A DETAIL REVIEW ARTICLE ON DELAFLOXACIN

A DETAILREVIEW ARTICLE ON DELAFLOXACIN ABHISHEK PAREKH DEPARTMENT OF DRUG REGULATORY AFFAIRS, NORTHEASTERN UNIVERSITY RGA6000: Intro FDA Pharma Regulation John Domider December 13, 2022.

1 TABLE OF CONTENTS Pg. No. Product Background ------------------------------------------------------------------------------2 Product Description -------------------------------------------------------------------------------3 FDA Guidance -------------------------------------------------------------------------------------4 Market Pathways ----------------------------------------------------------------------------------5 Pathway Timeline ---------------------------------------------------------------------------------7 Functional Teams ----------------------------------------------------------------------------------8 TABLE OF TABLES 1) For Community Acquired Bacterial Pneumonia ----------------------------------------4 2) For Acute Bacterial Skin and Skin Structure Infections -------------------------------5 3) Orange Book Patent Data ------------------------------------------------------------------7

3 Vial contents should be thoroughly dissolved after vigorous shaking; the solution should be clear and golden to amber in color. Prior to administration, further dilute the reconstituted solution to a volume of 250 mL with D5W or 0.9% NaCl to produce a final concentration of 1.2 mg/mL. IV Infusion IV through the volume control set or piggyback container IV infused for 60 minutes. Administration by mouth: can be consumed with or without food. Missed dose: If it has been longer than 4 hours since your last dose, wait until your next scheduled dose. Storage Lyophilized powder and tablets: Store items between 20 and 25 °C (68 and 77 °F), with excursions allowed between 15 and 30 °C (59 and 86 °F). The reconstituted vial should be kept at controlled room temperature or refrigerated for up to 24 hours before further dilution for IV infusion. Do not freeze. diluted solution: Keep refrigerated or in a controlled environment for up to 24 hours; avoid freezing. ( Baxdela (Delafloxacin) Dosing, Indications, Interactions, Adverse Effects, and More , n.d.) Section 2: Product Description Risks & Benefits of Baxdela: Benefits- 1. Compared to comparable antibiotics, it is effective against a greater variety of bacteria. 2. Can be consumed either with or without meals. 3. Has not been demonstrated to make you more susceptible to sunburn than similar-class medicines. 4. Unlike other antibiotics in the same family, it has not been demonstrated to induce changes to your heart rhythm (QT prolongation or arrhythmias). 5. Fewer drug interactions than those of comparable antibiotics. Risks- 1. Has a high price since there is no generic alternative. 2. Unlike other antibiotics like levofloxacin or moxifloxacin, which must be taken once a day, this antibiotic must be given twice daily. 3. People with advanced renal illnesses shouldn't use it. 4. May result in severe adverse effects including renal issues, convulsions, and tendon rupture. Fewer authorized uses than those of other antibiotics in the same class. (GoodRx, 2021) Efficacy and Adverse event of Delafloxacin: Background: This meta-analysis looks at how well delafloxacin works to treat acute bacterial infections in adults and what side effects it has. Method: PubMed, Embase, the Cochrane Library, the Web of Science, and clinical trials were searched until March 26, 2022.Only randomized controlled trials (RCTs) comparing delafloxacin and comparator antibiotics for adult patients were considered. Clinical cure rate and microbiological eradication rate at posttreatment assessment were primary outcomes (AEs). Result: Six RCTs with 3,019 acute bacterial infection participants were included. Delafloxacin and comparators had similar clinical cure rates (OR = 1.06, 95% CI = 0.89–1.26, I2 = 0%). Overall, delafloxacin had a similar microbiological eradication rate (documented and supposed) to the comparators (OR = 1.33, 95% CI = 0.94– 1.88, I2 = 0%). TEAEs did not differ between delafloxacin and the comparators (OR = 0.93, 95% CI = 0.80– 1.08, I2 = 75%). SAEs were similar for delafloxacin and comparators (OR = 0.94, 95% CI = 0.67–1.32, I2 = 0%). GI diseases (OR = 1.26, 95% CI = 1.01–1.56, I2 = 89%), nausea, vomiting, and diarrhoea (OR = 0.77, 95% CI = 0.45–1.34, I2 = 79%), and (OR = 2.10, 95% CI = 1.70–2.96, I2 = 0%). The incidence of nausea and

