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): December 12, 2024
(Exact name of registrant as specified in its charter)
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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 registered | ||||||||||||
| Common Stock | KRYS | 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 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
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Item 7.01 Regulation FD Disclosure.
On December 12, 2024, Krystal Biotech, Inc. (the “Company”) issued a press release announcing an initial clinical update for its rare respiratory disease programs KB408 and KB407, including early clinical evidence of gene delivery to the lung of AATD patients and increase in lung AAT to therapeutic levels. In addition, the press release indicated that the Company would host a conference call and webcast at 8:30 a.m. ET on December 12, 2024, to discuss the interim clinical data and its KB408 and KB407 clinical development programs. For purposes of the call and webcast, the Company provided a slide presentation, which will be available on the “Investors” section of the Company’s website at www.krystalbio.com. Copies of the press release and the slide presentation are attached hereto as Exhibit 99.1 and Exhibit 99.2, respectively, and are incorporated by reference herein.
The information in this Item 7.01 of this Current Report on Form 8-K and in Exhibits 99.1 and 99.2 attached hereto shall not be (i) deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section, or (ii) incorporated into any registration statement or other document filed with the Securities and Exchange Commission by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing, except as shall be expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
| Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 99.2 | ||||||||
| 104 | Cover Page Interactive Data file (embedded within the Inline XBRL document) | |||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Date: December 12, 2024 | KRYSTAL BIOTECH, INC. | |||||||||||||||||||
| By: | /s/ Krish S. Krishnan | |||||||||||||||||||
| Name: | Krish S. Krishnan | |||||||||||||||||||
| Title: | Chairman and Chief Executive Officer | |||||||||||||||||||
Krystal Biotech Announces Initial Clinical Update for Rare Respiratory Disease Programs KB408 and KB407 Including Early Clinical Evidence of Gene Delivery to the Lung of AATD Patients and Increase in Lung AAT to Therapeutic Levels
Clear evidence of SERPINA1 gene delivery and AAT expression following KB408 administration in AATD patients
Both KB408 for AATD patients and KB407 for patients with cystic fibrosis were safe and well tolerated at all dosing regimens evaluated to date
Conditional sanctioning of the KB407 Phase 1 CF Study CORAL-1 protocol by CFF TDN
Investor call and webcast to be held December 12 at 8:30 am ET to discuss data update
PITTSBURGH, December 12, 2024 (GLOBE NEWSWIRE) – Krystal Biotech, Inc. (the “Company”) (NASDAQ: KRYS), a commercial-stage biotechnology company, announced today clinical data updates for both KB408 and KB407, the Company’s clinical-stage, inhaled genetic medicine programs in Phase 1 for the treatment of rare respiratory diseases. Today’s updates include molecular data from multiple patients demonstrating SERPINA1 delivery and alpha-1 antitrypsin (AAT) expression within the respiratory tract following KB408 administration as well as safety and tolerability data for both KB407 and KB408 that, taken together, highlight the potential of the Company’s platform to safely deliver genetic cargo to the lung.
“To achieve meaningful AAT expression levels and functionality with the first dose of KB408 is a very exciting development for this program and for our alpha-1 antitrypsin deficiency (AATD) patients,” said Robert A. Sandhaus, MD, PhD, FCCP, Professor of Medicine at the National Jewish Health in Denver, Executive Vice President and Senior Medical Director of AlphaNet, as well as Clinical Director of the Alpha-1 Foundation. “Even though the first intravenous augmentation therapy was approved decades ago, we still don’t have a good understanding of the impact these therapies are having on lung disease. A safe, effective, non-invasive therapy that is less burdensome on patients and supported by molecular evidence of function in the lung is needed, and we look forward to additional clinical updates on KB408 in the months to come.”
The Company will host an investor conference call and webcast today, Thursday, December 12, 2024, at 8:30 am ET, to discuss the clinical data updates. Investors and the general public can access the live webcast at: https://www.webcaster4.com/Webcast/Page/3018/51767. For
those unable to listen to the live webcast, an archived version will also be available on the Investors section of the Company’s website for at least 30 days.
KB408 for the treatment of alpha-1 antitrypsin deficiency (AATD) lung disease
KB408 is being evaluated in the Company’s Phase 1 SERPENTINE-1 study. SERPENTINE-1 is an open label, single dose escalation study in adult patients with AATD with a Pi*ZZ or a Pi*ZNull genotype. SERPENTINE-1 is designed to include up to three dose escalation cohorts evaluating single administrations of 109, 1010, and 1011 PFU of KB408 via inhalation. Additional details of the SERPENTINE-1 study can be found at www.clinicaltrials.gov under NCT identifier NCT06049082.
