Passage BIO, Inc 8-K, filed Dec 14, 2022
Passage BIO, Inc. (PASG)
About this 8-K
Passage BIO, Inc filed this 8-K on December 14, 2022.
Items reported
- Item 7.01: Regulation FD disclosure
- Item 9.01: Financial statements and exhibits
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Item 7.01 Regulation FD Disclosure.
On December 14, 2022, Passage Bio, Inc. (the “Company”) issued a press release regarding updates to the Company’s Imagine-1 Trial, a Phase 1/2 clinical trial of PBGM01, in patients with a diagnosis of early and late infantile GM1 gangliosidosis (“Imagine-1”). In addition, on December 14, 2022, the Company will present a corporate presentation describing updates to the Imagine-1 clinical trial.
A copy of the press release and corporate presentation are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K.
The information in this Item 7.01, including Exhibits 99.1 and 99.2 to this report, shall not be deemed to be “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act. The information contained in this Item 7.01 and in the accompanying Exhibits 99.1 and 99.2 shall not be incorporated by reference into any other filing under the Exchange Act or under the Securities Act, except as shall be expressly set forth by specific reference in such filing.
Item 9.01Financial Statements and Exhibits.
(d) Exhibits
Exhibit No. |
| Description |
99.1 | | |
99.2 | | |
104 | | Cover Page Interactive Data File (formatted as Inline XBRL). |
2
Exhibit 99.1
Passage Bio Announces Positive Interim Clinical Data from First Six Patients with GM1 Gangliosidosis in Imagine-1 Study
– | Interim safety data up to 20 months showed the low and high dose of PBGM01 were well tolerated and had a favorable safety profile |
– | Intra-cisterna magna administration of PBGM01 resulted in dose-dependent increases in CSF β-Gal activity and decreases in CSF GM1 gangliosides |
– | PBGM01 administration resulted in a meaningful improvement across developmental areas in a subset of patients, as assessed by investigators and caretakers |
– | Completed dosing of all patients in dose-ascending portion of study; initial safety and biomarker data from Cohort 4 expected by mid-2023 |
– | Management to host a conference call and webcast today at 8:30 a.m. ET |
PHILADELPHIA, December 14, 2022 — Passage Bio, Inc. (Nasdaq: PASG), a clinical-stage genetic medicines company focused on developing transformative therapies for central nervous system (CNS) disorders, today announced new interim safety, biomarker, and clinical development results from cohorts 1-3 in the Imagine-1 clinical study. Imagine-1 is a Phase 1/2, global, open-label, dose-escalation study of the AAVhu68 gene therapy PBGM01 delivered by intra-cisterna magna (ICM) injection in four cohorts of pediatric subjects with early and late infantile GM1 Gangliosidosis (GM1). GM1 is a rare, fatal lysosomal storage disease in which mutations in the GLB1 gene result in very low activity of the enzyme beta-galactosidase (β-Gal).
The interim data include six treated patients from the first three cohorts. Cohort 1 (late infantile, low dose), Cohort 2 (late infantile, high dose) and Cohort 3 (early infantile, low dose) each consisted of two patients. Cohort 4 (early infantile, high dose) patients have been dosed and data is expected by mid-2023.
“We are excited to share interim data from this first six patients in our Imagine-1 study, which further reinforce our confidence in PBGM01 as a promising treatment option for GM1 gangliosidosis,” said William Chou, M.D., chief executive officer of Passage Bio. “The goals of this Phase 1/2 study are to establish the safety profile for PBGM01, determine the optimal dose for therapeutic effect, and gain understanding of how PBGM01 can benefit patients across infantile GM1 populations. We are encouraged by emerging trends in the data and look forward to receiving results from Cohort 4 to further inform our program and support interactions with regulatory authorities. We couldn’t be more thankful for the conviction and perseverance of the families and investigators participating in our Imagine-1 trial.”
