Passage BIO, Inc 8-K, filed Dec 17, 2021
Passage BIO, Inc. (PASG)
About this 8-K
Passage BIO, Inc filed this 8-K on December 17, 2021.
Items reported
- Item 7.01: Regulation FD disclosure
- Item 8.01: Other events
- Item 9.01: Financial statements and exhibits
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Item 7.01 Regulation FD Disclosure.
On December 17, 2021, Passage Bio, Inc. (the “Company”), issued a press release announcing positive interim safety and 30-day biomarker data for cohort 1 of its global Phase 1/2 clinical trial for PBGM01 (“Imagine-1”) for the treatment of early and late infantile GM1 Gangliosidosis (“GM1”). A copy of the press release is attached as Exhibit 99.1 to this Current Report on Form 8-K, which is incorporated herein by reference.
On December 17, 2021, the Company will also give a presentation describing its positive interim safety and 30-day biomarker data for cohort 1 of Imagine-1. A copy of this presentation is attached as Exhibit 99.2 to this Current Report on Form 8-K, which is incorporated herein by reference.
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 8.01 Other Events.
PBGM01 Program Updates
The Company announced the following updates with respect to Imagine-1 for the treatment of early and late infantile GM1:
· | The Independent Data Monitoring Committee (the “IDMC”) recommended proceeding with two additional planned cohorts in the Imagine-1 clinical study. |
· | Based on the IDMC recommendation, the Company has initiated recruitment in parallel for both a high-dose cohort of patients with late infantile GM1 (cohort 2) and a low-dose cohort of patients with early infantile GM1 (cohort 3). |
· | Topline interim results from the Imagine-1 cohort 1, consisting of two patients (patient 1 data through eight months and patient 2 data through two months), showed: |
o | With respect to safety, no serious adverse events were reported, and the reported adverse events were all mild to moderate. All moderate adverse events resolved without intervention and were deemed not to be treatment related. No complications related to intra cisterna magna injection were observed, and there was no evidence of dorsal root ganglion toxicity in nerve conduction studies. |
o | With respect to beta-galactosidase enzyme activity levels, following PBGM01 administration, beta-galactosidase activity in cerebrospinal fluid (“CSF”) and serum increased in both patients. |
In CSF, for patient 1, enzyme activity at 30 days was 1.5-fold over baseline and the increase was maintained at six months. For patient 2, enzyme activity at 30 days was 4.8-fold over baseline.
In serum, for patient 1, enzyme activity was slightly above baseline at 30 days, 1.7-fold over baseline at three months and the increase was maintained at six months. For patient 2, enzyme activity at 30 days was 1.2-fold over baseline.
2
o | With respect to GM1 gangliosides in CSF, large differences were observed at baseline, with patient 2 showing baseline values four times higher than patient 1. For patient 1, levels increased approximately 85 percent at 30 days and remained stable at that level at six months. For patient 2, levels decreased approximately 46 percent at 30 days consistent with high increases in CSF enzyme activity. |
Other Updates
On December 8, 2021, the Company announced that it had exercised two additional options under the research, collaboration and licensing agreement with the Trustees of the University of Pennsylvania for programs in Huntington’s disease and Canavan disease. The Company also announced that it expects to dose the first patients in global Phase 1/2 trials for frontotemporal dementia with granulin mutations and Krabbe disease in early 2022, and to provide updated guidance on the timing of data readouts for these two studies after the first patients have been dosed.
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). |
3
Exhibit 99.1
Passage Bio Announces Positive Interim Safety and Biomarker Data and Advances Phase 1/2 Trial of PBGM01 in GM1 Gangliosidosis
– Independent Data Monitoring Committee recommends proceeding with two additional planned patient cohorts, which are now being recruited in parallel
– Positive safety profile, including no serious adverse events, no complications related to intra-cisterna magna injection and no evidence of dorsal root ganglion toxicity
– Intra-cisterna magna delivery resulted in substantial increases in beta-galactosidase enzyme activity observed in both cerebrospinal fluid and serum
– Additional data to be shared in late-breaker presentation at the 18th Annual WORLDSymposium, February 11, 2022
– Management to host a conference call and webcast today at 8 a.m. ET
PHILADELPHIA, December 17, 2021 — Passage Bio, Inc. (Nasdaq: PASG), a clinical-stage genetic medicines company focused on developing transformative therapies for central nervous system (CNS) disorders, today announced that the Independent Data Monitoring Committee (IDMC) recommended proceeding to additional planned cohorts 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. The primary goal of the study is to first assess safety and tolerability and then efficacy of PBGM01.
