ML Bio Solutions
MENA Congress for Rare Diseases May 16-19 2024
BridgeBio Pharma, Inc. © 2024
Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company
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BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
LGMD2I, LGMDR9 FKRP-Related (LGMD2I/R9) is caused by mutations in FKRP and characterized by an established genotype/phenotype association
L276I
Homozygotes
Prevalence
(L276I/L276I)
68%
Birth | Early Childhood |
Asymptomatic Asymptomatic
Late Childhood
- Age of symptom onset 18 ± 3 years old
- Lower limb & proximal weakness
- +/-calfhypertrophy, muscle pain, ↑ serum CK levels
Adolescence to adulthood
Loss of ambulation: 25% by age 40
Respiratory decline: Non-invasiveassistance required by 10% by age 40 and invasive assistance required by <1%
Cardiac dysfunction: ~30%
Other FKRP genotypes
Prevalence
(L276I/ (non-L276I/non-L276I)non-L276I)
29% 2%
Age of symptom onset | Lower limb & proximal |
5 ± 1 years old | weakness |
Asymptomatic Lower limb & proximal | +/-calf hypertrophy, muscle |
weakness | pain, ↑ serum CK levels |
+/-calf hypertrophy, muscle | |
pain, ↑ serum CK levels |
Loss of ambulation: most by age 20
Respiratory decline: Invasive assistance required by 5% by age 30
Cardiac dysfunction: ~60%
Source: 1) Sveen et al, Annals of Neurology, 2006; 2) Richard et al, Neuromuscular Disorders, 2016 3) Gedlinske et al, Neurology, 2020 4) GnomAD database 5) Liu, et al, Genet Med., 2018 6) Libell et al, Muscle Nerve, 2020 | 3 |
BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
Alpha Dystroglycan (⍺DG), disrupted in LGMD2I/R9, is an integral part of the dystrophin-glycoprotein complex
Figure from Wicklund et al., The limb-girdle muscular dystrophies. Neurologic Clinics, 2014. | 4 |
BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
Oral BBP-418 is under investigation as an upstream substrate supplement to drive residual activity of mutant FKRP in LGMD2I/R9, targeting the disease at its source
LGMD2I/R9 Disease Mechanism
Functional FKRP fully glycosylates alpha-dystroglycan (αDG) which stabilizes myocytes by binding extracellular ligands to act as a "shock absorber" for muscle fibers
Partial loss of function mutation in FKRP results in dysfunctional, hypo-glycosylated αDG in myocytes which increases susceptibility to damage
Endogenous CDP- endogenous
ribitolribitol
Mutations in FKRP prevent addition of ribitol-5-P to alpha- dystroglycan (hypo-glycosylated αDG) limiting αDG's ability to function as a "shock absorber" for muscle fibers
Proposed BBP-418 Therapeutic Approach
Supply supraphysiological levels of pharmaceutical-substrate upstream aiming to drive residual activity of mutant FKRP enzyme and increase αDG glycosylation levels
Orally-administered BBP-
418
CDP- ribitol
Potential partial restoration
of αDG glycosylation
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BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
Natural history data supports the premise that glycosylation of αDG in muscle | |
mirrors the severity of LGMD2I/R9 disease and remains stable over time | |
⍺ | Glycosylated αDG levels remain stable over 6─12 months in |
Reduced DG glycosylation in other FKRP genotypes vs. | |
L276I/L276I homozygous LGMD2I/R9 patients | untreated LGMD2I/R9 patients |
glycosylated αDG levels (% of normal)
Source: MLB-01-001 Listing 16.4.1 and 16.1.4.2. | Source: MLB-01-001 Listing 16.4.1 and 16.1.4.2. |
Other FKRP genotypes, which are more rare and typically have a more severe clinical presentation, have lower glycosylated αDG levels compared
to L276I/ L276I homozygous patients; both groups have reduced levels compared to healthy individuals
Patient samples were interpolated to standard curve to determine % of normal glycosylation of | Patient samples were interpolated to standard curve to determine % of normal glycosylation of | |
αDG; median and 25-75% percentile are shown; figure includes all patients with repeat biopsies in | ||
αDG; lines show medians; figure includes all patients with biopsies in MLB-01-001 | ||
MLB-01-001 | 6 | |
BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
BBP-418 is under investigation in a small, open label Phase 2 study in individuals with LGMD2I/R9
Dose | Maximum | Long-term | ||
escalation | dose | extension | ||
90 days (N=14) | 90 days (N=14) | 24 months | ||
After Part 1, all participants transitioned to highest dose 12g BID
Cohort 1 | 6g QD | 12g BID | |||||||||
n=4 | n=4 | ||||||||||
Cohort 2 | 6g BID | 12g BID | |||||||||
