Bitopertin Regulatory Update

February 2026

Bitopertin received a Complete Response Letter from the FDA

• Main objection related to the sufficiency of protoporphyrin IX (PPIX) as a surrogate biomarker, with the

  FDA requesting to see the outcome of the ongoing APOLLO study before making a decision

• Disc is committed to delivering bitopertin to patients and will focus on diligently completing the APOLLO study by Q4 2026 and responding to the FDA

November 2024 January 2025

July 2025

September 2025

October 2025

November 2025

EOP2

Meeting

Type C

Meeting

Pre-NDA

Meeting

NDA

Submitted

Awarded CNPV

NDA

Accepted

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• Accelerated approval relies on (1) whether there is evidence of an effect on the proposed surrogate endpoint (% change in whole blood metal-free PPIX) and (2) whether the proposed surrogate endpoint, including the magnitude of change, is reasonably likely to predict a clinical benefit

  • AURORA and BEACON provided sufficient evidence that bitopertin significantly lowers whole blood metal-free PPIX

  • Based on review of AURORA and BEACON results, FDA concluded that the trials did not show evidence of association between percent change in PPIX and sunlight exposure-based endpoints, as measured in the trials, despite the strong mechanistic and biological plausibility supporting the use of the PPIX biomarker in protoporphyria

• FDA guided that for this application to be approved, Disc will need to provide additional evidence demonstrating the efficacy of bitopertin for the treatment of protoporphyria based on clinical endpoint(s)

  • Stated willingness to discuss options to meet this requirement, including completion and submission of results from the ongoing APOLLO trial

• Other requests:

  • FDA requested that Disc provide a standard safety update as part of the resubmission

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  • Disc will provide the new APOLLO safety data in the CRL response, which will be integrated with the prior safety database of over 4,000 subjects

PPIX Change:

% Change in WB PPIX

0

Bitopertin 60 mg

Sunlight Exposure:

12

Tertiles of PPIX Change

-10

-20

-30

-40

-50

8

4

0

-4

0 2 4 6 8 10 12 14 16

Diff vs Placebo in

Pain-Free Sunlight Exposure (hr)

Study Week

PPIX Decreased

PPIX Increased

Phototoxic Reactions

Placebo Bitopertin 60 mg

= Phototoxic Reaction = 2 Phototoxic Reactions

• Treatment with bitopertin led to a 49% reduction in whole blood PPIX and 63% reduction in plasma PPIX vs placebo at month 4

• PPIX reductions with bitopertin are similar to those seen in pregnant EPP patients and a photoinactivation study in which 30-50% reductions in PPIX led to marked improvements in light tolerance

CONFIDENTIAL

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Robust Endpoint

Longitudinal analysis leverages robust model that demonstrated significance in AURORA

Accounts for time-dependent PPIX lowering effects with bitopertin and for waning of a placebo effect

Focuses efficacy on month 6, after PPIX is fully reduced and potential placebo effect is expected to have waned

Robust Study Design

Rigorous evaluation of baseline light tolerance required during screening and factored into analysis of the primary endpoint

Stratification by geography to minimize confounding factors affecting light exposure across study arms

Well-powered; blinded sample size recalculation completed in January 2026 with no change required

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AURORA: Sunlight Tolerance Over Time†

AURORA: PPIX Over Time

p=0.03 vs PBO*

28

2-Week Aggregated Time (hr)

p=0.013 vs PBO*

24

20

16

12

1 3 5 7 9 11 13 15 17

20

% Change in WB PPIX

0

-20

-40

-60

0

15 29 43 71 121

Study Day

+8.1%

-21.5%

(p=0.004 vs PBO)

-41.7%

(p<0.001 vs PBO)

Placebo (n=24)

Week

Bitopertin 60 mg (n=25)

Placebo (n=24)

Bitopertin 20 mg (n=26) Bitopertin 60 mg (n=25)

* nominal p value

= last month of study = last 2-weeks of study

Longitudinal analysis demonstrated significance and was robust in AURORA

Accounts for time-dependent PPIX lowering effects with bitopertin and for waning of a placebo effect

Prespecified primary endpoint with consistent, high statistical significance in BEACON and AURORA

Recommended as co-primary by FDA, reflecting agency's

acknowledgement of the importance of lowering PPIX in EPP

† Post-hoc longitudinal analysis adjusted for baseline 7

Expect to request Type A meeting with FDA to review our approach for resubmission Expect to complete enrollment in March 2026, several months ahead of guidance Expect to present topline data in Q4 2026 and use this data to submit a response to

the CRL

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Typical FDA goal date for review of CRL response is ~6 months, implying potential for an updated decision by mid-2027

• Disc's belief in the importance of bringing a potential disease modifying therapy to the EPP community and the potential for bitopertin to set a new standard of care in EPP has not changed

• Disc has made every effort to bring bitopertin to the EPP community more quickly; while these efforts have not come to fruition, we remain committed to advancing the program and pursuing FDA approval of bitopertin

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• During this process, Disc is committed to providing continued access to bitopertin for current clinical trial participants

Maintaining cash runway guidance into 2029

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