CLINICAL TRIALS PROFILE FOR GIVINOSTAT HYDROCHLORIDE

All Clinical Trials for Givinostat Hydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00606307 ↗	Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases	Completed	Italfarmaco	Phase 2	2007-12-01	Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results. Secondary Objective: To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).
NCT00928707 ↗	Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera	Completed	Italfarmaco	Phase 2	2009-06-01	The primary objective of the study was to evaluate the efficacy of Givinostat in combination with hydroxyurea in patients with JAK2V617F-positive Polycythemia Vera (PV) non-responders to the maximum tolerated dose of hydroxyurea monotherapy. The secondary objectives of this study were: - To evaluate the safety and tolerability of Givinostat in combination with hydroxyurea in patients with JAK2V617Fpositive PV non-responders to the maximum tolerated dose of hydroxyurea monotherapy; - To explore the impact in terms of efficacy and tolerability of Givinostat 50 mg dose escalation in patients not achieving at least a partial response at the time when the primary endpoint was assessed (week 12); - To evaluate the molecular response (JAK2 mutated allele burden) by quantitative Real Time-Polymerase Chain Reaction (RT-PCR); - To evaluate the reduction of the fraction of JAK2V617F positive clonogenic progenitors.
NCT01261624 ↗	Efficacy and Safety Dose Finding Study of Givinostat to Treat Polyarticular Course Juvenile Idiopathic Arthritis	Terminated	Italfarmaco	Phase 2	2010-10-01	The present study has been designed in order to evaluate the efficacy and safety of two doses of Givinostat in subjects with polyarticular course JIA Givinostat ready-to-use suspension especially intended for paediatric administration, will be administered orally at different daily doses. Patients with an established diagnosis of one of the following JIA forms (Polyarticular JIA rheumatoid factor positive or negative, Oligoarticular extended JIA, Systemic JIA without active systemic features) will be enrolled. The treatment regimen will remain unchanged for 12 weeks and the clinical response will by assessed by applying the ACR Pediatric response criteria. Patients achieving at least an ACR Pediatric 30 response will continue receiving the assigned dose for 12 further weeks. After the end of study (week 24) responder patients will be allowed to extend the treatment until they maintain a clinical benefit.
NCT01557452 ↗	Open-Label Extension of the Dose Finding Study (DSC/08/2357/36) in Patients With Poly Juvenile Idiopathic Arthritis	Terminated	Parexel	N/A	2011-12-28	Primary Objective of the study: the purpose of this extension study was to determine the safety of Givinostat in a long term treatment of patients who participated in DSC/08/2357/36 study with good results (clinical benefit at least pediACR30 response);
NCT01557452 ↗	Open-Label Extension of the Dose Finding Study (DSC/08/2357/36) in Patients With Poly Juvenile Idiopathic Arthritis	Terminated	Italfarmaco	N/A	2011-12-28	Primary Objective of the study: the purpose of this extension study was to determine the safety of Givinostat in a long term treatment of patients who participated in DSC/08/2357/36 study with good results (clinical benefit at least pediACR30 response);
NCT01761292 ↗	A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD	Completed	Italfarmaco	Phase 1/Phase 2	2013-04-01	The primary objective of Parts 1 and 2 of the study were to establish the histologic effects of givinostat administered chronically at the selected daily dose. The secondary objectives of Parts 1 and 2 of the study were as follows: - To establish the effects of givinostat administered chronically at the selected daily dose on functional parameters, such as the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and performance of upper limb (PUL) - To establish the safety and tolerability of givinostat administered chronically at the selected daily dose in children with Duchenne muscular dystrophy (DMD) - To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as magnetic resonance imaging (MRI) and biomarkers - To explore the acceptability/palatability of the oral suspension - To explore whether the effects of givinostat on disease progression may be related to the type of DMD mutation. The primary objective of the Extension of the study was to evaluate the safety and tolerability of long-term administration of givinostat administered chronically at the selected daily dose in children with DMD. The secondary objectives of the Extensions were: - To establish the effects of givinostat administered chronically at the selected daily dose on muscular functional parameters, such as the 6MWT, NSAA, and PUL (Extensions 1, 2, and 3) - To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as MRI (Extension 1) - To collect information related to 2 biomarkers, latent Transforming growth factor β (TGFβ) binding protein 4 (LTBP4) and osteopontin genotype (at the beginning of Extension 2 only) - To collect information related to time to wheelchair and how much time the children spend in wheelchair (Extension 3 - only for the children who were not able to complete the 6MWT)
NCT01761968 ↗	Long-term Study Evaluating the Effect of Givinostat in Patients With Chronic Myeloproliferative Neoplasms	Active, not recruiting	Italfarmaco	Phase 2	2013-03-01	This is a multicenter, open label, long-term study testing the long-term safety, tolerability and efficacy of givinostat in patients with Polycythemia Vera, Essential Thrombocythemia, primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis following core protocols in chronic myeloproliferative neoplasms and/or patient-named compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments). Patients will continue at their last tolerable dose and treatment schedule of givinostat monotherapy. If patients previously received givinostat in combination with other drugs during a core protocol or a compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments), they will be treated at the last tolerable dose of the combination. Assessment of safety and efficacy will be performed at each quarterly visit and each visit will also include laboratory tests and ECG examination. During the visits the clinical benefit will be assessed by Investigator according to the revised European LeukemiaNet response criteria (for PV and ET) and EUMNET response criteria (for MF). The dose of Givinostat will be modified for protocol specified toxicities. The treatment may continue up to Marketing Authorization of givinostat, currently planned in the next 5 years (note: only for Germany, this long-term study is initially limited up to 2 years of treatment). Patients may discontinue study treatment at any time and remain on study therapy as long as they derive clinical benefit. Safety will be monitored at each visit throughout the entire duration of the study. In case the approved label will not cover the whole study population, givinostat will be provided by the Sponsor to those patients not fulfilling the criteria for the approved label of the drug that are still deriving benefit from givinostat at the time of its commercial availability.

