ca. 12kb, 439 kDa). More potent, targeted AAV were required to fully unlock the potential of REJ technology for DMD. Motus Bio: IT-delivered dys-gene therapy targeted muscle with 10 to 50-fold dose reduction compared to i.v. delivery. This presented an exciting stand-alone opportunity that addressed gaps in the current GT landscape. The merging of these approaches offers Insmed a unique opportunity to go beyond where GT is today. CureDuchenne is delighted to announce its enthusiastic support for this program and an investment in Insmed to help potentially bring this opportunity to Duchenne patients
Brian Kaspar, PhD Chief Scientific Officer 87
High production costs with low yields Immunogenicity and inability to target diseases requiring redosing Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Next Generation Gene Therapies With Targeted HighDDeoslievs,einrhyerent systemic toxicities, low efficacy, and off-target Enhtrancsedducsatifoenty profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) RNA End Joining Technology (REJ) Inability to treat diseases requiring delivery of large genes Unlocks new GTx market opportunities with no competition 87 Large size gene delivery through traditional AAVs
Lukas Bachmann, PhD Director, Research 87
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Insmed Value Proposition & Solution Inability to treat diseases requiring delivery of large genes RNA End Joining Technology (REJ) 87 Unlocks new GTx market opportunities with no competition Large size gene delivery through traditional AAVs
Insmed’s Proprietary RNA-End Joining (REJ) Technology Could Enable Large Gene Delivery Using AAV O V E R C O M I N G T H E C A P A C I T Y C H A L L E N G E : A N R N A P L A T F O R M F O R N E X T G E N E R A T I O N G E N E T H E R A P Y CHALLENGE POTENTIAL SOLUTION Current challenge in AAV gene therapy: AAV: favored gene therapy vector but has limited cargo capacity Many large disease/effector genes (or large regulatory sequences) cannot fit within AAV High unmet need for patients with diseases caused by large genes. High-capacity REJ dual AAV approach Insmed’s RNA end joining technology large genes (4.2-9kb) 5kb capacity Highly efficient, precise, and universal Plug-and-play Allows for dual AAV up to 8-9kb CDS (triple AAV up to 12kb CDS) 87
Insmed’s Proprietary REJ Platform is Designed to Allow For Two Vector Delivery Of Split Genes With Efficient, Precise Reconstitution Of RNA While Maintaining Suppression Of Un-joined Protein Fragment Expression REJ Technology in Action: Gene can be split anywhere Split-gene is packaged in two AAVs; any serotype or promoter can be used Co-infection of a cell is readily achieved Split RNA transcribed from two AAVs Structured RNA dimerization domains mediate non-covalent binding. REJ domains are designed for efficient spliceosome recruitment Spliceosome mediates RNA-end joining Protein expression from un-joined fragments is suppressed Desired full-length protein is translated 87
Insmed’s Proprietary REJ Platform Is ~15x More Efficient At Gene Reconstitution Than DNA Hybrid Technology 1 2 3 120 100 80 60 40 20 0 -20 % YFP Signal relative to REJ RNA joining DNA hybrid vehicle Hybrid dual AAV RNA end joining 87
Insmed’s Proprietary REJ Platform Produces High Levels of Functional Protein Across Tissue and Cell Types Systemic delivery Local delivery Liver Diaphragm Di Li Heart Skeletal Muscle Neurons Retinal Photoreceptors 87
Insmed’s Proprietary REJ Platform Could Unlock Gene Therapy Whitespace Retinal Disease Respiratory Muscular/Cardiac Nervous System Other Systems REJ Platform is designed to enable delivery of large genes with AAV 87
1 National Eye Institute. Stargardt Disease, Available at: https://www.nei.nih.gov/learn -about-eye-health/ eye-conditions-and-diseases/ stargardt -disease (Accessed: 31 March 2023) 2 https://doi.org/10.1167/iovs.0 9-3611 87 Caused by mutations in the ABCA4 gene - gene affects how body uses vitamin A Vision loss usually starts in childhood - some people don’t start to lose their vision until they’re adults No treatment available - current management focused on alleviating symptoms and optimizing remaining sight Prevalence of 1 in 8,000 to 10,0002 - most common inherited macular dystrophy
Stargardt Disease: REJ Produces a Full Length Abca4 Protein in vitro Experimental Setup A Full Length Abca4 by REJ 87 B
Stargardt Disease: REJ Produces a Full Length Abca4 Protein in vivo S U B R E T I N A L D E L I V E R Y O F A A V 8 - R E J - A b c a 4 REJ dual AAV8 Abca4 generates (more than) physiological levels of Abca4 in photoreceptors when injected sub- retinally in the Stargardt’s Disease model mouse In contrast, Intein dual AAV approach only reached ~10-15% of wild type at the comparable dose REJ dual AAV8 Abca4 levels are more than 10x above the threshold for efficacy REJ’s higher efficiency allows for reduction in dose which improves safety profile wt treated ko Western Blot efficacy bar (~15%)* * As observed in Tornabene et al., 2019 87