Topline interim results from cohorts 1-3 of the Imagine-1 study
Safety (patient follow-up ranged from three to 20 months)
· | No treatment-related serious adverse events (SAEs) |
· | All treatment-related adverse events (AEs) were mild to moderate in severity |
· | No clinically significant changes in liver function requiring intervention |
· | No evidence of dorsal root ganglion (DRG) toxicity in nerve conduction studies |
· | No complications related to ICM administration |
Biomarkers
· | PBGM01 administration resulted in dose-dependent increases in CSF β-Gal activity, with both patients who received the high dose (Cohort 2, late infantile) exhibiting increases in enzyme activity well above baseline |
o | For the first patient in Cohort 2, enzyme activity increased 4.7-fold and 3.6-fold over baseline at 30 days and six months, respectively |
o | For the second patient in Cohort 2, enzyme activity increased 5.2-fold over baseline at 30 days |
o | Patients treated with the low dose exhibited variable responses in enzyme activity at 30 days, which ranged from 1.2 to 2.8-fold increase over baseline at six months |
· | PBGM01 administration also resulted in dose-dependent decreases in CSF GM1 ganglioside levels, with both patients in Cohort 2 showing decreases in substrate levels from baseline |
o | For the first patient in Cohort 2, levels decreased by 30% and 75% from baseline at 30 days and six months, respectively |
o | For the second patient in Cohort 2, levels decreased by 21% from baseline at 30 days |
o | Patients treated with the low dose exhibited variable levels of response |
Clinical Development
· | Patients with milder development delay at dosing showed a higher response to PBGM01 treatment, as determined by investigators and caretakers |
o | Patients 1 (late infantile, low dose) and 5 (early infantile, low dose), who both demonstrated modest developmental delay at baseline, showed increases in overall developmental age |
“The new interim data from cohorts 1-3 continue to strengthen the favorable safety profile of PBGM01, with no treatment-related serious adverse events, no complications related to ICM administration and no evidence of DRG toxicity,” said Mark Forman, M.D., Ph.D., chief medical officer of Passage Bio. “We are also seeing dose-dependent increases in CSF β-Gal enzyme activity, decreases in CSF GM1 ganglioside levels, and meaningful improvement across developmental areas on both the Vineland and Bayley scales in a subset of patients with more modest developmental delay at baseline. We look forward to presenting additional data from cohorts 1-3 at the 19th Annual WORLDSymposium in February 2023.”
Passage has completed dosing of PBGM01 in the dose-escalation portion of the study and will evaluate dosing further patients at the current high dose and/or a higher dose as data from cohorts 1-4 mature. Data from Cohort 4 is anticipated by mid-2023.
Conference Call Details
Passage Bio will host a conference call and webcast today at 8:30 a.m. ET. To register for the event, please use the following link. A live audio webcast of the event will be available on the Investors & News section of Passage Bio’s website at investors.passagebio.com. The archived webcast will be available on Passage Bio's website approximately two hours after the completion of the event and for 30 days following the call.
About Imagine-1
Imagine-1 is a Phase 1/2, global, open-label, dose-escalation study of PBGM01 administered by a single injection into the cisterna magna in pediatric subjects with early and late infantile GM1. The clinical program has treated a total of four cohorts of two patients each, with separate dose-escalation cohorts for late infantile GM1 and early infantile GM1. The primary goal of the study is to first assess safety and tolerability and then efficacy of PBGM01 in patients. The U.S. Food and Drug Administration (FDA) has granted PBGM01 Fast Track, Orphan Drug, and Rare Pediatric Disease designations. PBGM01 has also received an Orphan designation from the European Commission.
To learn more about the clinical trial program, please visit ClinicalTrials.gov: NCT04713475.
About PBGM01
PBGM01 is an AAV-delivery gene therapy currently being developed for the treatment of infantile GM1, in which patients have mutations in the GLB1 gene causing little or no residual beta-galactosidase enzyme activity and subsequent neurodegeneration. PBGM01 utilizes a next-generation AAVhu68 capsid administered through the cisterna magna to deliver a functional GLB1 gene encoding beta-galactosidase to the brain and peripheral tissues. By increasing beta-galactosidase activity, PBGM01 has the potential to reduce accumulation of toxic GM1 gangliosides and reverse neuronal toxicity, thereby restoring developmental potential. In preclinical models, PBGM01 has demonstrated broad brain distribution and high levels of expression of the beta-galactosidase enzyme in both the CNS and critical peripheral organs, suggesting potential treatment for both the CNS and peripheral manifestations of GM1.
About GM1
GM1, a rare monogenic lysosomal storage disease, is caused by mutations in the GLB1 gene, which encodes the lysosomal enzyme beta-galactosidase (β-gal). Reduced β-gal activity results in the accumulation of toxic levels of GM1 gangliosides in neurons throughout the brain, causing rapidly progressive neurodegeneration. GM1 accumulation also results in progressive damage to other tissues including the heart, liver, and bones and manifests with hypotonia (reduced muscle tone), progressive CNS dysfunction, seizures, and rapid developmental regression. Life expectancy for infants with GM1 ranges from 2-10 years, and infantile GM1 represents approximately 60 percent of the global GM1 incidence of 0.5 to 1 in 100,000 live births.
