Progerinin + Lonafarnib for Progeria

Overseen By Kush Dhody, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: PRG Science & Technology Co., Ltd.

Must be taking: Lonafarnib

Must not be taking: Progerinin metabolism

Disqualifiers: Liver disease, Uncontrolled infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 months

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the best way to treat Hutchinson-Gilford Progeria Syndrome (HGPS), a rare condition that causes rapid aging in children. Researchers will compare the effects of using the standard treatment, lonafarnib, alone versus in combination with a new drug, progerinin. Participants will either continue their current treatment with lonafarnib or add progerinin to determine which option is safer and more effective. Those who have taken lonafarnib for at least four months and show signs of Progeria may be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in Progeria treatment.

Do I need to stop my current medications for the trial?

The trial requires participants to continue taking lonafarnib, which is the standard treatment for Progeria. However, other drugs specifically targeting Progeria are not allowed, and medications that significantly affect the metabolism of Progerinin are also excluded. If you are taking such medications, you may need to stop them.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is investigating the safety of a new treatment combining progerinin and lonafarnib for children with Hutchinson-Gilford Progeria Syndrome (HGPS). Past studies have shown that lonafarnib, a key component of this new treatment, is generally safe and can improve weight gain, heart health, and bone strength in children with progeria.

Early lab results suggest that the new combination might be more effective than lonafarnib alone. However, this is a Phase 2 clinical trial, so researchers are still assessing its safety and determining the optimal dose. This phase is crucial to ensure the treatment's safety before wider testing. Participants will be closely monitored for any side effects, with safety as the primary concern. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for progeria?

Researchers are excited about Progerinin combined with Lonafarnib for treating progeria because it offers a fresh approach compared to existing options. While Lonafarnib is already used to manage progeria, adding Progerinin may enhance its effectiveness by specifically reducing the levels of progerin, the toxic protein responsible for the disease. This combination targets the root cause of progeria more directly, potentially improving outcomes for patients. Additionally, the treatment is tailored to the patient's body weight, which could optimize its efficacy and minimize side effects. This innovative approach represents a promising step forward in managing this rare and severe condition.

What evidence suggests that this trial's treatments could be effective for Hutchinson-Gilford Progeria Syndrome?

Research has shown that lonafarnib, a key component of the treatment, helps children with progeria gain weight, improve heart health, and strengthen bones. In studies, children treated with lonafarnib lived longer than those who did not receive it. In this trial, some participants will receive lonafarnib alone, while others will receive a combination of lonafarnib and progerinin. Laboratory evidence suggests that adding progerinin to lonafarnib might enhance these benefits. The combination could be more effective than lonafarnib alone for treating progeria. These findings suggest a hopeful future for better outcomes in patients with this condition. ^{2 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for patients with Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic condition. Participants must be currently taking the standard treatment, Lonafarnib, and will either continue this alone or in combination with a new drug called Progerinin.

Inclusion Criteria

I can travel to Boston for tests and exams.

I've been on lonafarnib for 4+ months without severe side effects for 2+ months.

I understand the study and its risks.

Exclusion Criteria

I am not taking any drugs specifically for Progeria, only for its symptoms.

I am on medication that affects Progerinin metabolism.

I have a stomach or intestine problem that affects how I absorb medicine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment with progerinin plus lonafarnib or lonafarnib alone. Dose escalation occurs through intra-subject dose titration.

4 months

Monthly visits for dose titration and monitoring

Toxicity Assessment

A 28-day period for toxicity assessment of the treatment.

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Progerinin

Trial Overview The study aims to find the best dose of Progerinin when used with Lonafarnib, and to check how safe and tolerable this combination is. Patients are randomly chosen to receive either just Lonafarnib or both drugs together.

How Is the Trial Designed?

Group I: Progerinin + Lonafarnib Experimental Treatment 2 Interventions

Subjects who have successfully completed the Screening phase will enter the treatment phase of the study and be randomized to a treatment arm. Subjects randomized to the progerinin + lonafarnib arm will take progerinin at a dose dependent on their body weight and will continue taking lonafarnib per the package insert. For each dose cohort, subjects will complete a 28-day treatment period of toxicity assessment, and a minimum four-month treatment period for plasma progerin evaluation. After the last subject completes the toxicity assessment period, the independent Data Monitoring Committee (iDMC) will meet to confirm that subjects can be escalated to the next dose. All subjects will remain on the current dose until the iDMC decision is confirmed. Each subject will only be escalated to the next dose after their 4-month (±2 weeks) plasma progerin sample is collected.

Group II: Lonafarnib Naïve Experimental Treatment 1 Intervention

Subjects with no prior treatment with lonafarnib (i.e., no commercial or managed access program source) may be enrolled to initiate treatment with lonafarnib monotherapy. These subjects will initiate lonafarnib therapy in preparation for an upcoming phase of the study following the completion of phase 2a. These subjects will be excluded from the analysis of this phase 2a study. They will come to the study site for a baseline visit and at one year for assessment as described later in this protocol.

