As filed with the Securities and Exchange Commission on November 3, 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 FIRST WAVE BIOPHARMA, INC. (Exact name of registrant as specified in its charter) (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classification Code Number) Delaware 2834 46-4993860 (I.R.S. Employer Identification Number) 777 Yamato Ro ...

Financial Performance - For the three months ended June 30, 2023, total operating expenses decreased by approximately $1.2 million, or 23%, to $4.2 million compared to $5.4 million for the same period in 2022[144]. - The net loss for the three months ended June 30, 2023, was approximately $4.2 million, a decrease of approximately $1.2 million, or 23%, compared to a net loss of approximately $5.4 million for the same period in 2022[153]. - For the six months ended June 30, 2023, total operating expenses decreased by approximately $6.5 million, or 44%, to $8.2 million compared to $14.8 million for the same period in 2022[154]. - The net loss for the six months ended June 30, 2023, was approximately $8.2 million, a decrease of approximately $6.8 million, or 45%, compared to a net loss of approximately $15.0 million for the same period in 2022[164]. Research and Development - Research and development expenses for the three months ended June 30, 2023, totaled approximately $1.4 million, a decrease of approximately $1.5 million, or 53%, from approximately $2.9 million in the same period of 2022[145]. - Research and development expenses for the six months ended June 30, 2023, totaled approximately $2.7 million, a decrease of approximately $5.2 million, or 66%, from approximately $7.9 million in the same period of 2022[155]. - The company is currently focused on developing adrulipase and niclosamide drug candidates, with ongoing clinical trials and regulatory submissions[134]. - The company anticipates that research and development expenses will decrease as it closes out the Phase 2b adrulipase SPAN clinical trial[147]. Cash Flow and Financing - As of June 30, 2023, the company had cash and cash equivalents of approximately $1.2 million and cumulative losses attributable to common stockholders of approximately $176.8 million[139]. - The company raised approximately $2.1 million from the July 2023 Offering, which is expected to fund operations through September 2023[139]. - Net cash used in operating activities for the six months ended June 30, 2023, was approximately $5.6 million, a decrease from $12.5 million in the same period of 2022, reflecting an improvement of 55%[166][167]. - Net cash provided by financing activities for the six months ended June 30, 2023, was approximately $5.5 million, slightly higher than $5.4 million in the same period of 2022[168][169]. - The financing activities in 2023 included net proceeds of approximately $2.2 million from the exercise of warrants and $3.7 million from the March 2023 Offering[168]. - Cash repayments related to note payable financing for corporate insurances amounted to approximately $0.4 million during the first half of 2023[168]. - The decrease in cash and cash equivalents for the six months ended June 30, 2023, was $126,850, a significant improvement compared to a decrease of $7.1 million in the same period of 2022[165]. - Non-cash expenses in operating activities for the first half of 2023 were approximately $0.7 million, primarily related to stock-based compensation[166]. - Increases in accounts payable and accrued expenses contributed approximately $1.0 million to the cash flow in the first half of 2023[166]. Accounting Policies - There were no material changes to critical accounting policies during the six months ended June 30, 2023[171]. - The company continues to assess its accounting policies, which are essential for interpreting financial results[170].

As filed with the Securities and Exchange Commission on July 13, 2023 Registration No. 333-272404 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Amendment No. 3 to FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 FIRST WAVE BIOPHARMA, INC. (State or other jurisdiction of incorporation or organization) (Exact name of registrant as specified in its charter) (Primary Standard Industrial Classification Code Number) Delaware 2834 46-4993860 (I.R.S. Employer Identification ...

As filed with the Securities and Exchange Commission on July 11, 2023 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Amendment No.2 to FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 (Name, address, including zip code, and telephone number, including area code, of agent for service) FIRST WAVE BIOPHARMA, INC. (Exact name of registrant as specified in its charter) (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classificati ...

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 As filed with the Securities and Exchange Commission on July 6, 2023 Registration No. 333-272404 FIRST WAVE BIOPHARMA, INC. (Exact name of registrant as specified in its charter) (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classification Code Number) Delaware 2834 46-4993860 (I.R.S. Employer Identification ...

As filed with the Securities and Exchange Commission on June 5, 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 FIRST WAVE BIOPHARMA, INC. (Exact name of registrant as specified in its charter) (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classification Code Number) Delaware 2834 46-4993860 (I.R.S. Employer Identification Number) 777 Yamato Road, ...

Financial Performance - For the three months ended March 31, 2023, total operating expenses decreased by approximately $5.3 million, or 57%, to $4.1 million from $9.4 million in the same period in 2022[135]. - The net loss for the three months ended March 31, 2023, was approximately $4.1 million, a decrease of approximately $5.6 million, or 58%, compared to a net loss of $9.6 million for the same period in 2022[145]. - Net cash used in operating activities for the three months ended March 31, 2023, was approximately $2.8 million, compared to $7.9 million for the same period in 2022[146]. Expenses Breakdown - Research and development expenses for the three months ended March 31, 2023, totaled approximately $1.4 million, a decrease of approximately $3.6 million, or 73%, compared to $5.0 million for the same period in 2022[136]. - General and administrative expenses for the three months ended March 31, 2023, totaled approximately $2.7 million, a decrease of approximately $1.7 million, or 39%, from $4.4 million in the same period in 2022[140]. Cash Position - As of March 31, 2023, the company had cash and cash equivalents of approximately $2.1 million and cumulative losses attributable to common stockholders of approximately $172.6 million[129]. - Net cash provided by financing activities for the three months ended March 31, 2023, was approximately $3.5 million, primarily due to net proceeds from a private placement offering[149]. Future Outlook - The company anticipates that research and development expenses will remain stable during the remainder of the fiscal year as it works towards completion of the Phase 2b Adrulipase SPAN clinical trial[138]. - The company is dependent on obtaining additional funding from outside sources to continue operations and develop its drug candidates[130]. - The company is evaluating potential asset acquisitions and business combinations to expand its product pipeline[131]. Internal Controls - The CEO and CFO confirmed the effectiveness of disclosure controls and procedures as of the end of the reporting period[155]. - There were no changes in internal control over financial reporting that materially affected the company's reporting[156]. Market Risks - No applicable market risks were disclosed in the report[153].