The IDMC recommendation followed positive interim safety and biomarker data from Cohort 1 (n=2) patients with late infantile GM1 who received a low dose of PBGM01. Based on the IDMC recommendation, Passage Bio has initiated recruitment in parallel for both a high-dose cohort (Cohort 2) of patients with late infantile GM1 and a low-dose cohort (Cohort 3) of patients with early infantile GM1.
Passage Bio was also able to compare the Cohort 1 interim results with initial data from an ongoing natural history study being run in collaboration with the Orphan Disease Center at the University of Pennsylvania. This study measured both cerebrospinal fluid (CSF) and serum levels of beta-galactosidase in patients with juvenile and early infantile GM1. The natural history study data showed mean values of enzyme activity in CSF and serum comparable to the baseline levels observed in both patients in Cohort 1 in the Imagine-1 trial.
Topline interim results from the Imagine-1 Cohort 1 (patient 1 data through eight months and patient 2 data through two months):
| ● | Safety |
| o | No serious adverse events (AEs) |
| o | Reported AEs were all mild to moderate; all moderate AEs resolved without intervention and were deemed not treatment related |
| o | No complications related to ICM injection were observed |
| o | No evidence of dorsal root ganglion (DRG) toxicity in nerve conduction studies |
| ● | Beta-galactosidase enzyme activity levels |
| o | Following PBGM01 administration, beta-galactosidase activity in CSF and serum increased in both patients. |
| ◾ | CSF |
| ● | For patient 1, enzyme activity at 30 days was 1.5-fold over baseline and the increase was maintained at six months |
| ● | For patient 2, enzyme activity at 30 days was 4.8-fold over baseline |
| ◾ | Serum |
| ● | For patient 1, enzyme activity was slightly above baseline at 30 days, 1.7-fold over baseline at three months and the increase was maintained at six months |
| ● | For patient 2, enzyme activity at 30 days was 1.2-fold over baseline |
| ● | GM1 gangliosides in CSF |
| o | Large differences were observed at baseline, with patient 2 showing baseline values four times higher than patient 1 |
| o | For patient 1, levels increased approximately 85 percent at 30 days and remained stable at that level at six months. |
| o | For patient 2, levels decreased approximately 46 percent at 30 days consistent with high increases in CSF enzyme activity |
“We are extremely encouraged by the interim data in this first low dose cohort of patients with late infantile GM1. The favorable safety profile of PBGM01 as well as the increase in beta-galactosidase activity in both CSF and serum with the lowest dose at this early timepoint supports moving forward in two additional cohorts.” said Bruce Goldsmith, Ph.D., president and chief executive officer, Passage Bio. “We are most grateful to the children with GM1, their families and caregivers, as well as the clinical trial investigators who have chosen to participate in Imagine-1. We also could not have progressed to this point without our strong collaboration with University of Pennsylvania’s Gene Therapy Program, whose experience in developing optimal AAV technologies is unmatched. The results from the first cohort reinforce our confidence in our selected AAV technology as well as the ICM route of administration for our GM1 program and our additional clinical programs.”
Roberto Giugliani, M.D., Ph.D., Department of Genetics UFRGS and Medical Genetics Service HCPA, Porto Alegre, Brazil, who is an expert in lysosomal storage diseases and a principal investigator in the Imagine-1 study, said: “Children with infantile GM1 experience a rapid decline in neurologic function and unfortunately there are no disease-modifying treatments available to them. The disease is devastating to patients and their families, so I am encouraged by the early data with PBGM01 – that it was not only well-tolerated but also showed an increase in activity of the beta-galactosidase enzyme in both serum and CSF. I look forward to the continued clinical advancement of PBGM01 and learning its potential for GM1 patients.”
Eliseo Salinas, M.D., MSc., chief research and development officer, Passage Bio, commented: “With PBGM01 we believe we have selected an optimal AAV capsid, expression cassette and delivery method, and we look forward to longer-term follow up. With ICM delivery we are also seeing preliminary evidence that we may be able to target central and peripheral disease while minimizing viral dose and the use of immunosuppression. We thank the IDMC for their thorough review of this interim data and plan to share detailed findings, including additional clinical data, at the 18th Annual WORLDSymposium in February.”