As of the December 6, 2024 data cut-off, a total of seven (7) patients had been enrolled in SERPENTINE-1, including 3 patients in Cohort 1 who had received the 109 PFU KB408 dose and 4 patients in Cohort 2 who had received the 1010 PFU KB408 dose. One patient in each of Cohort 1 and Cohort 2 were receiving background intravenous (IV) augmentation therapy.
Two patients in Cohort 2 also received bronchoscopies to assess SERPINA1 delivery and AAT levels in the lung. Both a baseline bronchoscopy and a post-dose bronchoscopy, conducted 24 to 48 hours after KB408 dosing, were completed. One of the two patients who received bronchoscopies was receiving background IV augmentation therapy.
Clear evidence of successful gene delivery was observed in both patients, including high rates of transduction and AAT expression in the conducting airways of both patients as assessed via bronchoscopy. Key molecular findings for each patient are summarized below:
Patient Not on Background IV Augmentation
•A clinically meaningful proportion of conducting airway epithelial cells were transduced following administration of a single dose of KB408, with the percentage of cells positive for AAT expression increasing from 0% at baseline to 39% after KB408 dosing.
•Free AAT levels in lung epithelial lining fluid increased over 8-fold, rising from 85 nM at baseline to 729 nM after KB408 dosing.
•AAT functionality was also confirmed by detection of AAT-NE binding, with the percentage of active, unbound neutrophil elastase in epithelial lining fluid dropping from 97.2% at baseline to 40.2% – an over 50% absolute reduction achieved within 48 hours after dosing.
Patient on Background IV Augmentation
•Again, a clinically meaningful proportion of conducting airway epithelial cells were transduced following administration of a single dose of KB408, with the percentage of cells positive for AAT expression increasing from 3% at baseline to 35% after KB408 dosing.
•Lavage samples could not be successfully collected from this patient, preventing accurate quantification of AAT and neutrophil elastase binding in lung epithelial lining fluid. However, both KB408 genomes and SERPINA1 RNA transcripts were detected in multiple bronchial brushing samples, with an average of 4 x 103 genome copies and 4 x 102 transcript copies detected, providing further support of successful gene delivery and expression in the KB408 treated lung.
In addition to evidence of KB408 transduction and AAT expression in the lungs of these two patients, increases in serum AAT levels were also detected in all four Cohort 2 patients after KB408 dosing, suggestive of broad dissemination of KB408-encoded AAT following expression in the lung. Increases in serum AAT relative to baseline ranged from 270 nM to 5.3 µM in the three patients that were not on confounding background IV augmentation, including in one case increases in serum AAT from 4.4 µM at baseline to 9.7 µM after KB408 dosing.
KB408-related adverse events for all seven patients treated in Cohort 1 and Cohort 2 were mild to moderate and transient. No serious adverse events have been reported.
“With clear evidence of gene delivery, including detection of high nanomolar concentrations of AAT in lung epithelial lining fluid, as well as corresponding reductions in the percentage of unbound, active neutrophil elastase by over 50%, today’s initial clinical data is a major step forward towards our goal of developing a safe, effective, and non-invasive therapy for AATD patients to maintain therapeutic AAT levels in the lung,” said Suma Krishnan, President, Research & Development, Krystal Biotech, Inc. “These data, together with the attractive tolerability profile observed to date, also reinforce our conviction in HSV-1 based gene delivery to the lung and our entire inhaled genetic medicines pipeline. We look forward to sharing additional updates on our respiratory programs in 2025.”
The Company will enroll two additional patients in Cohort 2 of SERPENTINE-1 and expects to provide additional data updates in 2025. In parallel, the Company will open Cohort 3 to explore safety and gene delivery at the highest dose of KB408.
KB407 for the treatment of cystic fibrosis (CF)
Based on preclinical data submitted to date by the Company, the Cystic Fibrosis Foundation (CFF) Therapeutic Development Network (TDN) Clinical Research Executive Committee has granted conditional sanctioning of the Company’s KB407 Phase 1 CORAL-1 study protocol subject to review of the data monitoring committee charter, if required, to align with CFF TDN standards. No additional preclinical updates for KB407 are required, and the Company expects to be fully sanctioned and open sites within the CFF TDN shortly.
KB407 is being evaluated in the Phase 1 CORAL-1 study. CORAL-1 is an open label, dose escalation study in adult patients with CF. CORAL-1 is designed to include up to three dose escalation cohorts evaluating either one, two, or four daily administrations of 109 PFU of KB407 via inhalation. Additional details of the CORAL-1 study can be found at www.clinicaltrials.gov under NCT identifier NCT05504837.
As of the December 6, 2024 data cut-off, a total of five (5) patients had been enrolled in CORAL-1. Three patients received a single 109 PFU KB407 dose in Cohort 1 and three patients, including one roll-over from Cohort 1, received two daily 109 PFU KB407 doses in Cohort 2. All but one patient was on background modulator therapy.