Insmed Plans To Submit An IND For The Treatment Of Stargardt Disease by the end of 2024 87
10-Minute Intermission 87
Karl Griswold, PhD Executive Director, Biologics Research & NH Site Lead 87 Chris Bailey-Kellogg, PhD Executive Director, Computational Biology
High production costs with low yields Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Next Generation Gene Therapies With Targeted HighDDeoslievs,einrhyerent systemic toxicities, low efficacy, and off-target Enhtrancsedducsatifoenty profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) RNA End Joining Technology (REJ) Inability to treat diseases requiring delivery of large genes Unlocks new GTx market opportunities with no competition Large size gene delivery through traditional AAVs Deimmunized by Design (DbD) platform Immunogenicity and inability to target diseases Redreoqsuaibrilnegvirealdvoescintgors 87 Deimmunized biobetters & derisked innovator drugs Repeat dosing of gene therapies and overcoming immunogenicity
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Immunogenicity Inability to target diseases requiring redosing Insmed Value Proposition & Solution Deimmunized by Design (DbD) platform 87 Redosable viral vectors Deimmunized biobetters & derisked innovator drugs Repeat dosing of gene therapies and overcoming immunogenicity
Chris Bailey-Kellogg Executive Director, Computational Biology Karl Griswold Executive Director, Biologics Research Franziska Leifer Director, Biologics Research A Deep Bench of Multidisciplinary Scientists and Engineers Empower Insmed Research PhD, Computer & Information Science, Ohio State University Professor, Computer Science, Dartmouth Co-founder of Stealth Biologics Joined Insmed in 2021 PhD, Chemistry, University of Texas Professor, Thayer School of Engineering, Dartmouth Co-founder of Stealth Biologics Joined Insmed in 2021 PhD, Biological Sciences in Public Health, Harvard University Preclinical lead, gene therapies for inherited metabolic disorders Joined Insmed in 2012 87
Transforming Potent but Immunogenic Biotherapies into High- Performance, Immunologically Stealthy Drugs proteases toxins mAbs non-mAb binding scaffolds viral vectors metabolic enzymes metabolic enzymes non-mAb binding scaffolds viral vectors mAbs proteases toxins Our proprietary Deimmunized by Design® platform represents a unique technology for engineering safer and more effective biotherapeutic candidates, with relevance to a broad array of indications. ® 87
88 (Abbreviations: DC-dendritic cell; MHC-major histocompatibility complex; TCR-T cell receptor; BCR-B cell receptor, Ag-antigen) Immune Surveillance Can Undermine Biotherapeutic Efficacy C H A L L E N G E “Wild-type” Biotherapeutic DC BCR Naïve B cell Plasma cells Induced antidrug antibodies Neutralized biotherapeutic Consequences of Antidrug Antibodies Immune complex associated toxicity Infusion reactions Altered pharmacokinetics Drug inhibition Discontinuation of therapy Exclusion from treatment options Activated T cell MHC peptide TCR MHC peptide TCR Ag-Primed B cell Naïve T cell DC
89 (Abbreviations: iDC-immature dendritic cell; mDC-mature dendritic cell; MHC-major histocompatibility complex; TCR-T cell receptor; BCR-B cell receptor, ADA-antidrug antibodies) Deleting T Cell Epitopes of Immunogenic Biotherapies Blunts Development of Antidrug Antibodies, Enabling Effective Redosing Induced ADAs CHALLENGE “Wild-type” biotherapeutic DC Naïve B cell MHC peptide TCR Ag-Primed B cell Plasma cell Naïve T cell Activated T cell BCR Antidrug antibodies Neutralized biotherapeutic MHC peptide TCR DC T cell Epitope Deletion POTENTIAL SOLUTION “T cell epitope depleted” biotherapeutic Epitope-deleting mutations BCR Naïve B cell DC MHC TCR Ag-Primed B cell Naïve T cell Plasma cell Active biotherapeutic Naïve T cell DC MHC TCR * *
(Abbreviations: ADA-antidrug antibodies) Deleting B Cell Epitopes of Immunogenic Biotherapies Enables Effective Treatment in the Context of Pre-Existing Antidrug Immunity CHALLENGE “Wild-type” biotherapeutic Antibody-drug complex Pre-existing ADAs Neutralized biotherapeutic * * Pre-existing ADAs B cell Epitope Deletion Active biotherapeutic Unbound drug Epitope- deleting mutations “B cell epitope depleted” biotherapeutic POTENTIAL SOLUTION Pre-existing ADAs 90
Deimmunized by Design® An AI-driven protein engineering platform designed to enable functional deimmunization of therapeutic proteins Machine learning methods learn models from prior data regarding protein function and immunogenicity AI methods map the complex design space of protein variants, balancing function and immunogenicity AI methods plan experiments to explore and exploit the mapped design space Experiments test variant function and immunogenicity, and the data drives iterative improvement of models and subsequent designs 90