Clinical Trial Conditions for Givinostat Hydrochloride

Condition Name

Condition Name for Givinostat Hydrochloride
Intervention	Trials
Polycythemia Vera	3
Drug Drug Interaction	2
Duchenne Muscular Dystrophy	2
Juvenile Idiopathic Arthritis	1

Condition MeSH

Condition MeSH for Givinostat Hydrochloride
Intervention	Trials
Muscular Dystrophy, Duchenne	5
Muscular Dystrophies	5
Polycythemia Vera	3
Polycythemia	3

Clinical Trial Locations for Givinostat Hydrochloride

Trials by Country

Trials by Country for Givinostat Hydrochloride
Location	Trials
Italy	41
United States	25
Canada	7
Spain	5
United Kingdom	5

Trials by US State

Trials by US State for Givinostat Hydrochloride
Location	Trials
California	3
Virginia	2
Pennsylvania	2
Oregon	2
Missouri	2

Clinical Trial Progress for Givinostat Hydrochloride

Clinical Trial Phase

Clinical Trial Phase for Givinostat Hydrochloride
Clinical Trial Phase	Trials
Phase 3	2
Phase 2/Phase 3	1
Phase 2	5

Clinical Trial Status

Clinical Trial Status for Givinostat Hydrochloride
Clinical Trial Phase	Trials
Completed	8
Active, not recruiting	3
Terminated	2

Clinical Trial Sponsors for Givinostat Hydrochloride

Sponsor Name

Sponsor Name for Givinostat Hydrochloride
Sponsor	Trials
Italfarmaco	15
Cromsource	1
Parexel	1

Sponsor Type

Sponsor Type for Givinostat Hydrochloride
Sponsor	Trials
Industry	17
Other	2

Givinostat Hydrochloride: Clinical Trials, Market Analysis, and Projections

Introduction

Givinostat hydrochloride, also known as ITF2357 hydrochloride, is a histone deacetylase (HDAC) inhibitor that has been under intense scrutiny for its potential in treating Duchenne muscular dystrophy (DMD) and other conditions. Here, we delve into the recent clinical trials, market analysis, and future projections for this promising drug.

Clinical Trials Overview

Phase 3 EPIDYS Study

The pivotal Phase 3 EPIDYS clinical trial, conducted by Italfarmaco S.p.A., has been a significant milestone in the development of givinostat hydrochloride. This multicenter, randomized, double-blind, placebo-controlled trial enrolled 179 ambulant boys aged 6 years and older with DMD across North America and Europe[3][4].

• Primary Endpoint: The trial met its primary endpoint, which measured the mean change in the ability to climb four stairs from baseline to 72 weeks. Givinostat-treated participants showed a slower decline in performing this functional task compared to the placebo group, with a difference of 1.78 seconds (p=0.037)[3][4].

• Secondary Endpoints: Givinostat treatment was associated with favorable outcomes on several secondary endpoints, including a 40% less decline in the North Star Ambulatory Assessment (NSAA) total score and item loss, and a 30% reduction in the vastus lateralis fat fraction (VLFF) compared to the placebo group. These results indicate givinostat’s potential to delay disease progression in DMD patients[3][4].

• Safety and Tolerability: Givinostat was well tolerated, with a safety profile consistent with previous trials. Common treatment-related adverse events included decreased platelet count/thrombocytopenia, increased blood triglycerides/hypertriglyceridemia, diarrhea, and abdominal pain. None of these events were severe or led to study withdrawal[3][4].

Open-Label Extension Study

Following the 18-month double-blind period, participants were eligible to enroll in an open-label extension study (OLE study) to receive givinostat on an ongoing basis. The median follow-up of participants in the EPIDYS + OLE studies is 4.7 years, providing long-term safety and efficacy data[3][4].

