APOLLO: A Randomized, Double-Blind, Placebo-Controlled Study of Bitopertin to Evaluate the Efficacy, Safety, and Tolerability in Participants with Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)

This study evaluates bitopertin in participants with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP), rare metabolic disorders characterized by cutaneous photosensitivity and accumulation of protoporphyrin IX. The primary objectives are to assess average pain-free sunlight exposure tolerance after 6 months of treatment, to evaluate changes in whole-blood metal-free protoporphyrin IX (PPIX) levels after 6 months of treatment, and to assess safety and tolerability. These endpoints are clinically relevant as they address both the functional limitation of sunlight intolerance and the underlying biochemical abnormality in these porphyrias. The secondary objectives include: assessment of the occurrence of phototoxic reactions, evaluation of cumulative total pain-free sunlight exposure over 6 months of treatment, and assessment of changes in time to prodromal symptoms. Additional exploratory objectives are defined in the study protocol.

This clinical trial enrolled a total of **94 participants** diagnosed with **X-Linked Protoporphyria (XLP)** or **Erythropoietic Protoporphyria (EPP)**. The study population included both **male** and **female** subjects aged **12 years or older**, encompassing adolescents, adults, and elderly individuals, with a **vulnerable population** included. Participants were selected based on confirmed diagnosis of EPP or XLP through **ferrochelatase (FECH)** or **aminolevulinic acid synthase 2 (ALAS2)** genotyping or biochemical **porphyrin** analysis. Key selection criteria required a minimum body weight of 32 kg for adolescents aged 12 to under 18 years and a **body mass index** of at least 18.5 kg/m² for those aged 18 years and above. Participants were required to demonstrate high compliance with daily **sun exposure** diary entries during the screening period and to have completed at least one **Sun Exposure Challenge** or provide historical recall of time to **prodrome**. Individuals who had previously received **afamelanotide** or **dersimelagon** were required to undergo a washout period of at least 2 months prior to screening. Participants needed to maintain adequate hepatic function with **aspartate aminotransferase** and **alanine transaminase** levels below 3 times the upper limit of normal and **total bilirubin** below 2 times the upper limit of normal, unless documented **Gilbert syndrome** was present, and **albumin** levels above the lower limit of normal. Females of childbearing potential were required to have negative pregnancy tests at screening and baseline. Both males with partners of childbearing potential and females of childbearing potential were required to practice highly effective methods of **birth control** throughout the study period and for at least 30 days following the last dose of study drug.

This clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **Bitopertin** in participants with **Erythropoietic Protoporphyria** (EPP) or **X-Linked Protoporphyria** (XLP). The study is classified as a **Phase 3** clinical trial. Bitopertin, administered as a **film-coated tablet** via **oral use**, will be compared against a matching **placebo**. The maximum daily dose of Bitopertin is 60 mg. Bitopertin has been designated as an **orphan drug** for the treatment of these rare diseases.

The primary objectives of the study are to assess average pain-free sunlight exposure tolerance after 6 months of treatment, to evaluate changes in whole-blood metal-free **protoporphyrin IX** (PPIX) levels after 6 months of treatment, and to assess safety and tolerability. The **primary endpoints** include average monthly total time in sunlight on days without pain from a **phototoxic reaction** between 10:00 to 18:00 after 6 months (24 weeks) of treatment, percent change from baseline in whole-blood metal-free PPIX levels at 6 months, and safety and tolerability as assessed by **adverse events** (AEs) and laboratory results over the 6-month treatment period. **Secondary endpoints** include the occurrence of phototoxic reactions over the 6-month treatment period, cumulative total time in sunlight on days without pain from a phototoxic reaction between 10:00 to 18:00 over the 6-month treatment period, and change from baseline in 2-week average daily sunlight exposure time (minutes) to first **prodromal symptom** (eg, burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post-sunrise and 1 hour pre-sunset at 6 months.

