BridgeBio Pharma : BBIO BBP 418 – MENA 2024 – Oral Presentation

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.

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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

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BridgeBio Pharma, Inc. © 2024

Courtesy from and proprietary to: ML Bio Solutions Inc., a BridgeBio company