The initial focus of Cohorts 1 and 2 was safety of single and repeat inhaled administration of KB407 in patients with CF. As observed with KB408, KB407 has been well tolerated in all patients dosed to date. KB407-related adverse events for all five patients treated in Cohort 1 and Cohort 2 were mild to moderate and transient. No serious adverse events have been reported. The Company expects to report data from Cohort 3 in 1H 2025, including data on CFTR gene delivery and expression in patients with cystic fibrosis.
About Krystal Biotech, Inc.
Krystal Biotech, Inc. (NASDAQ: KRYS) is a commercial-stage biotechnology company focused on the discovery, development and commercialization of genetic medicines to treat diseases with high unmet medical needs. VYJUVEK® is the Company’s first commercial product, the first-ever redosable gene therapy, and the first medicine approved by the FDA for the treatment of dystrophic epidermolysis bullosa. The Company is rapidly advancing a robust preclinical and clinical pipeline of investigational genetic medicines in respiratory, oncology, dermatology, ophthalmology, and aesthetics. Krystal Biotech is headquartered in Pittsburgh, Pennsylvania. For more information, please visit http://www.krystalbio.com, and follow @KrystalBiotech on LinkedIn and X (formerly Twitter).
Forward-Looking Statements
Any statements in this press release about future expectations, plans and prospects for Krystal Biotech, Inc., including statements about the potential of the Company’s platform to safely deliver genetic cargo to the lung; the Company’s clinical-stage, inhaled genetic medicines programs in Phase 1 for the treatment of rare respiratory diseases; the Company’s plans to enroll two additional patients in Cohort 2 of its SERPENTINE-1 study and provide additional data updates in 2025; the Company’s plans to open Cohort 3 of its SERPENTINE-1 study to explore safety and gene delivery at the highest dose of KB408; the Company’s expectation to be fully sanctioned and open sites within the CFF TDN shortly; the Company’s expectation that it will report data from Cohort 3 of its CORAL-1 study in 1H 2025, including data on CFTR gene delivery and expression in cystic fibrosis patients; and other statements containing the words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “likely,” “will,” “would,” “could,” “should,” “continue,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including uncertainties inherent in the initiation and conduct of clinical trials, as well as regulatory review of clinical trials and applications for marketing approvals; and such other important factors as are set forth under the caption “Risk Factors” in the Company’s annual and quarterly reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements included in this press release represent the Company’s views as of the date of this press release. The Company anticipates that subsequent events and developments will cause its views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this press release.
CONTACT
Investors and Media:
Stéphane Paquette, PhD
Krystal Biotech
spaquette@krystalbio.com
© Copyright 2024 Krystal Biotech, Inc. All rights reserved. Rare Respiratory Pipeline Interim Clinical Update December 2024
Krystal | 2 Forward Looking Statements and Disclosures Forward Looking Statements This presentation and the accompanying oral presentation that are collectively referred to as this presentation contain forward-looking statements that involve substantial risks and uncertainties. Any statements about future expectations, plans and prospects for Krystal Biotech, Inc. (the “Company”), including but not limited to statements about the Company’s HSV-1-based platform being able to safely and effectively deliver and express genetic cargo when administered to the lung via repeated inhalation; the initial positive clinical data from the Company’s rare respiratory disease programs, KB408 and KB407 and the implications thereof for the Company’s broader pipeline targeting diseases of the lung; the prevalence and incidence of AATD and cystic fibrosis; the Company’s intention to accelerate its clinical study of KB408 and simultaneously enroll confirmatory patients in Cohort 2 and open Cohort 3 to explore safety and gene delivery at the top dose; the Company’s belief that the positive initial data from the KB408 study demonstrates a clinically relevant dosing range; the targeted patient segments for KB407 and the estimated number of patients in such segments; the Company’s belief that KB407 sanctioning by CFF TDN will accelerate enrollment and shorten time to bronchoscopies and KB407 molecular data; the Company’s plans to share molecular data from the KB407 program in 1H 2025; and other statements containing the words “anticipate”, “believe”, “estimate”, “expect”, “intend”, “may”, “plan”, “predict”, “project”, “target”, “potential”, “likely”, “will”, “would”, “could”, “should”, “continue” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties associated with regulatory review of manufacturing processes and clinical trials and the content and timing of decisions made by regulatory authorities; the uncertainties inherent in the initiation and conduct of clinical trials; availability and timing of data from clinical trials and utility of such data; and such other important factors as are set forth in the Company’s filings with the U.S. Securities and Exchange Commission. The forward-looking statements included in this presentation represent the Company’s views as of the date of this presentation and should not be relied upon as representing the Company’s views as of any subsequent date. This presentation may contain estimates and statistical data. These estimates involve assumptions and limitations, and investors are cautioned not to give undue weight to such estimates. Neither the Company nor any other person makes any representation as to the accuracy or completeness of such estimates or data or undertakes any obligation to update such estimates or data. Any projections, assumptions and estimates of the Company’s future performance and the future performance of the markets in which the Company operates are necessarily subject to a high degree of uncertainty and risk. Disclosures Other than VYJUVEK®, all products described in this presentation are investigational therapies. The Company is using the Aerogen Solo® Nebulizer System and Aerogen® Ultra in its clinical trials evaluating KB407, KB408, and inhaled KB707.