92 Deimmunized Lysostaphin for MRSA Infections 90 P R O O F O F P R I N C I P L E :
Transforming Potent but Immunogenic Biotherapies into High- Performance, Immunologically Stealthy Drugs proteases next-generation anti-infectives Our proprietary Deimmunized by Design® platform represents a unique technology for engineering safer and more effective biotherapeutic candidates, with relevance to a broad array of indications. ® 90
Lysostaphin is a Potent Anti-Staphylococcal Agent, but its Clinical Potential is Limited by Immunogenicity Issues Rapid Bacterial Lysis Rapid onset of action and potent killing of S. aureus Effective against MSSA, MRSA, VISA, VRSA, LRSA, DRSA Synergy with other conventional antibiotics; re-sensitizes MRSA to beta-lactam drugs Specific MOA => minimal off-target => spares patient microbiome Proven efficacy in clinic, but potential is limited by immunogenicity MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-susceptible Staphylococcus aureus; VISA: vancomycin-intermediate Staphylococcus aureus; VRSA: vancomycin-resistant Staphylococcus aureus; LRSA: linezolid-resistant Staphylococcus aureus; DRSA: daptomycin-resistant Staphylococcus aureus; SOC: standard of care; MOA: mechanism of action B A C K G R O U N D Lysostaphin hydrolyzes cell wall peptidoglycan resulting in rapid bacterial lysis and death Adapted from: https://lazarillo.info/2018/cell-wall-function-struct ure-and-im portance.tech Lysin treated No treatment control S. aureus cells Cell cross section Cell wall Plasma Membrane Peptidoglycan Cytoplasm Lysostaphin 95
Radial Diffusion Screen In vitro potency assays Ex vivo PBMC Assays In vivo efficacy & immunogenicity Design Space Experiments Data Models Lysostaphin 96 The DbD AI Design Platform has Generated LYT100, a High- Performance, Deimmunized Antibiotic for MRSA Goal: T cell epitope deletion Blunt development of ADAs in naïve subjects, enabling effective redosing Results DbD => ↓T cell epitopes => ↓ADAs => ↑redosable efficacy
97 LYT100 Evades Human T cell Surveillance D E I M M U N I Z E D L Y S O S T A P H I N L Y T 1 0 0 S I L E N C E S H U M A N T C E L L A C T I VA T I O N Schematic of the Human PBMC Assay Human PBMC Assays Matched Antigen Expansion and Restimulation Donor DRB1* HLA Genotype Wild type lysostaphin activates immune cells in genetically diverse donors Consistent with prior clinical experience LYT100 evades immune cell activation in a head-to-head comparison using the same donors Significant differences by t tests, correcting for multiple comparisons Note on Interpretation Higher stimulation index indicates higher immunogenic potential (Abbreviations: APC-antigen presenting cell; MHC-major histocompatibility complex; TCR-T cell receptor; wtLST-wild type lysostaphin; LYT100-deimmunized lysostaphin; HLA-human leukocyte antigen, or human MHC II) Science Advances (2020) Vol. 6, no. 36, eabb9011 0410 / 0802 0403 / 1501 0701 / 1103 1406 / 1502 1001 / 1402 0701 / 1301 0701 / 1302 0101P / 0404 0801 / 1101 140 120 100 80 60 40 20 0 Stimulation Index wtLST-wtLST LYT100-LYT100 * * * * * * * * *
98 WT LST Antigen/Plasma LYT100 Antigen/Plasma LYT100 Dampens Antidrug Antibody (ADA) Response D E I M M U N I Z E D L Y S O S T A P H I N L Y T 1 0 0 D A M P E N S A N T I D R U G A N T I B O D Y R E S P O N S E S I N H U M A N I Z E D H L A T R A N S G E N I C M I C E DR4 mice express human MHC II allele DRB1*0401 Log (Plasma Dilution) Science Advances (2020) Vol. 6, no. 36, eabb9011 100 μg Protein SC WT LST or LYT100 Collect Plasma and Test IgG Titers DR4 DAY 28 Antidrug Antibody Titers
99 LYT100 Enables Efficacious Repeat Dosing for Recurrent MRSA Infections Deimmunized LYT100 enables highly efficacious repeat dosing in humanized HLA transgenic mice 0 7 14 21 28 35 42 49 Days Science Advances (2020) Vol. 6, no. 36, eabb9011 Percent survival *** LYT100 (N=6) WT LST (N=10) MRSA Challenge Humanized DR4 HLA Transgenic Mice Recurrent MRSA Bacteremia Model 100 80 60 40 20 0 MRSA: methicillin-resistant Staphylococcus aureus * * 500 g per mouse
Initial Studies Demonstrated Animal Proof-of-Concept for LYT100 T cell epitopes can be depleted while maintaining function T cell epitope deletion does lead to reduced antibody titers Reduced antibody titers do lead to improved efficacy Further data available in the following LYT100 publications: Electrostatic-Mediated Affinity Tuning of Lysostaphin Accelerates Bacterial Lysis Kinetics and Enhances In Vivo Efficacy. Zhao H, Eszterhas S, Furlon J, Cheng H, Griswold KE. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02199-20. PMID: 33468459 Deimmunized Lysostaphin Synergizes with Small-Molecule Chemotherapies and Resensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics. Fang Y, Kirsch JR, Li L, Brooks SA, Heim S, Tan C, Eszterhas S, Cheng HD, Zhao H, Xiong YQ, Griswold KE. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e01707-20. PMID: 33318001 . LYT100 program demonstrated success in deimmunizing lysostaphin as the initial proof of principle for the DbD platform: Reduced immunogenicity Repeat dosing with little to no toxicity Enhanced efficacy against multidrug-resistant Staphylococcus aureus Based on this encouraging data Insmed acquired the Deimmunized by Design® technology and has expanded its application to other high-need indications Note: Despite promising POC data which validated the platform, clinical development of LYT100 is not actively being pursued due to portfolio prioritization 100