Conference Call Details
Passage Bio will host a conference call and webcast today at 8 a.m. ET. To access the live conference call, please dial 833-528-0605 (domestic) or 830-221-9711 (international) and reference conference ID number 6048996. 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 will enroll a total of four cohorts of two patients each, with separate dose-escalation cohorts for late infantile GM1 and early infantile GM1. Initial dosing in the first cohort included late infantile patients older than one year of age to establish safety before beginning dose escalation or moving into younger patients. With the IDMC recommendation, Passage Bio has initiated recruitment for Cohorts 2 and 3.
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
At Passage Bio (Nasdaq: PASG), we are on a mission to provide life-transforming genetic medicines for patients with CNS diseases that replace their suffering with boundless possibility, all while building lasting relationships with the communities we serve. 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. This provides our team with 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 into clinical testing. 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 the timing of subsequent results from our Imagine-1 trial; initiation of clinical trials and the availability of clinical data from such trials; our expectations about our collaborators’ and partners’ ability to execute key initiatives; and the ability of our lead product candidates to treat their respective target 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:
Gwen Fisher
Passage Bio
215.407.1548
gfisher@passagebio.com
Exhibit 99.2
| PBGM01 Study in Infantile GM1 GangliosidosisInterim Safety and Biomarker Results from Low Dose, Late Infantile Cohort of Ongoing Imagine-1 Clinical StudyDecember 17, 2021 |
| 2 Welcome & Agenda Eliseo Salinas, M.D.Chief R&D OfficerBruce Goldsmith, Ph.D.Chief Executive OfficerExecutive Summary, Overview of GM1 Gangliosidosis & Our ApproachBruce GoldsmithImagine-1 Clinical Study Overview & Review of Cohort 1 Initial Safety and Biomarker DataEliseo SalinasClosing RemarksBruce GoldsmithQ&AAllJames M. Wilson, M.D., Ph.D.Director, Gene Therapy Program, University of Pennsylvania |
| 3 Forward-Looking StatementThis presentation includes “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 expectation about timing and execution of anticipated milestones, including the timing of subsequent results from our Imagine-1 trial; our planned initiation of clinical trials and the availability of clinical data from such trials; our expectations about our collaborators’ and partners’ ability to execute key initiatives; the expected impact of the COVID-19 pandemic on our operations; and the ability of our lead product candidates to treat their respective target 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, obtain regulatory approval for and commercialize PBGM01, PBFT02, PBKR03 and future product candidates; the timing and results of preclinical studies and clinical trials; 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; 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; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development 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; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; and the other risks and uncertainties that are described in the Risk Factors section of our most recent filings with the U.S. Securities and Exchange Commission. These statements are based on our current beliefs and expectations and speak only as of the date of this presentation. We do not undertake any obligation to publicly update any forward-looking statements except as required by law. By attending or receiving this presentation you acknowledge that you are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made; you will be solely responsible for your own assessment of the market and our market position; and that you will conduct your own analysis and be solely responsible for forming your own view of the potential future performance of Passage Bio. |
| 4 Executive Summary of Low Dose PBGM01Interim results from Cohort 1 in ongoing Imagine-1 clinical study IDMC recommends advancement to two planned cohorts which will be enrolled in parallel Well tolerated and positive safety profile with no serious AEs and no complications related to ICM injection No evidence of DRG toxicity based on nerve conduction studies Substantial increases in β-gal enzyme activity observed in both CSF and serum after ICM delivery Additional data to be presented at 18thAnnual WORLDSymposiumin February 2022 |