Krystal | 3 Krystal’s HSV-1 Based Approach for Lung Gene Delivery Developing redosable, non-invasive, inhaled gene therapies to address monogenic disorders of the lung Historical Challenges with Inhaled Gene Therapy1 Inhaled gene therapy has been explored for decades, with little success Focus to date has been on adenovirus, AAV, and non-viral approaches Multiple challenges including cargo limitations, low efficiency of gene transfer, toxicity, product instability, and burdensome delivery HSV-1 Platform Has Potential to Overcome Historical Challenges Clinically validated vector; tolerated and redosable in Phase 3 for DEB Large cargo capacity to load in full genes, including CFTR for cystic fibrosis Ability to redose and/or adjust dose over time as lung cells turnover Broad cellular tropism and efficient transduction of airway epithelium Expected nebulization time is under 30-minutes using off-the-shelf nebulizer Growing clinical dataset demonstrating that Krystal’s inhaled candidates are well-tolerated and distribute broadly in the lung 1. Vu A, et al. Human Gene Therapy 2020;31(17-18):921-939 AAV, adeno-associated virus; CFTR, cystic fibrosis transmembrane conductance regulator; DEB, dystrophic epidermolysis bullosa; HSV-1, herpes simplex virus 1 Delivered via off the shelf nebulizer Krystal’s Proprietary HSV-1 Vectors
Krystal | 4 1. Greene CM, et al. Nat Rev Dis Primers 2016;2:16051; 2. Brantly ML, et al. Int J Chron Obstruct Pulmon Dis. 2019;6:100–114; 3. Aboussouan LS, et al. Respir Med. 2009;103:335-341; 4. Stoller JK, et al. Int J Chron Obstruct Pulmon Dis. 2013;10:26-24; 5. Blanco I, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:561-569; *Severe AATD defined as patients with Pi*ZZ genotype AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; IV, intravenous; SERPINA1, serpin family A member 1; U.S., United States KB408 in Development as Redosable, Non-Invasive, Inhaled Gene Therapy to Enable Local AAT Expression in Lung Alpha-1 Antitrypsin Deficiency (AATD) Monogenic disorder that leads to progressive lung disease Severe AATD Prevalence3-5* Over 60K Patients in the U.S. Over 250K Patients Worldwide Unproven and Limited Treatment Options1.2 There is no cure available for patients with AATD Standard of care is weekly IV infusions of AAT but treatment is burdensome on patients and clinical benefit not well defined Alpha-1 antitrypsin (AAT) is a key regulator of protease activity, in particular neutrophil elastase in lungs3 AATD is an autosomal co-dominant inherited genetic disorder resulting from mutations in SERPINA1 gene encoding AAT, misfolding mutations Pi*ZZ and Pi*SZ are the most common Genetic deficiency of AAT can result in unopposed neutrophil elastase activity and progressive pulmonary impairment
Krystal | 5 AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; GLP, good laboratory practices; HSV-1, herpes simplex virus 1; IND, investigational new drug; NOAEL, no observed adverse effect level ; SERPINA1, serpin family A member 1 Inhaled Candidate KB408 for AATD Lung Disease Genetic medicine designed to achieve sustained, local AAT expression is supported by robust preclinical data package KB408 Replication-incompetent HSV-1 vector containing functional human SERPINA1 2 x SERPINA1 genes Airway administration to wild-type or SERPINA1 deficient mice yielded robust AAT expression detected by multiple independent assessments Repeat KB408 dosing well-tolerated in murine GLP IND-enabling toxicology study with only mild findings and NOAEL of top dose Data package strongly supportive of KB408 progression to the clinic Vector platform shown to be amenable to nebulization with broad airway transduction and tolerability in non-human primates – KB407 data Preclinical Summary Transduces human airway cells in vitro leading to dose-dependent expression and secretion of functional AAT AAT secreted from KB408 transduced cells is functional as demonstrated by binding to target neutrophil elastase
