Table of Contents As filed with the Securities and Exchange Commission on April 6, 2023. Registration No. 333-269775 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Amendment No. 1 to FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware (State or other jurisdiction of incorporation or organization) 2836 (Primary Standard Industrial Classification Code Number) 94-3171943 (I.R.S. Emp ...

Clinical Development and Product Candidates - Istaroxime, the lead product candidate, has shown significant improvement in cardiac function and systolic blood pressure in patients with acute heart failure (AHF) during Phase 2 clinical trials[31]. - The Phase 2 global clinical study for early cardiogenic shock demonstrated positive topline results, with istaroxime rapidly increasing systolic blood pressure while preserving renal function[31]. - Istaroxime has received Fast Track designation from the FDA for the treatment of AHF, indicating its potential to address significant unmet medical needs[49]. - The company plans to extend enrollment in the Phase 2 clinical trial for early cardiogenic shock by up to 30 patients to further characterize the effects of istaroxime[46]. - Istaroxime, the lead cardiovascular product candidate, has shown potential to improve blood pressure and cardiac function in Phase 2 clinical studies, with significant SBP increases observed (p=0.017) in early cardiogenic shock patients[68]. - In a Phase 2b trial, istaroxime demonstrated substantial increases in stroke volume, with a mean SVI of 5.33 ml/beat/m² for the 0.5 µg/kg/min group compared to 1.65 ml/beat/m² for placebo[72]. - The Phase 2 clinical trial for early cardiogenic shock included 60 patients, with significant improvements in SBP and cardiac index compared to the control group[67]. - The company plans to advance istaroxime for acute decompensated heart failure to a Phase 3-ready position, leveraging positive Phase 2 data[60]. - Istaroxime's dual mechanism of action may improve myocardial contractility and relaxation, potentially leading to better clinical outcomes compared to current therapies[65]. - Istaroxime was generally well tolerated, with the 1.0 µg/kg/min dose group showing better efficacy and safety compared to the 1.5 µg/kg/min group[75]. - The company plans to conduct an additional Phase 2 clinical trial for Rostafuroxin to demonstrate efficacy in African American patients with treatment-resistant hypertension[80]. Market Potential and Unmet Medical Needs - The estimated annual addressable market for AHF in the U.S., EU, and Japan is approximately two million patients, representing a multi-billion-dollar market value[42]. - There are over 1.3 million hospital admissions for heart failure in the U.S. each year, highlighting the significant market need for effective treatments[42]. - Nearly half of U.S. adults (116 million, or 47%) have hypertension, with only 24% having their condition under control, highlighting a significant unmet medical need in the hypertension market[53]. - Rostafuroxin targets a genetic profile found in approximately 20% to 25% of the adult hypertensive population, addressing a significant unmet medical need[76]. - Nearly half of U.S. adults (116 million, or 47%) have hypertension, with only 24% having their condition under control, highlighting the market potential for new treatments[77]. Financial and Capital Strategy - The company is seeking additional capital through various means, including public or private securities offerings and strategic partnerships, to support its development programs[38]. - The company recorded an impairment of the intangible asset related to Rostafuroxin due to the inability to secure a licensing transaction or strategic opportunity[80]. - Management plans to secure additional capital through public or private securities offerings, convertible debt financings, and strategic transactions, but there are no committed alternatives at this time[226]. - As of December 31, 2022, the company had cash and cash equivalents of $6.2 million and current liabilities of $2.5 million, raising substantial doubt about its ability to continue as a going concern[225]. - The company incurred operating losses of $41.3 million and $77.3 million for the years ended December 31, 2022, and 2021, respectively, with an accumulated deficit of $824.5 million as of December 31, 2022[228]. - The company expects to continue incurring significant research and clinical development expenses, which may prevent it from achieving profitability in the foreseeable future[230]. Licensing and Partnerships - The company has entered into an Amended and Restated License Agreement with Lee's (HK) and Zhaoke, which includes potential milestone payments of up to $78.9 million[36]. - The A&R License Agreement with Lee's Pharmaceutical includes potential milestone payments of up to $78.9 million and tiered royalties based on net sales ranging from low single digits to low teens percentages[85]. - The collaboration with Universita degli Studi di Milano-Bicocca involves funding of €0.2 million for research activities and joint ownership of results, with royalties on products generated from the collaboration[90]. - The company is pursuing licensing arrangements and partnerships for its product candidates, including rostafuroxin, to advance their development[52]. - The company is actively exploring potential licensing transactions and strategic partnerships for its preclinical heart failure product candidates[82]. - The strategic alliance with Esteve includes milestone payments upon regulatory approvals and contributions to Phase 3 clinical trials, with a maximum aggregate payment of $20 million for certain collaborations[98]. - The Johnson & Johnson license agreement requires milestone payments of up to $3 million and royalties ranging from high single-digit to low double-digit percentages of net sales[99]. Regulatory and Compliance - The FDA has granted Orphan Drug designation for the company's KL4 surfactant for multiple conditions, including RDS in premature infants and ARDS in adults, providing exclusive marketing rights for 10 years post-approval[123]. - The company has