About Passage Bio
Passage Bio (Nasdaq: PASG) is a clinical-stage genetic medicines company on a mission to provide life-transforming therapies for patients with CNS diseases with limited or no approved treatment options. Our portfolio spans pediatric and adult CNS indications, and we are currently advancing clinical programs in GM1 gangliosidosis and frontotemporal dementia and our preclinical pipeline, including programs in amyotrophic lateral sclerosis and Huntington’s disease. Based in Philadelphia, PA, our company has established a strategic collaboration and licensing agreement with the renowned University of Pennsylvania’s Gene Therapy Program to conduct our discovery and IND-enabling preclinical work. Through this collaboration, we have enhanced access to a broad portfolio of gene therapy candidates and future gene therapy innovations that we then pair with our deep clinical, regulatory, manufacturing and commercial expertise to rapidly advance our robust pipeline of optimized gene therapies. As we work with speed and tenacity, we are always mindful of patients who may be able to benefit from our therapies. More information is available at www.passagebio.com.
Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about timing and execution of anticipated milestones, including progress of the Imagine-1 clinical trial and the availability of clinical data from the trial; our expectations about our collaborators’ and partners’ ability to execute key initiatives; our expectations about manufacturing plans and strategies; our expectations about cash runway; and the ability of our lead product candidates to treat their respective target monogenic CNS disorders. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.
For further information, please contact:
Investors:
Stuart Henderson
Passage Bio
267.866.0114
shenderson@passagebio.com
Media:
Mike Beyer
Sam Brown Inc. Healthcare Communications
312.961.2502
MikeBeyer@sambrown.com
| PBGM01 Study in Infantile GM1 Gangliosidosis Interim Clinical Results from Cohorts 1 - 3 of Imagine - 1 Clinical Study December 14, 2022 |
| 2 Forward - Looking Statements This presentation includes “forward - looking statements” within the meaning of, and made pursuant to the safe harbor provisions o f, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about timing and execution of anticipated milestones, including progress of the Imagine - 1 clinical study and the availability of clinical data from the study; our expecta tions about our collaborators’ and partners’ ability to execute key initiatives; our expectations about manufacturing plans and strategie s; our expectations about cash runway; and the ability of our lead product candidates to treat their respective target monogenic CNS di sorders. These forward - looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expec t,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of sim ilar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in su ch statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and resul ts of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage cl ini cal activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities m ay require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrenc e o f adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent tr ial s or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce o ur intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manuf act ure of product candidates and other aspects of our business, which are outside of our full control; risks associated with current an d p otential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; and the other risks and uncertainties th at are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commi ssi on (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward - looking stat ement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or o the rwise. |
| 3 Welcome & Agenda Executive Summary Will Chou, M.D. Overview of GM1 Gangliosidosis Jeanine Jarnes, PharmD, BCOP, BCPS Review of Safety, Biomarker, and Preliminary Efficacy Results Mark Forman, M.D., Ph.D. Closing Remarks Will Chou, M.D. Q&A Will Chou, M.D. Chief Executive Officer, Passage Bio Mark Forman, M.D., Ph.D. Chief Medical Officer, Passage Bio Jeanine Jarnes, PharmD, BCOP, BCPS Assistant Professor, Department of Pediatrics, University of Minnesota Consultant for Passage Bio |