Krystal | 6 KB408 Phase 1 Study SERPENTINE-1 Open-label, single dose escalation study in adult patients with AATD with a PI*ZZ genotype Key Enrollment Criteria • Key Inclusion Criteria • Age ≥18 to ≤70 • PI*ZZ or Pi*ZNull genotype • Serum AAT < 11μM - Cohort 3b only • Key Exclusion Criteria • ppFEV1 <50% • IV AAT within 6 weeks - Cohort 3b only Study Objectives • Evaluate safety and tolerability, including • Frequency and severity of adverse events • Changes in vital signs, spirometry, ECGs, and clinical labs • Measure AAT and neutrophil elastase concentration in serum, sputum, and bronchoalveolar lavage fluid • Evaluate transgene expression in lung tissue • Exploratory evaluation of impact on inflammatory biomarkers, quality of life measures, and pharmacodynamic markers AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; ECG, electrocardiogram; ppFEV1, percent predicted forced expiratory volume in 1 second; IV, intravenous; PFU, plaque forming unit Cohort 3a 1011 PFU n = 3 on IV AAT Cohort 2 1010 PFU n = up to 6* Cohort 1 109 PFU n = 3* Safety Review Committee Safety Review Committee Cohort 3b 1011 PFU n = 3 off IV AAT Bronchoscopy cohorts * Cohort 1 and Cohort 2 patients may be on or off IV AAT Amended protocol to add bronchoscopies to Cohort 2 in 3Q 2024
Krystal | 7 Observation** D29D1-D3 D8 D15 D57 Scope of First SERPENTINE-1 Interim Readout Safety data from seven patients across two dose levels, and initial molecular data from two Cohort 2 patients Cohort 2 No Bronchoscopy 1010 PFU n = 2* Cohort 1 109 PFU n = 3* Cohort 2 Bronchoscopy 1010 PFU n = 2* Observation KB408 109 or 1010 PFU Day 1 D29D1-D2 D8 D15 D57 Safety Assessments Only Safety and Molecular Assessments KB408 1010 PFU Day 1 Baseline Bronchoscopy Minimum 14 Days Prior to Dosing Post Dose Bronchoscopy 24-72 Hours After Dosing * Cohort 1 and Cohort 2 patients may be on or off IV AAT **Safety follow up still ongoing; at least two weeks follow up completed for both patients as of data cutoff Data cutoff date of December 6, 2024 AAT, alpha-1 antitrypsin; IV, intravenous; PFU, plaque forming unit
Krystal | 8 Patient Demographics and Augmentation Therapy Status Study population predominantly elderly with variable augmentation therapy use, all Pi*ZZ genotype Cohort 2 No Bronchoscopy 1010 PFU n = 2* Cohort 1 109 PFU n = 3* Cohort 2 Bronchoscopy 1010 PFU n = 2* Safety Assessments Only Safety and Molecular Assessments * Cohort 1 and Cohort 2 patients may be on or off IV AAT Cohort Patient ID SERPINA1 Genotype Age Sex Background Augmentation 1 01 Pi*ZZ 60 Female No 02 Pi*ZZ 66 Female Yes 03 Pi*ZZ 67 Female No 2 04 Pi*ZZ 31 Male No 05 Pi*ZZ 56 Female No Cohort Patient ID SERPINA1 Genotype Age Sex Background Augmentation 2 06 Pi*ZZ 60 Male Yes 07 Pi*ZZ 58 Male No Data cutoff date of December 6, 2024 AAT, alpha-1 antitrypsin; IV, intravenous; PFU, plaque forming unit
Krystal | 9 KB408 Well Tolerated in All Patients Dosed To Date No serious adverse events or dose-limiting toxicities observed All KB408-related adverse events reported have been mild-to-moderate and transient No evidence of significant neutralizing antibody response following KB408 administration No systemic vector distribution after inhalation, based on blood and urine analysis
Krystal | 10 Bronchoscopy Sampling Plan and Molecular Data in Interim Readout Multiple assessments conducted to mitigate inherent variability in sample collection across patients Cohort 2 Bronchoscopy Timing Tissue Biopsies Bronchial Brushings Bronchoalveolar Lavage Assessments Included in Interim Readout Observation KB408 1010 PFU Day 1 Baseline Bronchoscopy Minimum 14 Days Prior to Dosing Post Dose Bronchoscopy 24-72 Hours After Dosing Sample Collection at Each Timepoint 1. Rate of KB408 transduction and AAT expression in cells of the conducting airways: Assessed by immunofluorescent staining for AAT positive cells in tissue biopsy samples 2. Secreted free AAT levels and residual active neutrophil elastase in lung ELF: Free AAT and % unbound neutrophil elastase assessed by ELISA in lung lavage samples, adjusted for lavage dilution factor 3. Change in SERPINA1 Expression Levels in Lung Airway Cells: Assessed by quantification of codon- optimized SERPINA1 genome copies and transcript levels by qPCR and qRT-PCR in brushings AAT, alpha-1 antitrypsin; ELISA, enzyme-linked immunosorbent assay; PFU, plaque forming unit; qPCR; quantitative polymerase chain reaction; qRT-PCR, quantitative reverse transcription polymerase chain reaction; SERPINA1, serpin family A member 1