Adrulipase (FW-EPI) for Exocrine Pancreatic Insufficiency (EPI) - First Wave BioPharma is developing targeted, non-systemic therapies for gastrointestinal diseases, focusing on billion-dollar markets[3] - Adrulipase is a recombinant lipase biologic for EPI treatment, targeting Cystic Fibrosis (CF) and Chronic Pancreatitis (CP) patients[8, 29] - The U S market for EPI treatment is approximately $1.7 billion[13] - The global PERT market exceeds $2.2 billion[22] - A Phase 2 bridging study for Adrulipase was initiated in January 2023, with topline data expected in the second half of 2023[8, 26] - Current projections show a potential 70% to 87% reduction in patient cost per month compared to 2020 GMP batch projections due to manufacturing optimization and reformulation[38] Niclosamide for Inflammatory Bowel Disease (IBD) - Niclosamide, a repurposed small molecule drug, is being developed for IBD, specifically Ulcerative Colitis-Ulcerative Proctitis and Immune Checkpoint Inhibitor-Associated Colitis[8] - Approximately 54% to 59% of patients fail to achieve remission with current 5-ASA treatments for ulcerative colitis[43] - The US market size for Ulcerative Colitis is approximately $5 billion, with $4.6 billion attributed to mild-moderate cases[49] - The US market size for Crohn's Disease is approximately $7.4 billion, with $4.3 billion attributed to mild-moderate cases[49]

Clinical Development - The company is focused on developing gut-restricted GI clinical drug candidates, including adrulipase and niclosamide [340]. - Adrulipase is designed to treat exocrine pancreatic insufficiency in cystic fibrosis and chronic pancreatitis patients, with topline data from a Phase 2b trial expected in Q3 2023 [342]. - The company completed enrollment in the FW-COV trial for COVID-19 GI infections in January 2022, but decided to discontinue this program due to mixed results [344]. - The company expects research and development expenses to increase in the foreseeable future as it focuses on clinical development efforts for product candidates [369]. - The company anticipates general and administrative expenses to increase to support expanded research and development activities and business development efforts [373]. Financial Performance - The company reported a stockholders' deficit of $(6,969,988) as of September 30, 2021, failing to meet Nasdaq's minimum stockholders' equity requirement of $2.5 million [351]. - The net loss for the year ended December 31, 2022, totaled approximately $14.6 million, a decrease of approximately $43.9 million, or 75%, compared to the net loss of approximately $58.5 million for the year ended December 31, 2021 [394]. - The total operating expenses for the year ended December 31, 2022, were approximately $12.7 million, a decrease of approximately $46.4 million compared to $59.1 million for the year ended December 31, 2021 [384]. - The company has not generated any revenues and has experienced net losses and negative cash flows from its activities [374]. - The company raised approximately $4.0 million from a private placement in March 2023, following cumulative losses of approximately $168.5 million as of December 31, 2022 [375]. Cash Flow and Funding - Net cash used in operating activities for the year ended December 31, 2022, was approximately $22.3 million, primarily due to a net loss of approximately $14.6 million and a decrease in payables related to the FWB acquisition of approximately $8.1 million [396]. - Net cash provided by financing activities for the year ended December 31, 2022, was approximately $15.7 million, mainly from the issuance of common stock under the ATM Agreement for net proceeds of approximately $7.7 million [400]. - The company is dependent on obtaining additional funding from outside sources to continue operations and may face substantial doubt about its ability to continue as a going concern [375]. Expenses and Impairments - Research and development expenses for the year ended December 31, 2022, totaled approximately $8.8 million, a decrease of approximately $8.2 million, or 48%, compared to $17.0 million for the year ended December 31, 2021 [386]. - General and administrative expenses for the year ended December 31, 2022, totaled approximately $12.0 million, a decrease of approximately $6.4 million, or 35%, compared to $18.4 million for the year ended December 31, 2021 [389]. - The company recognized an impairment charge of approximately $2.4 million on patents acquired in the Mayoly APA during the year ended December 31, 2021 [405]. - Non-cash expenses for the year ended December 31, 2022, included approximately $2.8 million, mainly related to the dissolution of a foreign subsidiary [396]. Stock and Goodwill - A 1-for-30 reverse stock split was completed on August 26, 2022, to regain compliance with Nasdaq's Bid Price Rule [354]. - The carrying value of goodwill was approximately $1.7 million and $1.9 million at December 31, 2022, and 2021, respectively, with a loss of approximately $1.7 million recognized related to foreign translation adjustments [408]. - The company performed its review of goodwill on its one reporting unit, with estimates impacting the carrying value of assets and liabilities [407].

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-Q (Mark One) ☒ 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 UNDER SECTION 13 OF 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 From the transition period from to Commission File Number 001-37853 FIRST WAVE BIOPHARMA, INC. (Exact name of registrant as specified in its charter) Delaware 46-4993860 (St ...