n=4 | n=4 | ||||||||||
Cohort 3 | 12g BID | 12g BID | |||||||||
n=6 | n=6 | ||||||||||
Key Endpoints
- North Star Assessment for limb girdle type muscular dystrophies (NSAD)
- 10-meterwalk test/100-meter timed test
- Forced vital capacity (FVC)
- Performance of Upper Limb (PUL2.0)
- Glycosylated αDG levels
- Serum creatine kinase (CK)
Key inclusion criteria
- Age between 12-55 years at enrollment
- Genetically confirmed LGMD2I/R9
- Body weight >30kg
- Able to complete 10MWT ≤12 seconds unaided (moderate disease) or unable to (severe disease)
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BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
BBP-418 has been well tolerated, with only minor GI related adverse events recorded in the Phase 2 study
- 159 adverse events (AEs) were recorded in the study
- Most of the reported TEAEs were Grade 1 (mild) or Grade 2 (moderate) in severity
- 20 were considered to be related to BBP-418 with the most common being diarrhea and bloating
- No discontinuations or interruptions in therapy due to AEs
- 3 severe adverse events recorded and were considered unrelated to BBP-418
Source: MLB-01-003 Listing 14.3.1.3 Part 3 month 15
Preliminary data, subject to change
Treatment related | # of incidents | # of patients | ||
TEAE | ||||
Diarrhea | 8 | 6 | ||
Dehydration | 1 | 1 | ||
Nausea | 3 | 2 | ||
Vomiting | 2 | 2 | ||
Dyspepsia | 1 | 1 | ||
Gastroenteritis | 1 | 1 | ||
Bloating | 2 | 2 | ||
Headaches | 1 | 1 | ||
Abdominal pain | 1 | 1 | ||
Overall | 20 | 9 | ||
8 |
BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
Data from an open-label Phase 2 study show that glycosylated αDG levels in muscle are responsive to therapy at 3 months and sustained over 15 months; this is supported by an impact on serum creatine kinase (CK)
Increase in glycosylated αDG in muscle observed post dosing
with BBP-418 (median ± 95% CI)
L276I/L276I homozygous | Other FKRP genotypes | ||||||||||||||||
glycosylated αDG levels (% of control) | |||||||||||||||||
Median (%) | 16.5 | 39.4 | 39.7 | 44.3 | 5.9 | 9.5 | 10.4 | 25.7 | |||||||||
N | 8 | 8 | 7 | 6 | 6 | 5 | 6 | 1 |
Patient samples were interpolated to standard curve to determine % of normal glycosylation of αDG
- 3 mo = Part 1, 90-day; +6 mo = Part 2, Month 3; + 9 mo = Part 3, Month 3; + 15 mo = Part 3, Month 9 Median and 25-75% percentile are shown, Wilcoxon test was used to determine significance
Source: MLB-01-003 Listing 16.4.1 and 16.1.4.2.
Preliminary data, subject to change
Reduction in mean serum creatine kinase (CK) observed post
dosing with BBP-418
Serum CK (Mean ± SE) | ||||||
10000 | ||||||
(U/L) | 8000 | |||||
6000 | ||||||
CK | ||||||
serum | 4000 | |||||
2000 | 1,000 U/L | |||||
0 | reference range | |||||
Baseline | 3 | 6 | 9 | 15 | 21 | |
(N=13) | (N=14) | (N=14) | (N=11) | (N=12) | (N=12) |
Months of BBP-418 Treatment
Cohort 1 Day 1 CK draw taken after functional assessments; all other draws done prior to functional assessment
After Day 90, all subjects received 12 g BID (weight-adjusted)
- 3 mo = Part 1, 90-day; +6 mo = Part 2, Month 3; + 9 mo = Part 3, Month 3; + 15 mo = Part 3, Month 9; +21 mo = Part 3, Month 15; Reference range for CK is 55─170 units/L for men and 30─135 units/L for women, figure shows reference range from 30─170 units/L
Source: MLB-01-003 Table 14.2.1.1.
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BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
Stabilization in ambulatory and clinical measures observed after 21 months of dosing with BBP-418 in Phase 2 study
Change from baseline in 10MWT (m/s) | Change from baseline in 100MTT (s) | Change from baseline in NSAD | ||||||||||||||
Source: MLB-01-001 Listing 16.2.1 and MLB-01-003 Listing 16.2.1 | Source: MLB-01-001 Listing 16.2.2 and MLB-01-003 Listing 16.2.2 | Source: MLB-01-001 Listing 16.2.5 and MLB-01-003 Listing 16.2.5 |
Blue lines denote natural history data and red lines denote on-treatment data collected during the Phase 2 study
Data exclude 1 subject from month 15 timepoint due to post-COVID decline
Phase 2 data: + 3 mo = Part 1, 90-day; +6 mo = Part 2, Month 3; + 9 mo = Part 3, Month 3; + 15 mo = Part 3, Month 9; +21 mo = Part 3, Month 15
Preliminary data, subject to change | 10 |
BridgeBio Pharma, Inc. © 2024 | Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company |
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BridgeBio Pharma Inc. published this content on 20 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 20 May 2024 15:29:04 UTC.