Krystal | 11 H&E DAPI AAT Merge CAS CAS CAS Baseline After KB408 Clear Evidence of Transduction and AAT Expression in KB408 Treated Lungs Patient 07, no background augmentation; clinically meaningful proportion of airway cells positive for AAT after single dose * Based on quantification of DAPI positive and DAPI + AAT co-positive cells lining the conducting airways of the lung by immunofluorescence; three biopsies assessed for post-dose DAPI + AAT co-positive cell quantification, total cell counts > 300 AAT, alpha-1 antitrypsin; CAS, conducting airway surface; DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin 39% AAT Positive Cells After Single KB408 Dose* 0% AAT Positive Cells at Baseline All imaging conducted at 40× magnification Post-dose biopsies harvested 48 hours after nebulization Biopsy locations: Baseline biopsy #1, top: lower lobe, right lung; post-dose biopsy #3, middle: lower lobe, left lung; post-dose biopsy #4, bottom: lower lobe, left lung Patient 07 Images Patient 07
Krystal | 12 Secreted AAT Reached Clinically Meaningful Levels after Single KB408 Dose Patient 07, no background augmentation; increase in AAT to high nanomolar range supports further exploration of mid dose 1. Average values from 2 lobes (pre-dose samples). Only 1 post-dose sample was evaluable due to low return from second lobe (<10%) AAT, alpha-1 antitrypsin; ELF, epithelial lining fluid; NE, neutrophil elastase Over 50% reduction in % unbound NE within 48 hours of first dose 85 729 0 100 200 300 400 500 600 700 800 Baseline Post Dose A AT L ev el (n M ) Free AAT Levels in Lung ELF1 Over 8-fold increase in ELF AAT with one dose Achieved target range of 5-10% of systemic levels % Free Neutrophil Elastase in ELF 97.2% At Baseline 40.2% After Single KB408 Dose
Krystal | 13 Clear Evidence of Transduction and AAT Expression in KB408 Treated Lungs Patient 06, on background augmentation; also detected meaningful proportion of airway cells positive for AAT after single dose 35% AAT Positive Cells After Single KB408 Dose* 3% AAT Positive Cells at Baseline [Placeholder Data] H&E DAPI AAT Merge CAS CAS CAS Baseline After KB408 All imaging conducted at 40× magnification Post-dose biopsies harvested 24 hours after nebulization Biopsy locations: Baseline biopsy #2, top: lingula (left lung); Post-dose biopsy #2, middle: lower lobe, right lung; Post-dose biopsy #3, bottom: lower lobe, right lung. Patient 06 Images Patient 06 * Based on quantification of DAPI positive and DAPI + AAT co-positive cells lining the conducting airways of the lung by immunofluorescence; four biopsies assessed for post-dose DAPI + AAT co-positive cell quantification, total cell counts > 600 AAT, alpha-1 antitrypsin; CAS, conducting airway surface; DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin
Krystal | 14 Increased SERPINA1 in Brushings Consistent with KB408 Mechanism Lavages not successfully collected in Patient 06 but increased SERPINA1 levels provide further evidence of successful delivery 1 10 100 1000 10000 SERPINA1 RNA Copies SERPINA1 DNA Copies Average Copy Number SERPINA1 DNA and RNA Levels After KB408 Dosing Challenges with lavage sample collection prevented evaluation of AAT levels in Patient 06 epithelial lining fluid However, KB408 transduction and SERPINA1 expression was independently confirmed by qPCR and qRT-PCR analysis Assays are specific for KB408-encoded, codon-optimized SERPINA1 No signal was detected from baseline samples (n = 3) I 1 D A Copies I A1 RNA Copies n = 3/3 Positive Samples n = 2/3 Positive Samples AAT, alpha-1 antitrypsin; DNA, deoxyribonucleic acid; qPCR; quantitative polymerase chain reaction; qRT-PCR, quantitative reverse transcription polymerase chain reaction; RNA, ribonucleic acid; SERPINA1, serpin family A member 1
Krystal | 15 Clear Evidence of Successful and Safe Gene Delivery with KB408 Positive initial data supports acceleration of KB408 and has positive read-through implications for pipeline KB408 delivery via inhalation well tolerated at both dose levels tested to date Free AAT levels in ELF of over 700 nM from first patient are already in clinically relevant range Over a third of airway cells positive for AAT in both patients after single 1010 PFU KB408 dose Increases in SERPINA1 transcript levels consistent with KB408 mechanism and AAT data Based on positive data will simultaneously continue enrollment in Cohort 2 and open Cohort 3 to explore higher end of dose range Encoded AAT is functional and binds neutrophil elastase; over 50% reduction from single dose AAT, alpha-1 antitrypsin; ELF, epithelial lining fluid; PFU, plaque forming unit; SERPINA1, serpin family A member 1
