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US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 215244 (May 15, 2025)

Issued May 15, 2025

Issued

May 15, 2025

Application

NDA 505b1 • 215244

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due May 15, 2026Requires resubmission addressing deficiencies.

Summary

The FDA has identified significant deficiencies in New Drug Application (NDA) 215244 for elamipretide, concluding that its effectiveness has not been established for traditional approval due to a lack of superiority over placebo in clinical trials (SPIBA-201 Part 1 & 2, SPIBA-001) and concerns regarding bias in endpoint measurements. The proposed surrogate endpoints (LVSV, MLCL:CL ratio, acylcarnitines) are also deemed insufficient for accelerated approval due to various limitations. The FDA suggests exploring muscle strength of knee extensors as a potential intermediate clinical endpoint for accelerated approval, contingent on demonstrating its predictive clinical benefit and proposing a confirmatory postmarketing trial. Additionally, the applicant must resolve facility inspection deficiencies, and address labeling and proprietary name issues.

Key points

  • Address the lack of established effectiveness for traditional approval, specifically regarding SPIBA-201 Part 1, Part 2, and SPIBA-001 study findings.
  • Address the limitations precluding the use of LVSV, MLCL:CL ratio, and acylcarnitines as surrogate endpoints for accelerated approval.
  • Request an End-of-Review meeting to discuss muscle strength of knee extensors as a potential intermediate clinical endpoint for accelerated approval.
  • Provide information on what clinical benefit the muscle strength endpoint would reasonably predict.
  • Propose the design of a confirmatory postmarketing clinical trial to verify the predicted clinical benefit.
  • Ensure the facility provides satisfactory responses to deficiencies conveyed during the CGMP inspection.
  • Coordinate with the facility for timely resolution of inspection deficiencies.
  • Include the date(s) of the facility's response(s) to the FDA Form 483 in the complete response.

Cited reasons

  • Lack of demonstrated superiority of elamipretide to placebo in primary endpoints (SPIBA-201 Part 1)
  • Inability to conclude meaningful treatment effect from open-label extension study (SPIBA-201 Part 2)
  • Significant limitations in externally controlled study (SPIBA-001)
  • Proposed surrogate/intermediate endpoints not suitable for accelerated approval
  • Unsatisfactory responses to CGMP inspection deficiencies at manufacturing facility
  • Labeling comments reserved pending application adequacy
  • Proprietary name re-submission required
  • Safety update required with complete response

Recommended actions

  • Address the lack of established effectiveness for traditional approval, specifically regarding SPIBA-201 Part 1, Part 2, and SPIBA-001 study findings.
  • Address the limitations precluding the use of LVSV, MLCL:CL ratio, and acylcarnitines as surrogate endpoints for accelerated approval.
  • Request an End-of-Review meeting to discuss muscle strength of knee extensors as a potential intermediate clinical endpoint for accelerated approval.
  • Provide information on what clinical benefit the muscle strength endpoint would reasonably predict.
  • Propose the design of a confirmatory postmarketing clinical trial to verify the predicted clinical benefit.
  • Ensure the facility provides satisfactory responses to deficiencies conveyed during the CGMP inspection.
  • Coordinate with the facility for timely resolution of inspection deficiencies.
  • Include the date(s) of the facility's response(s) to the FDA Form 483 in the complete response.

Deficiency summary

The application for elamipretide received a Complete Response Letter primarily due to a lack of substantial evidence of effectiveness for traditional approval, stemming from methodological flaws and insufficient statistical significance in clinical trials (SPIBA-201 Parts 1 & 2, and SPIBA-001). The proposed surrogate and intermediate endpoints for accelerated approval were also deemed unsuitable. Additionally, there are unresolved manufacturing facility deficiencies, and further information is required regarding safety updates and proprietary name resubmission.

Findings

Lack of demonstrated superiority of elamipretide to placebo in primary endpoints (SPIBA-201 Part 1)

Severity: critical

SPIBA-201, Part 1, the only randomized, placebo-controlled study, did not show superiority of elamipretide to placebo on the primary endpoint family of 6-minute walk test (6MWT) (p=0.97) and total fatigue score (TFS) (p=0.89). None of the secondary endpoints were nominally statistically significant.

Recommended response: Conduct new adequately powered and controlled clinical trials to demonstrate efficacy for traditional approval.

Inability to conclude meaningful treatment effect from open-label extension study (SPIBA-201 Part 2)

Severity: critical

Concerns related to bias involving effort-dependent endpoints and potential impact of subjects knowing they were receiving elamipretide. Effect sizes on endpoints were not large enough to overcome concerns of effort dependence and bias.

Recommended response: Redesign clinical studies to minimize bias and use objective, validated endpoints that are less susceptible to patient effort or knowledge of treatment assignment.

Significant limitations in externally controlled study (SPIBA-001)

Severity: critical

Bias involving effort-dependent endpoints, selection bias, comparability issues between control and treated arms, insufficient sample size for propensity score methodology, 100% interpolation of efficacy data, and uncertain reliability of control data due to lack of audit trail.

Recommended response: Address methodological flaws in study design, data collection, and statistical analysis, particularly for externally controlled studies, to ensure data interpretability and reliability.

Proposed surrogate/intermediate endpoints not suitable for accelerated approval

Severity: major

6MWT is considered an endpoint for full approval, not an intermediate clinical endpoint for accelerated approval. LVSV changes were within normal range with unclear clinical relevance. MLCL:CL ratio did not improve in an animal model and showed no significant differences in human study. Acylcarnitine results were exploratory and insufficient for use as a surrogate endpoint.

Recommended response: Engage with FDA to identify and validate appropriate surrogate or intermediate clinical endpoints for the accelerated approval pathway, providing robust scientific justification.

Unsatisfactory responses to CGMP inspection deficiencies at manufacturing facility

Severity: critical

The manufacturing facility needs to provide satisfactory responses to deficiencies conveyed during a CGMP inspection (FDA 483). Resolution of these deficiencies and potentially a re-inspection and pre-approval inspection (PAI) are required prior to approval.

Recommended response: Coordinate closely with the manufacturing facility to promptly address all FDA 483 observations, ensure CGMP compliance, and provide documentation of satisfactory responses.

Labeling comments reserved pending application adequacy

Severity: minor

FDA reserves comment on the proposed prescribing information and carton/container labeling until the application is otherwise adequate and all other deficiencies are resolved.

Recommended response: Review FDA labeling resources and guidance documents to prepare for future labeling submissions once clinical and manufacturing issues are resolved.

Proprietary name re-submission required

Severity: minor

The proposed proprietary name was conditionally acceptable but must be resubmitted when all application deficiencies have been identified and addressed.

Recommended response: Resubmit the proprietary name application after addressing all other deficiencies in the complete response.

Safety update required with complete response

Severity: major

A comprehensive safety update, including specific data for adverse events and case report forms for subjects who died or discontinued due to adverse events, is required as described at 21 CFR 314.50(d)(5)(vi)(b).

Recommended response: Prepare a comprehensive safety update, including detailed adverse event data and case report forms, for the complete response submission.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Regulatory context

Submission stage
final decision
Regulatory pathway
Traditional Approval (with consideration for Accelerated Approval)

Impact

Impact score
0.95
Estimated delay
540 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The primary themes are a fundamental lack of robust efficacy data for traditional approval, significant methodological flaws in clinical study design and data interpretation, unsuitability of proposed surrogate endpoints for accelerated approval, and unresolved manufacturing compliance issues. These deficiencies indicate a need for substantial additional data generation and regulatory engagement.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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