| 4 Executive Summary Will Chou, M.D. |
| 5 PBGM01 is a Potentially Transformative Therapy for GM1 Gangliosidosis, a Rare, Underserved Disorder GM1 GANGLIOSIDOSIS • Inherited lysosomal storage disease that leads to progressive damage to both the CNS and peripheral tissues • Caused by loss - of - function mutations in the GLB1 gene • No approved disease - modifying therapies PRECLINICAL EVIDENCE • Preclinical data in knock - out mouse model resulted in: • Dose - related histological correction, improvements in neurological function, and survival • Meaningful transduction of both CNS and critical peripheral organs OUR APPROACH – PBGM01 • Next - generation, proprietary AAVhu68 capsid delivers functional GLB1 transgene encoding β - gal to the brain and peripheral tissues through ICM delivery |
| 6 Interim Data from First 6 Treated Patients Positions PBGM01 as a Promising Potential Treatment Option for GM1 AEs=adverse events; ICM=intra - cisterna magna. SAFETY Favorable safety profile and well - tolerated • No serious AEs related to study treatment • No evidence of DRG toxicity • No evidence of cell - mediated immune response • No complications related to ICM injection BIOMARKERS • Dose - dependent increase in CSF b - Gal activity • Dose - dependent decrease in b - Gal substrates in CSF CLINICAL STATUS • In a subset of patients, meaningful improvement across developmental areas on both the Vineland and Bayley scales • Stage of disease at time of treatment emerging as an important determinant in treatment outcomes |
| 7 Overview of GM1 Gangliosidosis Jeanine Jarnes, PharmD, BCOP, BCPS |
| 8 GM1 Gangliosidosis: A Devastating Pediatric Disease FATAL, PEDIATRIC NEUROLOGICAL LYSOSOMAL STORAGE DISORDER caused by GLB1 gene mutations characterized by destruction of neurons in the brain and spinal cord. Characterized by rapidly progressive neurological decline resulting in reduced muscle tone, progressive CNS dysfunction, deafness, blindness, rigidity and skeletal dysplasia. RARE AND UNDERSERVED populations with incidence of up to ~1 per 100,000 live births worldwide. No disease - modifying therapies are presently approved. 1. Brunetti - Pierri N., Scaglia F. Mol Genet Metab. 2008;94(4):391 - 396. 2. Jarnes JR, et al. Mol Genet Metab .. 2017;121(2):170 - 179. |
| 9 GM1 Gangliosidosis Disease Continuum GM1 Gangliosidosis is a Continuum Disease Severity Residual Enzyme Activity (Serum) Focus of Imagine - 1 Trial Negligible to 5% ~ 1 – 5% ~ 3 – 10% Type 1 (Early Infantile) • Onset <6 months • Hypotonia • Neurodegeneration • Developmental regression • Seizures • Skeletal dysplasia • Survival: <2 years without supportive care Type 2a (Late Infantile) • Onset 6 – 24 months • Developmental plateau, followed by regression • Impaired ambulation • Impaired cognition • Seizures • Survival: 5 to 10 years Type 2b (Juvenile) • Onset 2 – 5 years • Impaired ambulation • Dysarthria • Variable skeletal disease • Decreased cognition • Survival into 2nd decade Disease severity inversely related to residual b - Gal enzyme activity Brunetti - Pierri N., Scaglia F. Mol Genet Metab. 2008;94(4):391 - 396. Jarnes JR, et al. Mol Genet Metab .. 2017;121(2):170 - 179. Lang FM, et al. Mol Genet Metab. 2020;129(3):228 - 235. Regier DS, Tifft CJ. Rothermel CE. GLB1 - related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. |
| 10 Onset before 6 months of age Rapid disease progression with no new developmental milestones reached after 3 - 6 months Survival: <2 years Early Infantile (Type I) Onset between 6 months to 2 years of age Relatively s lower disease progression with no new developmental milestones reached after 12 - 15 months Survival: 5 to 10 years Late Infantile (Type IIa) VS Natural History of Infantile GM1 Characterized by developmental delay, a brief plateau and followed by rapid regression 1. Brunetti - Pierri N., Scaglia F. Mol Genet Metab. 2008;94(4):391 - 396. 2. Jarnes JR, et al. Mol Genet Metab .. 2017;121(2):170 - 179. 3. Lang FM, et al. Mol Genet Metab. 2020;129(3):228 - 235 .. 4. Platt, F.M., et al. Nat Rev Dis Primers 4, 27 (2018). https://doi.org/10.1038/s41572 - 018 - 0025 - 4 |
| 11 Rapid Decline in Infantile GM1 with <20% Survival at 24 Months 1 1. Lang FM et al., Mol Genet Metab.2020;129:228 - 235 • S ymptom onset: 2.8 months • F irst admission: 6.3 months • D iagnosis: 8.7 months • D eath: 18.9 months Mean age of: Cumulative time - to - event analysis of key points during GM1 disease progression |
