Table of Contents

• Overview of the Sirolimus trial program
• Transplant-related studies
• Neurology and rare genetic disease studies
• Vascular and skin condition studies
• Other conditions studied with Sirolimus
• Main endpoints used in the trials
• Who the studies are designed for

Overview of the Sirolimus trial program

The trial data show that Sirolimus is being studied in many different diseases, especially in transplant medicine, rare diseases, and conditions that affect the brain, skin, blood vessels, and heart.^[1] The studies include both early and late phases, which means some are mainly checking safety while others are testing whether Sirolimus works better than placebo or another treatment.^[1]

Several trials are still authorised, some are completed, one is ongoing, and one was withdrawn or suspended in the source data.^[1] The planned study sizes range from very small groups, such as 3 or 5 participants, to larger studies with 300 participants.^[1]

Transplant-related studies

Many trials focus on people after kidney transplantation or combined pancreas-kidney transplantation.^[1] One Phase 3 study looks at renal recipients at high risk of post-transplant cytomegalovirus and measures whether CMV infection or disease appears within 6 months after transplant, while also checking CMV-specific immune response over time.^[1]

Another Phase 3 study in kidney transplant patients with BK Polyomavirus DNAemia tests whether a guided immunosuppression strategy can shorten the time to the end of BKPyV-DNAemia, using a viral load drop in blood as the main marker of improvement.^[1] A related Phase 3 BK-VAX project studies prevention of BK virus infection after kidney transplantation and follows changes in virus-specific immune response and viral load in blood.^[1]

One Phase 4 study in kidney transplant recipients in intensive care with septic shock and/or acute respiratory failure examines whether reducing immunosuppressive treatment improves organ failure, using a change in the SOFA score by day 5 as the main endpoint.^[1] Another Phase 3 study compares Sirolimus with mycophenolate mofetil in simultaneous pancreas and kidney transplantation to see whether one regimen leads to fewer incisional hernias.^[1]

Neurology and rare genetic disease studies

Sirolimus is also being studied in several brain and nerve-related conditions.^[1] In children with diffuse intrinsic pontine glioma, a Phase 2 trial evaluates safety and overall survival while adjusting treatment based on molecular markers.^[1] In paediatric high grade glioma, another Phase 2 study mainly checks safety by counting severe adverse reactions during treatment and follow-up.^[1]

In tuberous sclerosis complex, one Phase 3 placebo-controlled study looks at drug-resistant epilepsy and measures how many patients have at least a 50% seizure reduction, along with adverse events.^[1] A Phase 4 infant study compares Sirolimus with vigabatrin to prevent symptoms of tuberous sclerosis complex and tracks clinical seizures and tumor growth.^[1] The PROTECT study in children under 4 months of age looks at long-term neuropsychologic outcome at 24 months using the Bayley cognitive scale.^[1]

Other rare disease studies include BAG3-associated dilated cardiomyopathy, where a Phase 1/2 study first checks safety and tolerability and then looks at clinical impact, and fronto-temporal dementia with progranulin mutations, where a Phase 1 study measures safety, immune effects, and changes in progranulin levels in blood and cerebrospinal fluid.^[1] Sirolimus also appears in gene therapy studies for Duchenne muscular dystrophy, Danon disease, and severe Crigler-Najjar syndrome, where it is part of the treatment plan being tested alongside gene therapy or other study drugs.^[1]

Vascular and skin condition studies

Several studies focus on blood vessel and skin problems.^[1] A Phase 2 study in superficial arteriovenous malformations measures whether the malformation volume falls by at least 30% during the first year, using imaging criteria.^[1] A Phase 2 study of poor prognosis cervico-facial lymphatic malformations checks whether lesion volume falls after treatment, using volumetric MRI and defining a positive response as a decrease of more than one-fifth of the starting volume.^[1]

In lingual microcystic lymphatic malformations, a Phase 2 study tests topical Sirolimus in children and adults and measures global severity on a blinded photo-based score after 12 weeks.^[1] In port wine stains, a Phase 2 dose-ranging study tests topical Sirolimus cream after laser treatment and measures change in colour extent and intensity at week 12.^[1] In cutaneous sarcoidosis involving the face, a Phase 2 study looks for a clinical response defined by a reduction in the facial skin score at 16 weeks.^[1]

Other conditions studied with Sirolimus

Sirolimus is also being explored in thyroid eye disease, familial adenomatous polyposis, post-acute COVID syndrome, and other conditions.^[1] In active thyroid eye disease, a Phase 3 study compares Sirolimus with corticosteroids and uses a reduction in Clinical Activity Score at week 12 as the main endpoint.^[1] In familial adenomatous polyposis, one Phase 3 study and one Phase 2 safety study look at whether Sirolimus can delay disease progression or monitor safety in adolescents.^[1]

A Phase 2 study in post-acute COVID syndrome was withdrawn, but it planned to test whether Sirolimus could help physical performance, frailty reversal, and quality of life.^[1] Another Phase 2 study in simultaneous pancreas and kidney transplantation compares Sirolimus with mycophenolate mofetil to see whether the risk of incisional hernia changes after surgery.^[1]

Main endpoints used in the trials

The studies use a wide range of primary outcomes, which are the main results each trial wants to measure.^[1] These include infection rates, seizure reduction, survival, lesion or tumor size, disease progression, safety events, and changes in disease scores or imaging findings.^[1]

Safety is often measured by counting treatment-emergent adverse events, serious adverse events, or severe reactions graded by CTCAE, which is a standard system for classifying how serious side effects are in trials.^[1] Some studies also track lab tests, vital signs, ECG results, MRI findings, and immune markers, depending on the disease being studied.^[1]

Who the studies are designed for

The target groups are very broad, but each trial is specific to one condition.^[1] Some studies include infants or young children, such as those with tuberous sclerosis complex, Crigler-Najjar syndrome, Duchenne muscular dystrophy, or childhood brain tumors.^[1] Other studies focus on adults with sarcoidosis, thyroid eye disease, kidney transplant complications, or genetic heart disease.^[1]

Several trials are designed for people with rare diseases or hard-to-treat disorders, where the study goal is to find better control of symptoms, slow progression, or improve long-term outcomes.^[1] In transplant studies, the focus is often on infection prevention, immune response, and balancing treatment reduction with safety.^[1]