received Fast Track designation from the FDA for istaroxime, AEROSURF, and SURFAXIN®, aimed at expediting the development of these products for serious conditions[124]. - The FDA's Fast Track program allows for expedited development and review of drugs addressing unmet medical needs, with rolling reviews available[142][143]. - The FDA may grant Breakthrough Therapy designation for drugs showing substantial improvement over existing therapies, expediting their review[145]. - The FDA requires post-marketing testing and compliance with cGMPs for drug manufacturers after NDA approval[155]. - The FDA's approval process includes inspections of clinical sites and manufacturing facilities to ensure compliance with Good Clinical Practices (GCPs) and current Good Manufacturing Practices (cGMPs)[137]. - The FDA provides a five-year period of non-patent exclusivity for the first applicant to gain NDA approval for a new chemical entity (NCE)[150]. - Under the Orphan Drug Act, drugs for rare diseases may receive a seven-year exclusive marketing period if they meet specific criteria[141]. Intellectual Property and Patents - The company holds a patent portfolio related to cardiovascular agents and plans to continue patent activities for new compounds and treatment methods[101]. - A new U.S. patent for istaroxime was issued, covering extended infusion durations for improved outcomes in acute heart failure treatment[105]. - The company has filed international patent applications for new compounds aimed at treating heart failure, with expiration dates projected around 2039 and 2040[108][109]. - The company has filed multiple international patent applications for various treatments, including PCT/EP2010/053571 for rostafuroxin derivatives aimed at treating proteinuria and renal failure, with patents expiring around March 18, 2030[111]. - The company holds 120 in-force patents worldwide related to its Aerosol Delivery System (ADS) technology, with key patents expiring between Q3 2023 and 2039, including US Patent No. 9,713,687 expiring on February 10, 2035[119]. - The company is actively pursuing patent protection for innovations related to synthetic peptide formulations and delivery methods, focusing on improved dosage forms[114]. - The company has filed patents for aerosol-conducting airway connectors to enhance aerosol delivery efficiency, with key patents expiring between 2029 and 2033[120]. Competitive Landscape - The biotechnology industry is highly competitive, with the company facing intense competition from existing pharmaceutical firms and new entrants in respiratory and cardiovascular markets[125]. - The company's patent portfolio includes significant patents for surfactant compositions and methods for treating pulmonary disorders, with various patents expiring between 2026 and 2033[116]. Healthcare Environment and Challenges - The company is subject to increased governmental scrutiny regarding drug pricing, which may lead to legislative changes affecting its business[213]. - Future healthcare reform measures could limit government payments for healthcare products, resulting in reduced demand and pricing pressures[216]. - The company must navigate complex regulations regarding healthcare fraud and abuse, including anti-kickback and false claims laws[195][196]. - Compliance with state laws regarding marketing and reporting expenses can be costly and time-consuming for the company[205]. - The company may face civil monetary penalties for failing to report required information on payments to healthcare practitioners[204]. - Cost-containment programs and price controls implemented by government authorities could limit future revenues and operational results[206]. Employee and Human Capital - The company has 20 full-time employees, with 17 based in the U.S., skilled in drug development and corporate administration[219]. - The company believes its human capital resources are fundamental to its success, focusing on recruiting and retaining skilled personnel to increase stockholder value[220].

Table of Contents As filed with the Securities and Exchange Commission on February 14, 2023. Registration No. 333- UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware (State or other jurisdiction of incorporation or organization) 2836 (Primary Standard Industrial Classification Code Number) 94-3171943 (I.R.S. Employer Identification ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended September 30, 2022 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-26422 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware (State ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2022 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-26422 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware (State or ot ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended March 31, 2022 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-26422 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware (State or o ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-K ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2021 Or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission File Number: 000-26422 WINDTREE THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Securities registered pu ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended September 30, 2021 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-26422 Windtree Therapeutics, Inc. (Exact name of registrant as specified in its charter) Delaware (State ...

Table of Contents For the transition period from _____ to _____ UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q Commission file number 000-26422 ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 Windtree Therapeutics, Inc. For the quarterly period ended June 30, 2021 (Exact name of registrant as specified in its charter) or Delaware (State or other jurisdiction of incorporation or organization) ☐ TRANSITION REPORT PURSUANT TO SECTION ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-26422 Windtree Therapeutics, Inc. (Exact name of registrant as specified in its charter) Delaware (State or other jurisdiction of incorporation or organizatio ...