Mechanism of Action

Givinostat hydrochloride acts as an HDAC inhibitor, specifically targeting HDAC1 and HDAC3 with IC50 values of 198 and 157 nM, respectively. This mechanism modulates the deregulated activity of HDACs in dystrophic muscle, addressing the cascade of events leading to muscle damage and thereby slowing down muscle deterioration[2].

Market Analysis

Regulatory Status

Givinostat has received priority review, orphan drug, and rare pediatric disease designations from the U.S. FDA. A New Drug Application (NDA) has been filed, with a Prescription Drug User Fee Act (PDUFA) date set for March 21, 2024. Additionally, a Marketing Authorisation Application (MAA) has been submitted to the European Medicines Agency (EMA) and is under review[4].

Market Potential

Given the positive outcomes of the EPIDYS trial and the critical need for effective treatments for DMD, givinostat hydrochloride is poised to capture a significant share of the DMD treatment market. DMD has a prevalence of about 1 in 3,500 to 6,000 male births, and current treatments are largely palliative, making givinostat a potentially game-changing therapy[5].

Projections

Approval and Launch

With the PDUFA date approaching, givinostat is likely to receive FDA approval in the near future, followed by a launch in the U.S. and European markets. This approval will mark a significant milestone for Italfarmaco and for patients with DMD, offering a new treatment option that can delay disease progression[4].

Market Impact

The approval of givinostat hydrochloride is expected to have a substantial impact on the DMD treatment landscape. It will provide a new therapeutic option for patients and families affected by DMD, potentially improving quality of life and delaying the loss of ambulation. This could also drive further research into HDAC inhibitors for other muscular dystrophies and related conditions[3][4].

Financial Projections

Given the orphan drug designation and the unmet medical need in DMD, givinostat hydrochloride is likely to command a premium price. The market size for DMD treatments is expected to grow significantly with the introduction of givinostat, and Italfarmaco can anticipate substantial revenue from this drug. The exact financial projections will depend on factors such as pricing, market penetration, and competition, but the outlook is promising[4].

Safety Concerns and Monitoring

Hematological Changes

One of the major safety concerns with givinostat hydrochloride is the risk of hematological changes, particularly thrombocytopenia. This condition occurred in 33.1% of givinostat-exposed patients in clinical trials, although it was generally asymptomatic and reversible upon treatment discontinuation. The proposed labeling includes warnings and precautions for these hematological changes[5].

Gastrointestinal and Other Adverse Events

Other common adverse events include gastrointestinal disturbances, increased blood triglycerides, and QTc prolongation. These events are manageable with appropriate monitoring and dose adjustments, as observed in the clinical trials[3][5].

Key Takeaways

• Clinical Success: The Phase 3 EPIDYS trial demonstrated givinostat hydrochloride's efficacy in delaying disease progression in DMD patients.
• Regulatory Pathway: Givinostat has received priority review and orphan drug designations, with a PDUFA date set for March 21, 2024.
• Market Potential: The drug is poised to capture a significant share of the DMD treatment market due to its unique mechanism of action and positive clinical outcomes.
• Safety Profile: While givinostat is generally well-tolerated, it carries risks of hematological changes, gastrointestinal disturbances, and other adverse events that require monitoring.

FAQs

What is givinostat hydrochloride used for?

Givinostat hydrochloride is an investigational drug being developed for the treatment of Duchenne muscular dystrophy (DMD).

What were the key findings of the Phase 3 EPIDYS trial?

The trial met its primary endpoint, showing that givinostat-treated participants had a slower decline in climbing four stairs compared to the placebo group. Secondary endpoints also showed favorable outcomes in muscle function and fat infiltration.

What are the common adverse events associated with givinostat hydrochloride?

Common adverse events include thrombocytopenia, increased blood triglycerides, diarrhea, and abdominal pain.

What is the current regulatory status of givinostat hydrochloride?

Givinostat has received priority review, orphan drug, and rare pediatric disease designations from the FDA, with a PDUFA date set for March 21, 2024.

How does givinostat hydrochloride work?

Givinostat hydrochloride is an HDAC inhibitor that modulates the deregulated activity of HDACs in dystrophic muscle, addressing the cascade of events leading to muscle damage and thereby slowing down muscle deterioration.

Sources

1. Patsnap: Givinostat Hydrochloride - Drug Targets, Indications, Patents.
2. TargetMol: Givinostat hydrochloride.
3. Business Wire: Results from Italfarmaco Pivotal Phase 3 EPIDYS Study of Givinostat in Duchenne Muscular Dystrophy (DMD) Published in The Lancet Neurology.
4. Biospace: Results from Italfarmaco Pivotal Phase 3 EPIDYS Study of Givinostat in Duchenne Muscular Dystrophy (DMD) Published in The Lancet Neurology.
5. FDA: 217865Orig1s000 OTHER REVIEW(S).