Krystal | 16 Cystic Fibrosis Disease Overview A life-span shortening progressive disease of the lung 1. U.S. Cystic Fibrosis Foundation – About Cystic Fibrosis, accessible at: About Cystic Fibrosis | Cystic Fibrosis Foundation (cff.org); 2. U.S. Cystic Fibrosis Foundation – 2022 CFF Patient Registry Highlights; 3. O’Sullivan BP, et al. Lancet 2009;373:1891-904; 4. Elborn JS, et al. Lancet 2016; 388:2519-31; 5. Sanders DB, et al. Pediatr Clin North Am. 2016;63:567-84; 6. Stoltz DA, et al. N Engl J Med. 2015, 372 (4): 351-362; 7. Cystic Fibrosis Foundation (2022) Patient Registry Annual Data Report; 8. Hapnadak SG, et al. J Cyst Fibros. 2020;19(3):344-354 CF, cystic fibrosis; CFTR / CFTR, cystic fibrosis transmembrane conductance regulator; GI, gastrointestinal; U.S., United States CF Prevalence & Incidence1,2 Cystic fibrosis (CF) is a life-threatening inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), leading to reduced and/or loss of CFTR function3,4,5 Progressive lung disease is the primary cause of morbidity and mortality with loss of CFTR-mediated ion transport leading to6 Airway mucus obstruction Recurrent bacterial infection Inflammation According to the U.S. Cystic Fibrosis Foundation, the median age at death for patients with CF in the United States was 36.6 years in 20227 CFTR modulators, first approved in 2012 and now used in combination, are emerging as standard of care for eligible patients8 Limitations of CFTR Modulators: Not effective for all CFTR mutation types, heterogeneous patient response, GI / liver tolerability, frequent dosing8 105,000 CF Patients in 94 Countries 32,000+ CF Patients in U.S. Registry +1,000 New Cases Annually in U.S.
Krystal | 17 10K 19K 5K All 105K Target Segments for KB407 Patients ineligible for CFTR modulator therapy including CFTR null patients 10%+ of all CF patients11 Upside: Combination therapy or direct competition with TRIKAFTA if demonstrating superior dosing, efficacy, and/or safety+ Alternate regimen for patients that poorly tolerate TRIKAFTA 5% of patients otherwise eligible for TRIKAFTA2 3 Patients either weakly or non-responsive to TRIKAFTA®, ppFEV1 increase < 5% 15-25% of patients otherwise eligible for TRIKAFTA22 1. Krystal estimates based on CFF Patient Registry 2019, ECFS Patient Registry 2018; 2. Krystal estimates based on Middleton PG, et al. N Engl J Med. 2009;381:1809-1819; Heijerman HG, et al. Lancet 2019;394:1940- 1948; Trikafta® FDA Label, Revised 10/2021 CF, cystic fibrosis; CFTR / CFTR, cystic fibrosis transmembrane conductance regulator; HSV-1, herpes simplex virus type 1; ppFEV1, percent predicted forced expiratory volume in 1 second KB407 Replication-incompetent HSV-1 vector containing functional human CFTR 2x CFTR genes Estimated Patients KB407 Designed To Address Major Unmet Needs in CF Multiple opportunities for KB407 to improve CF patient outcomes as mutation agnostic, redosable gene therapy
Krystal | 18 CF, cystic fibrosis; CFF, Cystic Fibrosis Foundation; CFTR / CFTR, cystic fibrosis transmembrane conductance regulator; GLP, good laboratory practices; IND, investigational new drug; NHP, non-human primate; NOAEL, no observed adverse effect level; TDN, Therapeutic Development Network Robust Preclinical Data Package Supports Clinical Evaluation of KB407 Studies across multiple models have shown KB407 is amenable to lung delivery, well tolerated, and encodes functional CFTR KB407 recently received conditional sanctioning from CFF TDN subject to data monitoring committee charter review – no additional preclinical data requested Representative Image from NHP Lung All Key Preclinical Criteria for KB407 Have Been Met 1. Cellular Tropism: KB407 efficiently transduces human primary airway epithelial cells leading to dose dependent CFTR expression 2. Full-Length Payload: CFTR protein expressed in KB407 transduced cells is full-length, properly localized, and glycosylated 3. Functionality: Encoded CFTR has shown functionality in both in vitro CF patient model and in vivo rodent model 4. Tolerability: KB407 well tolerated in multiple preclinical studies including in GLP IND-enabling toxicology study with repeat delivery to the lung via inhalation – adverse level was not reached and NOAEL was top dose 5. Broad and Sustained In Vivo Expression: KB407 was broadly disseminated in NHP lungs after delivery via inhalation and CFTR detected out to at least 28 days after last dose Sample collected as part of GLP IND-enabling toxicology study one day after third weekly dose of roughly 109 PFU KB407 via inhalation