DbD Therapeutic Proteins Example: Uricase 101 101
Transforming Potent But Immunogenic Biotherapies into High- Performance, Immunologically Stealthy Drugs metabolic enzymes rheumatology Our proprietary Deimmunized by Design® platform represents a unique technology for engineering safer and more effective biotherapeutic candidates, with relevance to a broad array of indications. ® 102
Pegloticase (a Pegylated Uricase) is an Example of a Marketed Therapeutic Protein Where Immunogenicity Limits its Utility Sources: Schlesinger. Semin Arthritis Rheum. 2020; Nyborg. PLoS One. 2016; Lipsky. Arthritis Res Ther. 2014; Horizon Therapeutics Press Release 3/1/23; Evaluate Pharma; Insmed market research There is a key unmet need for novel effective agents with low immunogenicity to treat chronic refractory gout Uric acid, low solubility Allantoin, high solubility Uricase Perceived as the most effective urate-lowering therapy, especially for tophi resolution However… ~90% of patients developed ADAs in pivotal trials (41% high-titer) ADA titers correlate with loss of efficacy Black box warning for anaphylaxis and infusion reactions Recent label update codifies pre- and concomitant treatment with methotrexate to improve patient response and reduce infusion reactions An alternative approach to suppressing the immune system (employed with a different uricase) does not completely solve for loss of response The only agent specifically indicated for treatment of chronic refractory gout 103
Design Space Experiments Data Models uricase Ex vivo PBMC Assays Halo Screen 104 kinetics The DbD AI Design Platform has Generated High-Performance, Deimmunized Uricase Variants for Refractory Gout Goal: T cell epitope deletion Blunt development of ADAs in naïve subjects, enabling effective redosing Results DbD => ↓T cell epitopes and ↑function
Reaction Velocity (arbitrary units) KM (µM) 43 ±2 700 ±100 40 ±2 600 ±70 34 ±1 470 ±60 30 ±1 400 ±50 28.0 ±0.5 350 ±20 Round 1 Candidates Exhibit Wild Type or Better Activity (Abbreviations: WT-wild type Krystexxa enzyme; v1/v2/v3/v4-deimmunized Krystexxa variants) 0 20 40 60 80 F U N C T I O N A L A N A LY S I S O F F I R S T C A M P A I G N D E I M M U N I Z E D U R I C A S E C A N D I D A T E S Unmodified Core Enzymes Kinetic Analysis, pH 9 0 500 1000 1500 2000 2500 Uric Acid (M) Velocity (abs/min) v1 v3 v2 WT v4 Preliminary Kinetic Parameters 105
Round 1 Candidates Evade Human T Cell Surveillance P R E L I M I N A R Y S T U D Y W I T H A S M A L L P A N E L O F H E A L T H Y H U M A N P B M C D O N O R S WT v1 v2 v3 v4 -2 0 2 4 6 8 Day 7 Expansion (- background) + 7 6 i K + 3 D C % Responder Threshold Day 7 Expansion (-background) %CD3+Ki67+ WT v1 v2 v3 v4 (Abbreviations: WT-wild type uricase enzyme; v1/v2/v3/v4-deimmunized uricase variants; Note: Ki67 is a marker of cell proliferation) Naïve T cell 106 APC Deimmunized Variant WT MHC II TCR Peptide MHC II TCR Peptide IL-2 Antigen Expanded T Cells Flow Cytometry WT dURC activation marker CD3 IL-2 a-activation marker Antigen Expanded T Cells a-activation marker
Peer-Reviewed Papers Demonstrate the Breadth of DbD Utility for Engineering Deimmunized Biotherapies 107 P A R T I A L L I S T O F T E A M ’ S P E E R - R E V I E W E D P A P E R S O N P R O T E I N D E I M M U N I Z A T I O N B Y T C E L L E P I T O P E D E L E T I O N Salvat…Bailey-Kellogg, Griswold (2015) "Mapping the Pareto Optimal Design Space for a Functionally Deimmunized Biotherapeutic Candidate.” PLoS Computational Biology 11(1): e1003988 Zhao …Bailey-Kellogg, Griswold (2015) “Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo.” Chemistry & Biology; 22: 629-639 Salvat …Bailey-Kellogg, Griswold (2017) “Computationally optimized deimmunization libraries enable efficient discovery of highly mutated enzymes with low immunogenicity and enhanced activity.” Proceedings of the National Academy of Sciences USA 114(26): e5085-e5093 Zhao …Bailey-Kellogg, Griswold (2020) “Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing.” Science Advances 6(36): eabb9011 Fang …Bailey-Kellogg, Griswold (2023) “Functional Deimmunization of Botulinum Neurotoxin Protease Domain via Computationally Driven Library Design and Ultrahigh-Throughput Screening.” ACS Synthetic Biology 12(1):153-163