| 12 Review of Safety, Biomarker, and Preliminary Efficacy Results in Cohorts 1 - 3 Mark Forman, M.D., Ph.D. |
| 13 Imagine - 1: Global Phase 1/2 Trial with PBGM01 Completed dosing of all patients in dose - ascending portion of study COHORT 4 Early Infantile D OSE 2 (1.1e11 GC/g)* D O S E 1 (3.3e10 GC /g)* Expansion Cohort Early Infantile Expansion Cohort Late Infantile COHORT 2 Late Infantile COHORT 3 Early Infantile COHORT 1 Late Infantile 60 days between subject enrollment in Cohorts 1 - 4 IDMC review Recruiting Dosing complete *Genome copies per gram of estimated brain weight Trial Design Phase 1/2, multi - center, open - label, dose escalation and confirmatory study Route of Administration Intra - cisterna magna (ICM) Vector AAVhu68 Immunosuppression Low dose steroids for 4 weeks then taper Duration Two years, with rollover into long - term follow - up study Primary Endpoints • Safety and tolerability • Efficacy (confirmatory cohort) Biomarkers • β - gal activity (CSF & serum) • GM1 gangliosides (CSF) • Other exploratory biomarkers |
| 14 Imagine - 1 Baseline Patient Characteristics Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Diagnosis Late Onset Late Onset Early Onset Late Onset Early Onset Late Onset Dose level received Low dose Low dose Low dose High dose Low dose High dose Cohort 1 1 3 2 3 2 Gender Male Male Female Female Male Male Onset of symptoms (months) 14 12 5 11 birth 12 Chronological age at diagnosis (months) 2 30 6 13 2 15 Chronological age at baseline (months) 15 31 15 18 6 17 DBS β - Gal activity (nmol/ml/hr) (1) 0.0 0.2 0.0 0.0 0.1 0.0 Genotype c.601C>T, c.601C>T c.601C>T, c.1733AA>G c.694dupC, c.694dupC c.1370G>A, c.168C>G c.1577dup, c.1577dup c.1733A>G, c.802G>C DBS, dry blood spot (1) Lower limit of normal (LLN): <5.0 nmol/ml/hr |
| 15 Imagine - 1 Study: Cohorts 1 - 3 Safety & Tolerability No treatment - related serious adverse events (SAEs) All treatment - related adverse events (AEs) were mild - to - moderate in severity No clinically significant changes in liver function requiring intervention No evidence of DRG toxicity, as measured by nerve conduction studies No complications related to ICM administration PBGM01 was well tolerated and had a favorable safety profile at interim analysis* *Patient follow - up ranges from 3 to 20 months post - dosing as of a data cutoff of Nov 30, 2022 |
| 16 Favorable Immunological Profile At Interim Analysis Observations following ICM administration of PBGM01: Neutralizing antibodies to capsid detected at low levels in CSF after Day 30; not expected to affect CNS gene transfer As anticipated, moderate serum neutralizing antibodies developed to capsid No antibodies against the transgene product developed in the CSF or serum No T - cell response against the capsid or transgene No other laboratory or clinical signs of an immunological response Patients treated with abbreviated course of low dose steroids |
| 17 0 1 2 3 4 5 6 0 60 120 180 240 300 360 β - Gal, nmol/mL/3hr Time (days) β - gal, CSF P1 Late Infantile P2 Late Infantile P3 Early Infantile P5 Early Infantile NHS patient value range PBGM01 ICM Delivery Resulted in Increased Transgene Activity in CSF 0 1 2 3 4 5 6 0 60 120 180 240 300 360 β - Gal, nmol/mL/3hr Time (days) β - gal , CSF P4 Late Infantile P6 Late Infantile *Based on preliminary data from University of Pennsylvania’s ODC Natural History Study (NHS) (NCT04041102); value range (0.3 - 1. 81 nmol/mL/3hr) 4.7 - 5.2x baseline 3.6x baseline 1.2 - 2.8x baseline High dose Low dose Late Infantile: Circle Early Infantile: Square NHS patient value range • PBGM01 administration resulted in dose - dependent increase in CSF β - Gal activity • High dose PBGM01 resulted in 3.6 - 5.2x increase in CSF β - Gal activity relative to baseline • High dose PBGM01 resulted in CSF β - Gal activity well above levels seen in Natural History Study (NHS)* • Increased CSF b - Gal activity sustained for up to 12 months in Patient 1 • PBGM01 administration resulted in sustained β - Gal enzyme expression in blood Key Points |