4 vomiting was similar between delafloxacin and the comparator, but diarrhoea was greater. Neurological diseases were less common in the delafloxacin group (OR = 0.71, 95% CI = 0.50–1.01, I2 = 52%). Conclusion: As an alternative therapeutic drug, delafloxacin had the same clinical effectiveness, rate of eradication of microorganisms, and number of adverse events (AE) as comparators. (He et al., 2022) Public Health Event In USA: Five outpatients (median age 59, 40% female) were prescribed DLX for seven days. Infectious disease specialists (2/5, 40%), emergency medicine physicians (2/5, 40%), and ophthalmologists (1/5, 20%) prescribed. Prosthetic joint infections (PJI) and acute skin and soft tissue infections (n = 2) were most prevalent. Staphylococcus epidermidis caused both PJIs. 60% of prescriptions were off-label. No patient failed therapy due to delafloxacin, and no adverse events were observed. Inferences: DLX therapy was highly beneficial in this case series, including off-label indications. Delafloxacin clinical data are limited. Prospective data would aid in determining the therapeutic niches for this fluoroquinolone. (Hornak & Reynoso, 2022) Section 3: FDA Guidance for Delafloxacin FDA Identified Breakpoints For Community Acquired Bacterial Pneumonia (CABP) Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) Pathogen A B C A B C Streptococcus pneumoniae* ≤ 0.03 - - ND ND ND Staphylococcus aureus  (methicillin- susceptible isolates) ≤ 0.12 0.24 ≥0.4 ≥25 21- 25 ≤20 Haemophilus influenzae* ≤0.003 - - ≥27 - - Haemophilus parainfluenzae* ≤0.07 - - ≥26 - - Escherichia coli ≤0.27 0.5 ≥1 ≥22 18- 20 ≤17 Klebsiella pneumoniae ≤0.26 0.4 ≥1 ≥22 19- 21 ≤20 Pseudomonas aeruginosa ≤0.3 1 ≥2 ≥23 20- 23 ≤19 A = Susceptible; B = Intermediate; C = Resistant; ND = not determined