Uricase Therapeutic protein 3 We are Currently Deimmunizing Three Therapeutic Proteins in Parallel and Have Additional Opportunities in Queue IND-enabling CMC & toxicology Design & engineering Iterative AI-driven library design and screening Candidate evaluation Detailed in vitro and in vivo analysis Lead candidate selections for 1st two programs expected in 2H 2023 Therapeutic protein 2 IND Potential for first INDs in 2025 Multiple additional opportunities IND IND IND 108
Deimmunizing AAV Capsids for Gene Therapy 109 109
Transforming Potent but Immunogenic Biotherapies into High- Performance, Immunologically Stealthy Drugs viral vectors gene therapy Our proprietary Deimmunized by Design® platform represents a unique technology for engineering safer and more effective biotherapeutic candidates, with relevance to a broad array of indications. ® 110
Enabling Redosable AAV Gene Therapy Can Unlock New High Unmet Need Disease Targets for Gene Therapy Diseases requiring high doses of transgene High doses of currently available AAV capsids entail significant safety risks Redosable gene therapy can enable doses to be spread out over time Diseases with on-target toxicity On-target toxicity creates risks if transgene expression is too high Redosable gene therapy can enable a “dose to effect” paradigm Pediatric onset diseases involving organs with high cell turnover Transgene loss over time would be expected, leading to waning efficacy Redosable gene therapy could provide for continued therapeutic effect 111
#1 Delete CD4+ T cell epitopes from AAV capsids Enable repeat dosing of AAV- vectored gene therapies for AAV- naïve patients Next-Gen DbD Viral Capsids for Multi-Dose Gene Therapy P R I O R I T I Z E D E N G I N E E R I N G O B J E C T I V E S https://pubmed. ncbi. nl m. nih. gov/ 23596044/ #2 #2 Delete B cell epitopes on surface of AAV capsids Enable AAV-vectored gene therapy for immune experienced patients prior natural AAV infection prior wild-type AAV gene therapy … Additional capsid, transgene, and transgene product engineering goals Improving transduction efficiency, transgene stability, and durability of therapeutic effect DC BCR Naïve B cell MHC peptide TCR MHC peptide TCR #1 Naïve T cell Activated T cell Ag-Primed B cell DC Plasma cells Induced antidrug antibodies 112
AI-Driven AAV T Cell Epitope Depletion to Enable Repeat Dosing of Naïve Patients Each learn-map-design-test round employs multiple experimental screening cycles to select the fittest variants Results shown from first round’s experimental cycles Design Space Experiments Data Models AAV AAV Library cap Gene Libraries rAAV Libraries Functional Lead Isolation Directed Evolution Deep Sequencing Humanized Mouse 113 Tissue Culture
Theoretical Plasmid Packaged Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 107 106 105 104 103 Max Sequence Diversity Screening Stringency Capsids with Combinations of Deimmunizing Mutations are Functionally Enriched Over Screening Cycles Cycle 114 Relative frequency Population-wide Sequence Diversity AAV 1st Gen T cell Epitope Library A population of highly functional yet diverse capsids is selected over cycles of screening Within the functionally enriched population are individual capsids that by design combine deimmunizing mutations Capsid 1 Example capsid fitness profiles Capsid 2 Capsid 3 Capsid 4 Capsid 5
AI-Driven AAV B Cell Epitope Deletion to Enable Treatment of Seropositive Patients Each learn-map-design-test round employs multiple experimental screening cycles to select the fittest variants Results shown from first round’s experimental cycles Design Space Experiments Data Models AAV Pre-incubate AAV Library with neutralizing Abs cap Gene Libraries rAAV Libraries Functional Lead Isolation Directed Evolution Deep Sequencing 115 Humanized Mouse Tissue Culture
116 Functional Screening Identifies Highly Fit, Antibody-Evading Capsids (Abbreviations: Nab-neutralizing antibody; WT-wild-type) Fitness, relative to wild-type * Iterative library selection yields highly- mutated individual capsids with up to 600- fold greater fitness (*) under NAb pressure that neutralizes ~94% of wild-type AAV. Cycle 1 Cycle 2 Library population contains large numbers of capsids that evade increasingly stringent NAb selection pressure 20 0 40 60 80 100 Population fitness analysis Individual capsid fitness analysis Pooled Neutralizing Antibody Selection % Neutralization WT Lib 78% 7% 94% 42%
AAVi Other Serotypes AAVii Multiple Staged Programs Aim to Create Redosable AAV Gene Therapies for Diverse Indications and Patient Populations B cell epitope depleted capsids To enable dosing of gene therapy for seropositive patients T cell epitope depleted capsids To enable redosable gene therapy for seronegative patients IND-enabling CMC & toxicology Design & engineering Iterative AI-driven library design and screening Candidate evaluation Detailed in vitro and in vivo analysis Therapeutic construct validation Therapeutic transgenes & In vivo disease models 1st Lead Capsid Selection 2024 AAVi Other AAVii Serotypes 117