| 18 High Dose PBGM01 Led to Decreases in CSF GM1 Gangliosides 0 200 400 600 0 50 100 150 200 250 300 350 Gangliosides, apparent nM Time (days) GM1 Ganglioside, CSF P4 Late Infantile P6 Late Infantile 0 200 400 600 800 1,000 0 50 100 150 200 250 300 350 Gangliosides, apparent nM Time (days) GM1 Ganglioside, CSF P1 Late Infantile P2 Late Infantile P3 Early Infantile P5 Early Infantile High dose 75% drop from baseline Low dose Late Infantile: Circle Early Infantile: Square 1. Lang FM et al., Mol Genet Metab.2020;129:228 - 235; CSF= Cerebrospinal Fluid • PBGM01 administration resulted in dose - dependent decrease in CSF GM1 ganglioside levels • Decrease in CSF gangliosides correlated with higher levels of b - Gal activity • GM1 gangliosides hypothesized to mediate CNS manifestations of disease 1 Key Points |
| 19 Patients Manifest a Wide Range of Developmental Delay at Baseline Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Diagnosis Late Onset Late Onset Early Onset Late Onset Early Onset Late Onset Dosing Cohort Low dose Low dose Low dose High dose Low dose High dose Chronological age at baseline (months) 14 31 15 18 6 17 Developmental age at baseline (Bayley; months) 12 7 0.5 2.5 0.5 5 Developmental delay at baseline (Bayley; months) 2 24 14.5 15.5 5.5 12 Mild - moderate delay Developmental Delay at Baseline Marked delay |
| 20 Preliminary Trend: Milder Developmental Delay at Dosing Associated with Improved Treatment Response 10pt Calibri footer *The Vineland - II is caretaker - assessed. **The Bayley - III is based on direct observation by a neurodevelopmental specialist. 0 5 10 15 20 25 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Overall Developmental Age (months) Chronological Age (months) Vineland - II* P1 Late Infantile P2 Late Infantile P3 Early Infantile P5 Early Infantile P4 Late Infantile P6 Late Infantile Mild - to - moderate developmental delay Marked developmental delay 0 5 10 15 20 25 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Overall Developmental Age (months) Chronological Age (months) Bayley - III** P1 Late Infantile P2 Late Infantile P3 Early Infantile P5 Early Infantile P4 Late Infantile P6 Late Infantile Mild - to - moderate developmental delay Marked developmental delay Late Infantile: Circle Early Infantile: Square Low Dose: Solid Line High Dose: Dashed Line |
| 21 Summary AEs=adverse events; ICM=intra - cisterna magna. SAFETY Favorable safety profile and well - tolerated • No serious AEs related to study treatment • No evidence of DRG toxicity • No evidence of cell - mediated immune response • No complications related to ICM injection BIOMARKERS • High dose resulted in durable increases in CSF b - Gal well above NHS • High dose resulted in durable decreases in b - Gal substrate GM - 1 gangliosides in CSF CLINICAL STATUS • Milder developmental delay at the time of treatment is emerging as an important determinant of treatment outcomes • Pending results from high dose cohorts, we plan to incorporate degree of developmental delay into pivotal study inclusion/exclusion criteria |
| 22 Closing Remarks Will Chou, M.D. |
| 23 Key Objectives for Imagine - 1 Study Establish Safety Profile of PBGM01 Determine Optimal Dose for Therapeutic Effect Understand PBGM01 Benefit Across Infantile GM1 Patient Populations |
| 24 Data from Cohort 4 Will Add to Understanding of Dose and Patient Selection Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Diagnosis Late Onset Late Onset Early Onset Late Onset Early Onset Late Onset Early Onset Early Onset Dosing Cohort Low dose Low dose Low dose High dose Low dose High dose High Dose High Dose Chronological age at baseline (months) 14 31 15 18 6 17 7 5.5 Developmental age at baseline (Bayley; months) 12 7 0.5 2.5 0.5 5 5 1.5 Developmental delay at baseline (Bayley; months) 2 24 14.5 15.5 5.5 12 2 4 Mild - moderate delay Developmental Delay at Baseline Marked delay |
| 25 PBGM01 Program Anticipated Next Steps • Present additional data from Cohorts 1 - 3 at 19th Annual WORLD Symposium in February 2023 • Present initial data from Cohort 4 (early infantile, high dose) by mid - 2023 Share additional data throughout 2023 • Analyze data from Cohort 4 • Due to observed dose response and the absence of safety signals, evaluate dosing additional patients at the current high dose and/or higher dose Determine optimal dose for confirmatory study • Continued interactions with regulatory authorities as clinical data set matures to align on design of confirmatory study and pathway to Biologics License Application Engage with regulatory authorities |
| Q&A |