| 5 GM1 Gangliosidosis: A Devastating Pediatric Disease FATAL, PEDIATRIC NEUROLOGICAL LYSOSOMAL STORAGE DISORDER caused by GLB1gene 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 UNDERSERVEDpopulations with incidence of up to ~1 per 100,000 live births worldwide.No disease-modifying therapies are presently approved.Source: NIH, CHOP, American Journal of Neuroradiology |
| 6 GM1 Gangliosidosis Disease Continuum GM1 Gangliosidosis is a Continuum Disease SeverityResidual Enzyme Activity (Serum) Focus of Imagine-1 TrialNegligible 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 careType 2a (Late Infantile)•Onset 6–24 months•Developmental plateau, followed by regression•Impaired ambulation•Impaired cognition•Seizures•Survival: 5 to 10 yearsType 2b (Juvenile)•Onset 2–5 years•Impaired ambulation•Dysarthria•Variable skeletal disease•Decreased cognition•Survival into 2nd decade Adapted from Regier DS, et al. 2016 GLB-1 Disorders, In Adam MP, et al. GeneReviews.Elevate β-gal activity to preserve neurological function and improve clinical outcomes |
| 7 GLB1-/-mouse model•Dose-related histological correction, improvements in neurological function, and survival•Dose-dependent increases in β-gal activity in brain, CSF, serum, and critical peripheral tissues•Of the four doses evaluated, two were selected for clinical development–1.3e10 GC (dose 2):–Histological correction, improved neurological function, and increased survival–No impact on β-gal activity in serum; variable impact in CSF–4.4e10 GC (dose 3):–Histological correction, improved neurological function, and increased survival–Robust increases in β-gal activity in CSF and serumPBGM01 Supported by Compelling Preclinical Data Clinical Dose ScalingPre-clinical Dose Clinical Dose*1.3e10 GC3.3e10 GC/g (low dose)4.4e10 GC 1.1e11 GC/g (high dose)Dose response in β-gal activity and outcomesHinderer et. al, (2020)Hum GeneTher.31:1169–1177 Glb1-/-(KO)Glb1+/-(HET) 110100100010000120120180240Serum β-Gal Activity(nmol/mL/h)Day Vehicle 1.3 e 10 4.40E+10 CSF Serum * Genome copies per gram estimated brain weightGlb1 -/-Range |
| 8 Ongoing Natural History Study•The University of Pennsylvania's Orphan Disease Center is conducting an ongoing natural history study (NHS) in patients with infantile and juvenile GM1•Baseline CSF and serum samples from an initial NHS patient cohort were analyzed for β-gal activity–CSF samples: 7 patients (4 infantile, 3 juvenile)–Serum samples: 9 patients (4 infantile, 5 juvenile)–Samples were analyzed using the same assays used for Imagine-1 Cohort 1 samplesInfantile and juvenile GM1 patients Range: 0.30 -1.81 nmol/mL/3hrRange: 2.25 -10 nmol/mL/3hr Serum β-gal ActivityNCT04041102: Natural History Study of Infantile and Juvenile GM1 Gangliosidosis (GM1) Patients CSF β-gal Activity 04 812nmol/mL/3hr 0 1 23nmol/mL/3hr |
| 9 Imagine-1: Global Phase 1/2 Trial with PBGM01 COHORT 4Early Infantilen = 2DOSE 2 (1.1e11 GC/g)*DOSE 1 (3.3e10 GC/g)* Expansion CohortEarly Infantilen = 6 Expansion CohortLate Infantilen = 6 COHORT 2Late Infantilen = 2 COHORT 3Early Infantilen = 2 COHORT 1Late Infantilen = 2 IDMC review 60 days between subject enrollment * Genome copies per gram estimated brain weight Trial DesignPhase 1/2, multi-center, open-label, dose escalation and confirmatory study Route of AdministrationIntra-cisterna magna (ICM)VectorAAVhu68ImmunosuppressionLow dose steroids 4 weeks then taper DurationTwo years, with rollover into a separate long-term follow-up studyPrimary Endpoints•Safety and tolerability•Efficacy (confirmatory cohort)Biomarkers•β-gal activity (CSF & serum)•GM1 gangliosides (CSF)•Other exploratory biomarkers |
| 10 Key Study Inclusion Criteria Early Infantile(Type 1)Late Infantile(Type 2a)Age4 –24 months6 –36 months(12 –36 months for Cohort 1)Onset of SymptomsBefore 6 monthsSpecific developmental milestones remaining6 –18 monthsSpecific developmental milestones remainingDisease Confirmation(Pre-screening)Confirmed biallelic pathological GLB1 mutationsANDβ-galactosidase activity in DBS below lower limit of normal Note: neutralizing vector antibodies are not an exclusion criterionDBS, dry blood spot |
| 11 Imagine-1 Study: Baseline Patient CharacteristicsCohort 1 (n=2): Low dose (3.3e10 GC/g)*, Late Infantile (Type 2a) Patient 1Patient 2Gender MaleMaleAge at onset of symptoms (months)1412Age at gene transfer (months)1531DBS β-Gal activity(1)(nmol/ml/hr)0.00.2Pre-existing vector nAbs–CSF(2)NegativeNegativePre-existing vector nAbs–Serum(2)PositiveNegativeClinical status at baseline•Developmental delay, mostly on language domains•Developmental age: 11 months•Chronological age: 14 months•Developmental delay in all domains•Developmental age: 7 months•Chronological age: 31 monthsDose3.3e10 GC/g*GC administered3.3e13 GC3.6e13 GCDose administered(3)3.3e12 GC/kg body weight3.2e12 GC/kg body weightDBS, dry blood spot; nAbs, neutralizing antibodies * Genome copies per gram estimated brain weight(1) Lower limit of normal (LLN): <5.0 nmol/ml/hr(2)Assay threshold titer value of 5(3)Dose values in GC/kg are calculated based on patient body weight |