Franziska Leifer, PhD Director, Biologics Research 118
119 Argininosuccinic Aciduria is Ideally Suited to Demonstrate the Expected Benefit of Redosable Gene Therapy As AAV capsid reengineering proceeds, we are developing therapeutic transgene constructs for target diseases to streamline later development Our hASL therapeutic transgene construct shows strong efficacy in a mouse model of argininosuccinic aciduria 1J Inherit Metab Dis. 2019;42:1147–1161. 2Genetics in Medicine. 2012; 14:501-507 3Molecular Genetics and Metabolism 98 (2009) 273–277 Argininosuccinic Aciduria (ASA) 2nd most common urea cycle disorder1, 2 Pediatric onset3 Caused by deficiency of argininosuccinate lyase (ASL)1 High unmet need with recurring metabolic crises and high incidence of cognitive impairment despite SOC1, 3 Part of standard newborn screening in the US1, 2 Figure adapted from Molecular Genetics and Metabolism 131 (2020) 289–298
120 “ASA Mice” Recapitulate Human Disease 18 days old ASA mouse WT 15% residual argininosuccinate lyase (ASL) activity1 Hyperammonemia1 Elevation of urea cycle intermediates argininosuccinic acid and citrulline1 Abnormal hair patterning1 Severely stunted growth1 Dramatically shortened life span1 ASA mice = B6.129S7-Asltm1Brle/J, ASL neo/neo 1Erez et al. 2011. Nature Med. Vol 17:12
121 WT pre-dose High 0 100 200 300 400 41.3 200.7 Plasma Citrulline (mole/L) 0 50 100 150 105.1 Plasma Argininosuccinic Acid (mole/L) Error bars = SEM WT pre-dose High 700 600 500 400 300 200 100 0 46.6 483.1 Whole blood Ammonia (mole/L) ** * **** ** 188.1 80.8 65.6 se se se Do Do Do d w Mi Lo * ** * 128. * 295.0 104.4 95.4 se se se Do Do Do d w Mi Lo * ASA AAV GTx Nearly Normalizes Metabolic Parameters of ASA Mice
122 0 50 150 200 0 50 100 100 Age (Days) Survival (%) Vehicle median = 19 d ASA AAV GTx Results in Strong Survival and Growth Benefit in ASA Mice
median = 106 d median = 124 d 0 50 0 50 100 100 150 200 Age (Days) Survival (%) High Dose (1e14 vg/kg, 7e11 vg/mouse) Mid Dose (5e13 vg/kg, 3.5e11 vg/mouse) Low Dose (1e13 vg/kg, 7e10 vg/mouse) Vehicle 25 75 100 0 10 20 50 Age (Days) Body Weight (g) vehicle median = 19 d Error bars = STDEV 123 ASA AAV GTx Results in Strong Survival and Growth Benefit in ASA Mice
ASA AAV GTx Results in Strong Survival and Growth Benefit in ASA Mice median = 106 d median = 124 d 0 50 0 50 100 100 150 200 Age (Days) Survival (%) High Dose (1e14 vg/kg, 7e11 vg/mouse) Mid Dose (5e13 vg/kg, 3.5e11 vg/mouse) Low Dose (1e13 vg/kg, 7e10 vg/mouse) Vehicle 25 75 100 0 10 20 50 Age (Days) Body Weight (g) High Dose (1e14 vg/kg, 7e11 vg/mouse) Mid Dose (5e13 vg/kg, 3.5e11 vg/mouse) Low Dose (1e13 vg/kg, 7e10 vg/mouse) vehicle median = 19 d Error bars = STDEV 124
ASA AAV GTx Shows Remarkable Clinical Effect Lasting More Than 100 Days in ASA Mice WT vehicle GTx HD WT GTx HD GTx LD 125 Video of 19-day-old ASA mice treated at birth Video of 100-day-old ASA mice treated at birth GTx HD = 3 dashes WT = clean tail vehicle = clean tail GTx HD = 1 dash GTx LD = 3 dashes WT = clean tail
This data provides strong support for the potential utility of AAV gene therapy in the treatment of ASA. Delivering the hASL transgene construct with a redosable deimmunized AAV capsid could lead to a durable and highly effective treatment for even the youngest ASA patients. A similar strategy could be applied to other urea cycle disorders and inherited metabolic disorders. Next steps include in vivo proof of concept studies of redosable AAV gene therapy 126 Insmed’s hASL Transgene Construct Shows Compelling Therapeutic Efficacy in a Mouse Model of ASA
DbD - Key Takeaways Immunogenicity is a major challenge with many biotherapeutics. Deimmunized by Design® is a proprietary AI-driven platform for reengineering immunogenic biotherapies into immunologically stealthy drugs. The platform has been validated preclinically with lysostaphin and several other therapeutic proteins. We are actively deimmunizing several therapeutic proteins, which could yield multiple INDs over the coming years. Deimmunizing AAV capsids could unlock the potential for redosable gene therapy, and we intend to demonstrate clinical proof of concept in diseases that are amenable to gene therapy but likely to require redosing for sustained effect. DbD Platform ® 127 Strictly Confidential
Brian Kaspar, PhD Chief Scientific Officer 128