Eligible participants must meet the following principal inclusion criteria: aged 12 years or older at the time of study consent; diagnosis of EPP or XLP based on medical history by **ferrochelatase** (FECH) or **aminolevulinic acid synthase 2** (ALAS2) **genotyping** or by biochemical **porphyrin** analysis; minimum daily Sun Exposure Diary compliance of at least 85% during specified screening days and at least one successfully completed Sun Exposure Challenge (adults only, as this assessment is optional for adolescents) or historical recall of time to prodrome; body weight of at least 32 kg for ages 12 to less than 18 years or **body mass index** of at least 18.5 kg/m² for ages 18 years and older at **screening**; washout of at least 2 months prior to screening of **afamelanotide** and **dersimelagon**, if applicable; **aspartate aminotransferase** and **alanine transaminase** less than 3 times the **upper limit of normal** (ULN) and total **bilirubin** less than 2 times ULN (unless documented **Gilbert syndrome**) at screening, with **albumin** greater than the **lower limit of normal** (LLN); willingness to practice highly effective methods of birth control for both males who have partners of childbearing potential and females of childbearing potential during screening, while taking study drug, and for at least 30 days after the last dose of study drug; negative **pregnancy test** for females of childbearing potential at screening and baseline (Day 1) prior to dosing; ability to understand the study aims, procedures, and requirements and provide written **informed consent** (and **assent** if necessary); and ability to comply with all study procedures.

The estimated recruitment start date for the trial is October 16, 2025, with an estimated end date of December 31, 2026. The expected length of participant involvement is 6 months (24 weeks) of treatment. The study involves a screening period during which participants must complete daily Sun Exposure Diary entries and, for adults, at least one Sun Exposure Challenge. Following successful screening, participants will enter a baseline visit (Day 1) and receive either Bitopertin or matching placebo. Throughout the 6-month treatment period, participants will attend follow-up visits to assess efficacy outcomes, safety parameters, and tolerability. An end-of-study visit will be conducted at the conclusion of the 6-month treatment period. Conditions that may lead to early termination from the study include failure to meet inclusion criteria, occurrence of significant adverse events, non-compliance with study procedures, withdrawal of consent, or at the discretion of the investigator for safety or other reasons.

The experimental investigational medicinal product in this clinical trial is **Bitopertin**, a **film-coated tablet** formulation for **oral use**. Bitopertin (also known by the synonym RO 4917838 and sponsor product code DISC-1459) contains the active substance **bitopertin** of chemical origin. The maximum daily dose is **60 mg**. The treatment period is 1 day. Bitopertin has been designated as an **orphan drug** under the designation number EU/3/23/2761. The product is manufactured by DISC MEDICINE INC and is assigned the EU medicinal product number PRD12419036 and the Manufacturing and Import Authorization number MIA (IMP) 20377.

The study includes a **matching placebo** as a **comparator** treatment to enable double-blind evaluation of the experimental medication. The placebo is administered to maintain blinding in this randomized, placebo-controlled trial design. The placebo formulation is designed to match the experimental product to ensure that participants and investigators remain unaware of treatment allocation throughout the study.

Efficacy will be assessed through multiple parameters evaluating sunlight exposure tolerance, biochemical markers, and phototoxic reaction outcomes. The primary efficacy endpoints include average monthly total time in sunlight on days without pain from a phototoxic reaction between 10:00 to 18:00 (10:00 AM to 6:00 PM) after 6 months (24 weeks) of treatment, percent change from baseline in whole-blood metal-free **protoporphyrin IX** (PPIX) levels at 6 months, and safety and tolerability as assessed by adverse events and laboratory results over the 6-month treatment period. Secondary efficacy endpoints comprise the occurrence of phototoxic reactions over the 6-month treatment period, cumulative total time in sunlight on days without pain from a phototoxic reaction between 10:00 to 18:00 (10:00 AM to 6:00 PM) over the 6-month (24-week) treatment period, and change from baseline in 2-week average daily sunlight exposure time (minutes) to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post-sunrise and 1 hour pre-sunset at 6 months. Sunlight exposure data will be collected using a Sun Exposure Diary, with minimum daily compliance of at least 85% required during the screening period. The main objectives are to assess average pain-free sunlight exposure tolerance after 6 months of treatment, to assess changes in whole-blood metal-free PPIX levels after 6 months of treatment, and to assess safety and tolerability.