| 12 Imagine-1 Study: Cohort 1 Safety & Tolerability No serious adverse events (SAEs) in either patient Reported adverse events (AEs) were mild-to-moderate; all moderate AEs resolved without intervention and were deemed not treatment related No complications related to ICM administration No changes in liver function in either patient No evidence of DRG toxicity in either patient, as measured by nerve conduction studiesPBGM01 was well tolerated and had a positive safety profile at interim analysis** Patient 1 follow-up: 8 months; Patient 2 follow-up: 2 months |
| 13 Favorable Immunological Profile Observations following ICM administration of PBGM01: No neutralizing vector antibodies were measured in the CSF in either patient No antibodies against the transgene product developed in the CSF or serum in either patient No T-cell response was documented in either patient Moderate serum neutralizing vector antibodies developed as anticipated No other laboratory or clinical signs of an immunological response were detectedPatients treated with abbreviated course of low dose steroids |
| 14 CSF β-Gal Activity Increased in Both PatientsPost treatment β-Gal activity above NHS patient values (nmol/mL/3hr)BaselineD30D180Patient 11.281.971.91Patient 20.713.39 •Patient 1: enzyme activity was 1.5-fold over baseline at 1 month, maintained at 6 months•Patient 2: enzyme activity was 4.8-fold over baseline at 1 month•Baseline values consistent with values in NHS patients (Range 0.30 -1.81 nmol/mL/3hr)* Summary* Based on preliminary data from University of Pennsylvania’s ODC NHS study (NCT04041102) 012340306090120150180β - Gal Activity, CSF (nmol/mL/3hr) Time (Days) Patient 1 Patient 2+0.6+2.7 |
| 15 Serum β-Gal Activity Increased in Both PatientsPost treatment β-Gal activity above NHS patient values (nmol/mL/3hr)Baseline(1)D30D90D180Patient 18.99.314.814.9Patient 28.911.0 •Patient 1: enzyme activity was 1.7-fold over baseline at 3 months, maintained at 6 months•Patient 2: enzyme activity was 1.2-fold over baseline at 1 month•Baseline values consistent with values in NHS patients (Range: 2.25 -10 nmol/mL/3hr)* Summary* Based on preliminary data from University of Pennsylvania’s ODC NHS study (NCT04041102)(1)Baseline reflects the average of two samples collected within 48-hours of dosing 024 6 8101214160306090120150180β - Gal Activity, Serum (nmol/mL/3hr) Time (Days) Patient 1 Patient 2+6.0+2.1 |
| 16 Initial CSF GM1 Ganglioside Levels for Cohort 1CSF GM1 Gangliosides Decreased in Patient with High β-Gal Expression 02040 60 801001201401600306090120150180nM*Time (Days) Patient 1 Patient 2 (nM)*BaselineD30D180Patient 1336261Patient 213774 •Patient 1: ~85% increase at 1 and 6 months•Patient 2: ~46% decrease at 1 month•NHS data is needed to provide further context•Longer follow up is needed Summary* Apparent concentration due to certified internal standard not available and/or internal standard not chemically identical withmeasured analyte+28-63 |
| 17 Key Takeaways from Interim Cohort 1 DataWell tolerated with demonstration of functional transgene expression at lowest dose •PBGM01 was well tolerated and had a positive safety profile–No complications related to ICM injection–No evidence of DRG toxicity SAFETY •Post treatment CSF and serum β-gal activity above NHS patient values–Increases in CSF and serum β-gal activity for Patient 1 were sustained at 6 months BIOMARKERS •Gains in developmental milestones reported in both patients CLINICAL STATUS |
| 18 Program Anticipated Next StepsFollowing positive IDMC recommendation, Cohorts 2 and 3 are currently recruiting patients in parallel•Cohort 2: high dose, late infantile•Cohort 3: low dose, early infantileContinue to open additional trial sites in multiple countries•4 sites currently open, 6 additional plannedPlan to provide updated data from Cohort 1 and data from subsequent cohorts throughout 2022Presentations during 18thAnnual WORLDSymposiumFebruary 7-11th•Presentations on trial design for both GM1 clinical study and Krabbe clinical study•Late Breaker presentation –Safety, biomarker and preliminary efficacy results following ICM administration of PBGM01 in children with late onset infantile GM1-gangliosidosis |
| Thank you to the patients, families, caregivers and investigators for their participation in this study. |
