Immedica Pharma AB

BLA 761211 COMPLETE RESPONSE

Immedica Pharma AB

% DLRC Inc.

Attention: Gregory Dombal President

1 Broadway

Cambridge, MA 02142

Dear Gregory Dombal: Please refer to your biologics license application (BLA

or

We acknowledge receipt of your major amendment dated), which extended the goal date by three months.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We recognize that arginase 1 deficiency (ARG1-D) is a rare and serious disease and that there is high unmet need with no approved therapies.

We have described our reasons for this action below and, where possible, our recommendations to address these issues.

DEFICIENCIES AND INFORMATION NEEDED TO RESOLVE THE DEFICIENCIES

(1) Dose adjustment and monitoring of plasma arginine are required for the safe and effective use of AEB1102.

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(2) The effectiveness of AEB1102 has not been established for traditional approval,

even when appl

ying regulatory flexibility for this rare and serious disease.

The

primary evidence of efficacy for AEB1102 was evaluated in a single adequate

and well contro!

led trial (CAEB1102-300A) that included subjects with ARG1-D. Results showed a statistically significant reduction plasma arginine levels favoring AEB1102, with an estimated treatment di

pediatric and adult in erence

of -311uM (95% Cl -380, -242, p<0.0001). However, the trial did not achieve

either of its key

Domain part E p=0.14). The re had a treatmen

secondary endpoints: 2-minute walk tes! difference of 5.5, 95% Cl (-15.6, 26.7), p=0.60) and Gross Motor Function GMFM-E) (treatment difference of 4.1, 95% Cl (-1.5, 9.7), lated endpoint, Gross Motor Function Domain part D (GMFM-D) difference o'

(2MWT) (treatment

3.0 (95% Cl: 0.3, 5.7, nominal p=0.03). Thus, while

there were trends in improvement in clinical endpoints during the placebo-

controlled period of

the trial,

clinical benefit of AEB1102. clinical benefit in other data sources, such as the open label extension as subjects in the placebo grou

show numerical improvements in the c

treatment led to sta

submitted data are not adeq'

surrogate endpoint

supportive evidence sugges

predict clinical bene systematic review o'

We recommend thai

predictive of clinica

the results overall did not definitively establish a n addition, there was no definitive evidence of

p who received AEB1102 starting at Week 24 did not inical endpoints. While AEB1102

istically significant reductions in plasma arginine, the

uate to support plasma arginine as a validated benefit. However, the additional ed that plasma arginine may be reasonably likely to

fit based case st

you conduct a trial validate that plasma arginine and/or its

on correlations observed in the pivotal trial and a udies.

that assesses clinical outcomes to metabolites are predictive of clinical

benefit. Conceivably, because plasma arginine alone or in combination with

specific metabolites

may be

predict clinical bene

it, it may be accep

considered a reasonably likely surrogate endpoint to able that such a trial would be conducted

as a postmarketing confirmatory trial if your application was resubmitted via the accelerated approval pathway.'* We welcome dialog to discuss potential designs for such a trial and the possible acceptability of utilizing the accelerated approval pathway for the resubmission of your BLA.

1 For additional information on the accelerated approval pathway and their requisite confirmatory trials, see the FDA draft guidances for industry Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics, available at https://www.fda.gov/regulatory-information/search-fda- guidance-documents/accelerated-approval-expedited-program-serious-conditions, and Accelerated

Approval and Considerations for Determining Whether a Confirmatory Trial is Underway, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/accelerated-approval-and-

considerations-determining-whether-confirmatory-trial-underway.

2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database https://www.fda.gov/Regulatorylnformation/Guidances/default.htm.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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BLA 761211 Page 3

PRESCRIBING INFORMATION

We reserve additional comment on the proposed labeling at this time. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final Rule* websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov.®

PROPRIETARY NAME

Please refer to correspondence dated, oe , which addresses the proposed proprietary name, . This name was found conditionally acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to all of the application deficiencies that have been identified in this letter.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the product under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile. (2) When assembling the sections describing discontinuations due to adverse

events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

3 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

4 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

5 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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BLA 761211 Page 4

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in Clinical trials.

(3) Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

(4) Provide case report forms and narrative summaries for each subject who died during a Clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(5) Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

ADDITIONAL COMMENTS

We have the following comments/recommendations that are not approvability issues: Clinical

1. There is a lack of safety and efficacy data in subjects less than 2 years of age and safety concerns related to low arginine levels, especially in younger patients. Therefore, the provided information does not support the proposed inclusion of pediatric patients of all ages. We recommend a clinical trial in ARG1-D subjects less than 2 years of age to assess safety and efficacy in order to provide support for the proposed inclusion of patients less than 2 years of age in the indication.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Product Quality

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Clinical Pharmacology

9. The adequacy of AEB1102 dosing in the context of initiating treatment via the subcutaneous (SC) route, without prior intravenous AEB1102 treatment, has not been characterized in patients with ARG1-D. Provide clinical data, either from an ongoing or planned trial, to support the dosing and safety (including immunogenicity) of initiating AEB1102 treatment via the SC route of administration.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 601.3(b). If you do not take one of these actions, we

may consider your lack of response a request to withdraw the application under

21 CFR 601.3(c). You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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BLA 761211 Page 7

this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, contact om

Sincerely,

{See appended electronic signature page} (b) (4)

Center tor Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

(b) (4)

08/06/2025 07:08:09 AM

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