BBP-418 Demonstrates Significant Impact on Root Cause of Limb-Girdle Muscular Dystrophy Type 2i

Eleven of the 12 individuals demonstrated at least a 50% reduction in creatine kinase, with 75% of participants reaching twice the normal range, suggesting a reduction in muscle breakdown.

Newly published phase 2 data showed that BBP-418 (BridgeBio Pharma), an investigational agent for limb-girdle muscular dystrophy type 2i (LGMD2i), increased glycosylation of alpha-dystroglycan (aDG), signifying the oral therapy has the potential to address both the root cause of LGMD2i and drive functional improvements for patients.1,2

The preliminary findings, presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, in Nashville, Tennessee, also included a positive benefit of BBP-418 on creatine kinase (CK), a widely used biomarker of muscle injury. The company also believes the therapeutic has a potential effect on clinical function and the rate of disease progression, explained by findings from 90- and 180-day improvements on walk tests.

Across all the dose levels, there were no treatment-related serious adverse events, dose limiting toxicities, nor discontinuations. BridgeBio plans to engage with regulatory health bodies in 2022 to discuss potential paths to approval and intends to initiate a phase 3 trial in the second half of the year.

"To date, people with LGMD2i have no approved disease-modifying treatment options. Many of these patients see their quality of life deteriorate rapidly and lose their functional independence, including their ability to walk,” Douglas Sproule, MD, MSc, chief medical officer, ML Bio Solutions, an affiliate company of BridgeBio, said in a statement.1 "Our preliminary trial data holds promise for this unmet patient need as our investigational therapy is shown to be generally well-tolerated and to improve several key markers associated with a patient’s decline."

In Part 1 of this open-label study, 14 enrolled individuals with LGMD2i, both ambulatory and nonambulatory, were split into 3 ascending dose cohorts (cohort 1: 6 g daily, n = 4; cohort 2: 6 g twice daily, n = 4; cohort 3: 12 g twice daily, n = 6) and treated over a 3-month period. During Part 2 of the study, all patients received 12 g twice daily for 3 months, with weight adjusted for lower-weight patients.

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Preliminary data, which included 12 participants, showed that treatment with BBP-418 was well tolerated and led to an average increase of 0.21 (43%) in the ratio of glycosylated aDG. Furthermore, investigators observed statistically significant declines (70%) for CK in all cohorts at 90 days, and only statistically significant declines (77%) at day 180 for cohorts 1 and 2. Only 1 of the 12 participants did not achieve at least a 50% reduction in CK, and 75% of the cohort reached at least twice the normal range.

"The positive results from the phase 2 study exceed expectations and are incredibly exciting as they demonstrate consistent improvements in key markers of muscle function and support further study," primary investigator Amy Harmer, MD, professor, department of neurology, Virginia Commonwealth University, said in a statement.1 “The close collaboration with BridgeBio and ML Bio Solutions on this trial has provided patient focused data that addresses a serious unmet need in a rare disease."

Nine of the 12 patients were ambulatory, meaning they were ableto complete the 10-meter walk test (10MWT) in under 12 seconds. Overall, there was a 0.08 m/s (3%) increase in 10MWT after 90 days in all cohorts and a 0.12 m/s (4%) increase at day 180 for cohorts 1 and 2. At 6 months, the 10MWTs compared favorably with the natural history data where the same patients demonstrated a decline of 0.12 m/s in the 10MWT in the 6 months prior to enrollment.

The company also presented data from a phase 1 study at MDA 2022, mainly intended to explore safety and tolerability of single (SAD) and multiple (MAD) ascending doses of BBP-418 in healthy subjects. SAD dosing was assessed across 7 cohorts to a maximum of 15 g, wheras 5 MAD cohorts were enrolled to a maximum dose of 9 g BID. At the end of the assessment, all studied doses were well-tolerated with no dose-limiting toxicity. The geometric mean for Cmax and area under the curve following a single 15-g dose were 221 (12.6%) and 543 (12.3%) µg/mL, respectively.3

For more coverage of MDA 2022, click here.

REFERENCES
1. BridgeBio announces positive phase 2 data for Limb-girdle muscular dystrophy type 2i (LGMD2i). News release. BridgeBio Pharma. March 14, 2022. Accessed March 21, 2022. https://www.globenewswire.com/en/news-release/2022/03/14/2402463/0/en/BridgeBio-Pharma-Announces-Positive-Phase-2-Data-for-Limb-girdle-Muscular-Dystrophy-Type-2i-LGMD2i.html
2. Preliminary results from MLB-01-003: an open-label phase 2 study of BBP-418 in patients with Limb girdle muscular dystrophy type 2i. Presented at: MDA 2022; March 13-16; Nashville, TN. Poster 63.
3. A phase 1 randomized, blinded, placebo-controlled study of the safety, tolerability, and PK of BBP-418 (ribotol) in healthy subjects. Presented at: MDA 2022; March 13-16; Nashville, TN. Poster 64