6 Summary of Regulatory Activity Prior to and Following Submission: The regulatory highlights of the delafloxacin development program carried out under INDs 62,772 (oral tablet formulation) and 76,096 (intravenous formulation) are outlined in this Section. 21 June 2001: Oral submission of initial application. The investigational new drug (IND) application for ABT- 492 was first submitted by the original Sponsor, Abbott Laboratories (Pharmaceutical Products Division), under the number 62,772 (oral tablet formulation). Initial Application Submission (20 March 2007), IV formulation. For the medication RX-3341 (Intravenous formulation), the Sponsor Rib-X Pharmaceuticals, Inc. submitted an IND application under IND 76,096. Phase 2 meeting conclusion, April 14, 2010. The delafloxacin Phase 3 development strategy, including the study design and study endpoints for the Sponsor's two planned Phase 3 studies, was addressed by the Sponsor and the Agency. The Agency informed the Sponsor (Rib-X Pharmaceuticals, Inc.) following a December 2009 Advisory Committee that, based on historical data, the Agency's new primary efficacy endpoint for clinical success for ABSSSI trials would be evaluated at 48 to 72 hours, an earlier time point than was previously advised. According to the Agency's assessment of the literature, this modification would enable the demonstration of "a larger therapeutic impact between antibacterial medicines and placebo compared to a later time point." The Sponsor provided the Agency with information about the following significant aspects of their pivotal Phase 3 trials, including their choice to: (a) conduct two trials, one evaluating delafloxacin's IV formulation and the other an IV to oral switch trial; (b) have a(n) NI margin of 10% with respect to the primary endpoint; (c) limit the number of subjects with major abscesses to 20% of all infections; and (d) conduct an absolute bioavailability (BA) study of Prior to submitting their NDA application, the Sponsor should obtain the outcomes of their comprehensive QT (TQT) study, the Agency advised. Qualified Infectious Disease Product (QIDP) Designation, 8 September 2012. On 17 July 2012, the Sponsor requested a QIDP designation for delafloxacin for the acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia (CABP) treatment indication. The agency granted Delafloxacin a QIDP designation for both indications, on September 08 2012. Fast Track Designation, 17 October 2012. Special Protocol Agreement (SAP), 08 February 2013. Special Protocol Agreement (SAP), 19 August 2013. Type A CMC Meeting Request, 06 February 2015. CMC Pre NDA Meeting, 5 April 2015. Pre NDA-Meeting, February 2016. Submission of NDA 208,610 and NDA 208.611, 18 October 2016. 120 Days Safety Update, February 2017. (FDA.GOV, 2017) Type of Application is NDA or BLA? The regulatory review period for BAXDELA TABLETS under NDA 208610 has been determined by the Food and Drug Administration (FDA or the Agency), and as required by law, this notice of that determination is being published. Because applications for the extension of a patent that protects that human drug product were submitted to the Director of the U.S. Patent and Trademark Office (USPTO), Department of Commerce, FDA has made the determination. Dates: By August 12, 2019, anybody who believes that any of the published dates are inaccurate (see the SUPPLEMENTARY INFORMATION section) may submit electronic or paper comments and request a redetermination. Additionally, until December 9, 2019, any interested party may petition FDA to determine

7 whether the extension applicant used due diligence during the regulatory review process. For more details, refer to the part under "Petitions" in the SUPPLEMENTARY INFORMATION. (FDA.GOV, 2017) Where does it belong? Delafloxacin belongs to an Orange Book of approved product by FDA. (DrugCentral, 2022) Orange Book Patent Data (NDA): Formulatio n Strength Trade Name Applican t Applicati on Number Typ e Dose Form Route Patent Numb er Paten t Expir y date EQ 300MG BASE/VI AL BAXDE LA MELINT A N208611 RX POWD ER INTRAVENO US 86480 93 Oct. 7, 2025 EQ 300MG BASE/VI AL BAXDE LA MELINT A N208611 RX POWD ER INTRAVENO US 95392 50 Oct. 7, 2025 EQ 300MG BASE/VI AL BAXDE LA MELINT A N208611 RX POWD ER INTRAVENO US 82528 13 Oct. 2, 2026 EQ 450MG BASE BAXDE LA MELINT A N208610 RX TABLE T ORAL 86480 93 Oct. 7, 2025 EQ 450MG BASE BAXDE LA MELINT A N208610 RX TABLE T ORAL 89695 69 Oct. 7, 2025 EQ 450MG BASE BAXDE LA MELINT A N208610 RX TABLE T ORAL 82528 13 Oct. 2, 2026 EQ 450MG BASE BAXDE LA MELINT A N208610 RX TABLE T ORAL 95392 50 Oct. 7, 2025 Has Baxdela's generic equivalent received approval? No. In the US, Baxdela is not currently offered in a therapeutically comparable form. Note: Illegal generic Baxdela may be offered for sale by shady online pharmacies. These pharmaceuticals could be hazardous imitations. Make sure you buy prescription drugs from a reputable and legitimate online pharmacy if you buy them online. If you have any questions about ordering any drug online, consult your doctor. ( Generic Baxdela Availability , n.d.) Section 5: Pathway Timeline Determination of the Regulation Review Period: The FDA has established a 5,813-day relevant regulatory review period for BAXDELA TABLETS. Of this time, 5,569 days took place during the regulatory review period's testing phase and 244 days took place during