Group III: Lonafarnib Active Control 1 Intervention

Subjects in the main study arms (Progerinin + Lonafarnib and non-naïve Lonafarnib) will continue taking lonafarnib per the package insert. Subjects randomized to the lonafarnib alone arm will not take progerinin during this study.

Who Is Running the Clinical Trial?

PRG Science & Technology Co., Ltd.

Lead Sponsor

Trials

3

Recruited

90+

Published Research Related to This Trial

Lonafarnib, a farnesyltransferase inhibitor, has shown promise in clinical trials for treating Hutchinson-Gilford progeria syndrome (HGPS), leading to weight gain and improvements in cardiovascular and skeletal health in affected children.

Research into progeroid syndromes has advanced significantly, utilizing various experimental models to explore the underlying cellular and molecular mechanisms, which may also provide insights into the aging process in general.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progeria: a rare genetic premature ageing disorder. Sinha, JK., Ghosh, S., Raghunath, M.[2021]

In a study of 26 children with Hutchinson-Gilford progeria syndrome treated with lonafarnib for at least 2 years, there was a significant reduction in the frequency of clinical strokes, headaches, and seizures, suggesting improved neurologic status.

The treatment led to no new stroke events in patients with a history of transient ischemic attacks (TIAs), and four patients who had seizures before treatment did not experience any recurrent or new-onset seizures during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Ullrich, NJ., Kieran, MW., Miller, DT., et al.[2021]

In a trial involving 37 participants with Hutchinson-Gilford progeria syndrome, a combination therapy of pravastatin, zoledronic acid, and lonafarnib resulted in a significant improvement in weight gain or carotid artery echodensity in 71% of participants, indicating its efficacy in managing some disease symptoms.

While the combination therapy improved bone mineral density, it did not provide additional cardiovascular benefits compared to lonafarnib alone, as evidenced by unchanged carotid artery wall echodensity and increased plaque formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Gordon, LB., Kleinman, ME., Massaro, J., et al.[2018]

In a clinical trial involving 25 patients with Hutchinson-Gilford progeria syndrome (HGPS) treated with the farnesyltransferase inhibitor lonafarnib for at least 2 years, 9 patients showed a significant increase in weight gain, indicating potential efficacy of the treatment.

All patients demonstrated improvements in secondary outcomes such as reduced arterial stiffness and enhanced bone structure and hearing, suggesting that lonafarnib may positively impact multiple aspects of HGPS beyond just weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Gordon, LB., Kleinman, ME., Miller, DT., et al.[2021]

Progeria, a rare genetic disorder caused by mutations in the lamin A (LMNA) gene, provides valuable insights into the biology of premature aging and has led to the identification of potential drug targets through the farnesylation pathway.

Recent advancements include the development of animal models and the initiation of clinical trials aimed at treating children with progeria, marking significant progress in understanding and potentially addressing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New approaches to progeria. Kieran, MW., Gordon, L., Kleinman, M.[2008]

Citations

1. ahajournals.org ahajournals.org/doi/10.1161/circulationaha.116.022188

Clinical Trial of the Protein Farnesylation Inhibitors ... This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10023154/

Lonafarnib improves cardiovascular function and survival in a ... Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with ...

3. progeriaresearch.org progeriaresearch.org/clinical-trials/

Clinical trials Laboratory evidence shows that this drug, when taken in combination with lonafarnib, may be more effective than lonafarnib alone. PRF funded the laboratory ...

4. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2679278

Association of Lonafarnib vs No Treatment With Mortality ... In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched ...

5. withpower.com withpower.com/trial/progerinin-lonafarnib-for-progeria-2803e

Progerinin + Lonafarnib for Progeria Research shows that Lonafarnib, a component of the treatment, has been effective in improving weight gain, cardiovascular health, and bone structure in children ...

6. ctv.veeva.com ctv.veeva.com/study/study-to-determine-optimal-dose-and-evaluate-safety-tolerability-and-pharmacokinetics-of-progerini

Study to Determine Optimal Dose and Evaluate Safety ... Researchers will compare treatment with progerinin plus lonafarnib vs lonafarnib alone to assess optimal dosing, safety, tolerability, and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12112389/

Baricitinib and Lonafarnib Synergistically Target Progerin and ... Baricitinib and Lonafarnib synergistically target progerin and inflammation, improving lifespan and health in progeria mice.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/213969Orig1s000IntegratedR.pdf

213969Orig1s000 - accessdata.fda.gov patients respond similarly to lonafarnib. The available safety data show that lonafarnib is safe for its intended use. Common adverse.