Krystal | 19 Observation Cohort 3 n = 6 Cohort 2 n = 3 KB407 Cohort 1 n = 3 KB407 KB407 Phase 1 Study CORAL-1 Ongoing study to assess safety and transduction efficiency of ascending doses of KB407 in adults with CF Study Objectives • Evaluate safety and tolerability of ascending doses of nebulized KB407, as well as preliminary efficacy evaluation • KB407 transduction and CFTR transgene expression in lung (bronchoscopy sub-study only) • Effects of KB407 on pulmonary function (ppFEV1) • Effects of KB407 on lung-specific quality of life (CFQ-R respiratory domain) • Vector shedding and biodistribution will also be assessed in blood, urine, buccal, and sputum samples Key Enrollment Criteria • Age ≥ 18 years with confirmed diagnosis of CF • ppFEV1 ≥50% and ≤100% • Resting O2 saturation ≥92% on room air • Cohort 1 and 2: Participants may receive concurrent modulator therapy, bronchoscopy optional • Cohort 3: No more than 3 out of 6 participants may be on concurrent modulator therapy, bronchoscopy mandatory CF, cystic fibrosis, CFTR / CFTR, cystic fibrosis transmembrane conductance regulator; DMC, data monitoring committee; PFU, plaque forming unit; ppFEV1, percent predicted forced expiratory volume in 1 second Open Label Open Label 109 PFU KB407 Days 0, 1, 2, 3 DMC Review After Day 28 Cohort 1 DMC Review After Day 28 Cohort 2 109 PFU KB407 Day 0 D28D0 D2 D7 D14 D58D21 Observation 109 PFU KB407 Day 0 and 1 D0-D2 D58 Observation Mandatory bronchoscopy 1-4 days after last dose D0-D3 D58 D28D7 D14 D21 D28D7 D14 D21 KB407 Open Label
Krystal | 20 Scope of CORAL-1 Interim Safety Data Update and Patient Demographics Safety data available from five patients dosed once or twice with KB407* *One patient rolled over from Cohort 1 to Cohort 2 Data cutoff date of December 6, 2024 CFTR / CFTR, cystic fibrosis transmembrane conductance regulator; PFU, plaque forming unit; ppFEV1, percent predicted forced expiratory volume in 1 second Cohort 2 Two 109 PFU Doses n = 3* Cohort 1 Single 109 PFU Dose n = 3 Observation KB407 109 PFU Day 0 Only or Day 0 and Day 1 D28D0-D2 D7 D14 D58D21 Safety Assessments Only Cohort Patient ID CFTR Genotype Age Sex Modulator Therapy 1 01-01 F508del/F508del 35 Male Yes 01-02 F508del/F508del 28 Female Yes 01-03 G551D/E60X 34 Female Yes 2 02-01* F508del/F508del 36 Male Yes 02-02 F508del/F508del 27 Male Yes 02-03 F508del/F508del 29 Male No
Krystal | 21 KB407 Well Tolerated in All Patients Dosed To Date No serious adverse events or dose-limiting toxicities observed All KB407-related adverse events reported have been mild-to-moderate and transient No evidence of significant neutralizing antibody response following KB407 administration No systemic vector distribution after inhalation, based on blood and urine analysis
Krystal | 22 Working Towards a Highly Differentiated Respiratory Franchise Safe delivery of genetic cargo in Phase 1 is a key derisking event for the platform with read-through to broader pipeline First direct clinical evidence of safe gene delivery using HSV-1 Well-tolerated by patient population with underlying lung disease Delivering full-length genes and demonstrated functionality of KB408-encoded AAT in patients with AATD Successfully delivered to the lung using commercially available nebulization technology – off the shelf, non-invasive therapy Redosability provides opportunity to build on efficacy over time KB407 sanctioning by CFF TDN will accelerate enrollment and shorten time to bronchoscopies and KB407 molecular data Positive read though implications for all of Krystal’s inhaled genetic medicines portfolio KB408 For AATD Lung Disease KB407 For Cystic Fibrosis Inhaled KB707 For Solid Tumors of the Lung + future pipeline opportunities AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; CFF, Cystic Fibrosis Foundation; HSV-1, herpes simplex virus 1; IV, intravenous; TDN, Therapeutic Development Network
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