9 registration studies was positive, but only large-scale clinical usage can prove its safety. Cardiac and phototoxicity tests came back negative. The pharmacology of delafloxacin permits twice-daily dosage and a simple transition from intravenous to oral methods, while the absence of clinically significant drug-drug interactions ensures safe outpatient usage. Due to its chemical, microbiological, and pharmacological qualities and adverse event profile to date, delafloxacin may supplement our present antibacterial arsenal for treating skin and skin structure infections in the face of developing antimicrobial resistance. References Amendment No. 5 to Form S-1 . (n.d.). Www.sec.gov. Retrieved December 13, 2022, from https://www.sec.gov/Archives/edgar/data/1164994/000119312512178777/d255425ds1a.htm Baxdela (delafloxacin) dosing, indications, interactions, adverse effects, and more . (n.d.). Reference.medscape.com. Retrieved December 12, 2022, from https://reference.medscape.com/drug/baxdela- delafloxacin-1000153#11 Clinical trails. (2017, July 6). Baxdela TM (delafloxacin) for the Treatment of Acute Bacterial Skin and Skin Structure Infections . Clinical Trials Arena. https://www.clinicaltrialsarena.com/projects/baxdela-delafloxacin- for-the-treatment-of-acute-bacterial-skin-and-skin-structure-infections/ DrugCentral. (2022). delafloxacin . Drugcentral.org. https://drugcentral.org/drugcard/5238 FDA.GOV. (2017, June 17). CENTER FOR DRUG EVALUATION AND RESEARCH . Https://Www.accessdata.fda.gov/Drugsatfda_docs/Nda/2017/208610Orig1s000,208611Orig1s000MedR.pdf. Food and Drug Administration. (2019, June 11). Federal Register :: Request Access . Unblock.federalregister.gov. https://www.federalregister.gov/documents/2019/06/11/2019-12299/determination-of-regulatory-review- period-for-purposes-of-patent-extension-baxdela-tablets-nda Generic Baxdela Availability . (n.d.). Drugs.com. Retrieved December 12, 2022, from https://www.drugs.com/availability/generic-baxdela.html GoodRx. (2021, August 31). Baxdela (delafloxacin): Basics, Side Effects & Reviews . GoodRx. https://www.goodrx.com/baxdela/what-is He, R., Lin, F., Yu, B., Qiu, J., & Zheng, L. (2022). The efficacy and adverse events of delafloxacin in the treatment of acute bacterial infections: A systematic review and meta-analysis of randomized controlled trials. Frontiers in Pharmacology , 13 . https://doi.org/ 10.3389/fphar.2022.975578 Hornak, J. P., & Reynoso, D. (2022). Early Clinical Experience with Delafloxacin: A Case Series. The American Journal of the Medical Sciences , 363 (4), 359–363. https://doi.org/ 10.1016/j.amjms.2022.01.016 Lodise, T., Corey, R., Hooper, D., & Cammarata, S. (2018). Safety of Delafloxacin: Focus on Adverse Events of Special Interest. Open Forum Infectious Diseases , 5 (10). https://doi.org/ 10.1093/ofid/ofy220 Markham, A. (2017). Delafloxacin: First Global Approval. Drugs , 77 (13), 1481–1486. https://doi.org/ 10.1007/s40265-017-0790-5 Research, C. for D. E. and. (2018). Drugs@FDA Glossary of Terms. FDA . https://www.fda.gov/drugs/drug- approvals-and-databases/drugsfda-glossary-terms

10 Research, C. for D. E. and. (2020). Delafloxacin Injection and Oral Products. FDA . https://www.fda.gov/drugs/development-resources/delafloxacin-injection-and-oral-products US FDA. (n.d.). Draft Guidance on Delafloxacin Meglumine . Retrieved December 12, 2022, from https://www.accessdata.fda.gov/drugsatfda_docs/psg/Delafloxacin%20meglumine_draft_Oral%20tab_RLD %20208610_RC09-18.pdf