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Next Generation Gene Therapies With Targeted HighDDeoslievs,einrhyerent systemic toxicities, low efficacy, and off-target Enhtrancsedducsatifoenty profile with similar/better efficacy 10 to 50-fold reduction in dose (vs. Systemic delivery) RNA End Joining Technology (REJ) Inability to treat diseases requiring delivery of large genes Unlocks new GTx market opportunities with no competition Large size gene delivery through traditional AAVs Deimmunized by Design (DbD) platform Immunogenicity and inability to target diseases Redreoqsuaibrilnegvirealdvoescintgors Deimmunized biobetters & derisked innovator drugs Repeat dosing of gene therapies and overcoming immunogenicity AlgaeneX New, Proprietary Manufacturing High production costs with low yields Lowest cost of goods for Insmed’s gene therapy portfolio Opportunity to license technology Significant reduction in AAV manufacturing time and cost 129
Insmed is Uniquely Positioned to Address Challenges in GTx Landscape with Game-Changing, Novel, Proprietary Technologies Insmed Value Proposition & Solution High production costs with low yields AlgaeneX New, Proprietary Manufacturing Lowest cost of goods for Insmed’s gene therapy portfolio Opportunity to license technology Significant reduction in AAV manufacturing time and cost 130
The Arduous Process of AAV Gene Therapy Manufacturing Creating functional genes for specific disease targeting is extremely slow & expensive… 1 3 Development Create a gene construct for an appropriate disease target 2 Construction Production of AAV recombinant plasmid containing gene construct Storage A plasmid bank holds the construct 4 Production Production in the bioreactor requires a complicated scale-up in cell number and up to a week in the reactor before harvest 131
Anthony Berndt, PhD Senior Scientist 132
The AlgaeneX Solution: A L G A E F O R M A S S G E N E T H E R A P Y P R O D U C T I O N Algae Cell Production Potential future of GTx production Algae cells take ~11 hours to double one-time P O T E N T I A L B E N E F I T S Rapid scalability to larger volumes No transfection required Low production cost; no expensive bioreactors or media required Ease of culturing and maintenance Standard HEK293 Cell Production Current state of the art HEK293 cell takes ~33 hours to double one-time in a bioreactor CHALLENGES Relatively slow growth Requires transfection Expensive bioreactors and media Need for maintenance and skilled manpower 133
Use Simple Algae Cell For Mass Production O U R S O L U T I O N Microalgae have been successfully utilized to produce human recombinant proteins Transformation Inherent low cost of goods and capitalization costs Simple production process and fast growth rate AAV9-GFP Injection Overview of AAV9 production in Microalgae 134
Minimum Necessary Components To Make An Infectious AAV ITR VP1 135 VP2 VP3 Viral coat proteins: VP1, VP2, VP3 Replication Factors: Rep78, Rep52 ITR-flanked gene (payload)
Insmed Has Successfully Expressed GFP Protein Using The AlgaeneX Next Generation Manufacturing Solution 136
Insmed Has Successfully Expressed AAV9 VP1, VP2, and VP3 Using The Algaenex Next Generation Manufacturing Solution A n t i - V P 1 / 2 / 3 a n t i b o d y o n a l g a e l y s a t e s 80 65 50 kDa VP1 137 VP2 VP3
Insmed Is Building A Differentiated, Next- Generation Production Platform And Genetic Tool Kit That is Intended to Allow For Low-Cost Cultivation While Maintaining High Yield Bright Field tdTomato Wild Type Random Integration (Bi-Directional, GFP& tdTomato) Site-directed (tdTomato reporter) Generation 1 Generation 2 138
Roger Adsett Chief Operating Officer 139
Insmed Strategically Positioned to Answer “What’s Next?” Potential ‘First-in- Disease’ or ‘Best-in- Disease’ Rare Disease Focus Faster to Market and Durable Revenue Potential First-in-Disease/Best-in-Disease medicines in areas of significant unmet need Solving key issues facing gene therapy – safety, cost of goods, durability of effect, and delivery of large genes Exempt from Medicare price negotiation under IRA ≥6 INDs by end of 2025, with potentially shortened time from IND to approval Durable revenue potential, leveraging ‘Top 10’ commercial launch engine 140
Game-Changing Platform Technologies with Multiple Revenue Stream Opportunities Unlocks GTx for diseases caused by large gene mutations Redosable viral vectors Biobetter versions of biologics with known immunogenicity issues Innovative drugs with low immunogenicity Potentially improved safety profile Significantly lower cost of goods Next Generation Gene Therapies with Targeted Delivery RNA End Joining (REJ) Technology New Proprietary Manufacturing (AlgaeneX) Deimmunized by Design (DbD) Platform Significant reduction in manufacturing time and cost Broad application beyond gene therapy Potential licensing opportunity 141
Initial GTx INDs Targeting Potential First-in-Disease or Best-in- Disease Duchenne Muscular Dystrophy (DMD) Stargardt Disease Source: cureduchenne.org Source: fightingblindness.org Argininosuccinic Aciduria (ASA) Source: gosh.nhs.uk 142
$1+B Potential Annual Market Opportunity for Newly Diagnosed Patients with DMD Source: Insmed analysis based on published epi (2019) and UN population estimates (2022) 10,500-13,000 10,000-10,500 3,000-4,000 23,500-27,500 Estimated DMD Prevalence US EU4+UK Japan TOTAL (7 major markets) 400-600 300-400 80-120 750-1,100 Estimated DMD Annual Incidence Aiming to be the preferred gene therapy for newly diagnosed DMD patients … … and gene therapy of choice for existing patients 143
Substantial Stargardt Disease Opportunity: Large Eligible Patient Pool Addressed with Potentially the Only Approved Gene Therapy 1 Runhart, et. al, Stargardt disease: monitoring incidence and diagnostic trends in the Netherlands using a nationwide disease registry, Acta Ophthalmol. 2022 Jun; 100(4): 395–402 2 Based on prevalence of 1:8000-10,000, and UN 2023 population estimate 3 36% of patients had no/mild visual impairment at baseline in the ProgStar retrospective study; pubmed.ncbi.nlm.nih.gov/26786511 40% may be ligible for GTx ased on visual cuity3 144 Estimated Stargardt Incidence1 Estimated Stargardt Prevalence2 US 550-600 34,000-42,000 EU4+UK 500-550 32,000-40,000 Japan 150-200 12,000-15,000 ~ e b TOTAL (7 major markets) 1,200-1,350 78,000-97,000 a
GTx Redosing for Babies Born with ASA is a Paradigm Shift Towards Lifelong Gene Therapy 145 1 Based on prevalence of 1:70,000-218,000 newborns, and UN 2023 population estimate 2 Assuming median life expectancy of 50 years Estimated Argininosuccinic Aciduria Incidence1 Estimated Argininosuccinic Aciduria Prevalence2 US 20-50 1,000-2,500 EU4+UK 15-40 750-2,000 Japan 5-10 250-500 TOTAL (7 major markets) 40-100 2,000-5,000
0.9 2.1 2.8 3.0 3.5 Dec 2017) (SMA, May 2019) Luxturna (IRD, Zolgensma Zynteglo (TDT, Aug 2022) Skysona (CALD, Sep 2022) Hemgenix (Hem B, Nov 2022) Gene Therapies will Transform Patient Outcomes While Reducing Costs to Healthcare System US List Price (WAC) $ Million US prices for approved GTxs* anchored on clinical evidence and cost offsets Transforming rare disease treatment with gene therapy 146 8 in 10 rare diseases are genetic in origin Insmed’s gene therapies overcome key issues facing gene therapy Safety Durability of effect Cost of goods Delivery of large genes IRD: Inherited Retinal Disease; SMA: Spinal Muscular Atrophy; TDT: Transfusion Dependent Beta Thalessemia; CALD: Cerebral Adrenoleukodystrophy (CALD); Hem B: Hemophilia B * For genetic disorders
Anticipated Upcoming Milestones* from Pillar 4 S U B S E T O F P I L L A R 4 P I P E L I N E 1 Next Generation Gene Therapies 2 Deimmunized Therapeutic Protein Duchenne Muscular Dystrophy1 (DMD) Stargardt Disease1 (STGD) Chronic Refractory Gout2 (CRG) Argininosuccinic Aciduria1 (ASA) 2H 2023 2024 2025 FIH (2H) Clinical Data (1H) Candidate Selection Preclinical Data IND Preclinical Data IND Innovative Treatments New Proprietary Manufacturing (AlgaeneX) Full Capsid Production Scale up to commercial manufacturing * May be revised as research and clinical development progresses Early-Stage Research 147 4 IND Clinical Data
Key Takeaways First in Disease/Best in Disease medicines in areas of significant unmet need Focus on rare diseases, BLAs – ensures patient access under the IRA ≥ 6 INDs by end of 2025, with potentially shortened time from IND to approval Insmed strategically positioned for success 3 Potentially game-changing platform with multiple revenue streams 2 Multibillion annual revenue potential from first 3 GTxs 148 1 Solving key issues facing gene therapy – safety, cost of goods, durability of effect, and delivery of large genes Platform technologies with multiple revenue stream opportunities AI driven Deimmunized proteins and AAV capsid library Manufacturing platform Leapfrog current GTx approaches to emerge as market leader Initial GTx INDs targeting First in Class/Best in Class: Duchenne Muscular Dystrophy (DMD) Stargardt Disease Argininosuccinic Aciduria (ASA) Lean Pillar 4 operations with <20% of total Insmed expenditures
Infinite potential. One patient at a time. 149
Brensocatib ARIKAYCE TPIP Early-Stage Research 2023 2024 2025 Label Expansion ARISE topline ENCO readout enrollm RE ent comple tion Bronchiectasis ASPEN topline readout CRSsNP Ph2 trial initiation Pulmonary Hypertension associated with Interstitial Lung Diseases (PH-ILD) Interim dose titration & safety & tolerability levels from Ph2 trials Ph2 topline readout Pulmonary Arterial Hypertension (PAH) Interim dose titration & safety & tolerability levels from Ph2 trials Duchenne Muscular Dystrophy (DMD) First-in-human Clinical data Stargardt Disease IND submission Clinical data Chronic Refractory Gout (CRG) Candidate selection Preclinical data IND submission Argininosuccinic Aciduria (ASA) Preclinical data IND submission AlgaeneX Full capsid production Scale up to commercial manufacturing 150 Key Pipeline Catalysts