Date: 2015-08-17
Type of information: Results
phase: 1b
Announcement: results
Company: Summit Therapeutics (UK)
Product: SMT C1100
Action
mechanism: utrophin modulator. SMT C1100 is a proprietary, orally available small molecule with a novel mechanism of action for DMD. SMT C1100 acts to modify the progression of DMD by replacing dystrophin with an endogenous, functionally similar protein called utrophin. SMT C1100 is designed to upregulate and maintain the production of utrophin. Utrophin is a protein that is highly expressed in regenerating muscle, but decreases as the muscle fibre matures and is eventually replaced by dystrophin, a protein that maintains the integrity and healthy function of muscles. Patients with DMD are unable to make dystrophin, resulting in muscle fibre degeneration. However, if utrophin is continually expressed in the mature muscle fibre, it can replace the function of dystrophin and thereby overcome the deficit in patients with DMD.
This approach is expected to be a universal treatment for all DMD patients regardless of whether the disease was caused by an inherited or spontaneous genetic mutation. Summit has demonstrated in nonclinical efficacy studies that SMT C1100 is capable of increasing utrophin to restore and maintain the healthy function of muscles.
Disease: Duchenne muscular dystrophy (DMD)
Therapeutic area: Genetic diseases - Neuromuscular diseases - Rare diseases
Country: UK
Trial
details: The Phase 1b trial is a dose-escalating, open-label study and will be conducted in a total of 12 paediatric patients with DMD, aged between 5 and 11 years. It will evaluate the safety and tolerability of SMT C1100, and will measure blood concentration levels of the drug as Summit aims to confirm the dose to be used in a subsequent patient proof of concept efficacy trial. The Phase 1b trial will be conducted at up to four NHS hospitals located in the UK. The Chief Investigator for the trial is Professor Francesco Muntoni, Paediatric Neurologist at Great Ormond Street Hospital and Director of the Dubowitz Neuromuscular Centre. The Phase 1b modified diet trial is a placebo-controlled study that will enrol a total of 12 patients with DMD between the ages of 5 and 13. The patients will be divided into three cohorts of four patients each, and the trial will include three randomized 14-day treatment periods during which each patient will receive two different doses of SMT C1100 and placebo. There will be a 14-day wash-out period between each of the three treatment periods.The trial aims to demonstrate an increase in plasma levels of SMT C1100 compared to those observed in the open label Phase 1b trial that was completed earlier in 2014 with patients to follow specific dietary guidance that recommends balanced proportions of fat, protein and carbohydrates. The trial will also evaluate any changes in enzyme markers that are related to muscle health, and further evaluate the safety and tolerability of SMT C1100. The Phase 1b modified diet trial will be conducted at four NHS hospitals located in the UK.
Latest
news: * On August 17, 2015, Summit Therapeutics, a drug discovery and development company advancing therapies for Duchenne muscular dystrophy and C. difficile infection, announced that its Phase 1b modified diet clinical trial of SMT C1100 for the treatment of DMD met its primary objective with half of the patients who received the higher dose of SMT C1100 achieving desired plasma levels while following specific dietary guidance. Based on these results, Summit will advance SMT C1100 into a Phase 2 open label clinical trial. The Phase 1b clinical trial was designed to increase plasma levels of SMT C1100 in patients by recommending a diet with balanced proportions of fat, proteins and carbohydrates, combined with consuming a small glass of full fat, whole milk at the time of dosing. Initial analysis shows six of 12 patients achieved the desired plasma level after receiving a 2,500 mg dose of SMT C1100 twice daily for 14 days. Full data from this trial are expected to be presented at an upcoming medical meeting. In a prior Phase 1b trial, only two of 12 patients dosed with SMT C1100 achieved the desired plasma level. SMT C1100 was well tolerated at all doses tested in the modified diet trial with no serious adverse events reported. This outcome increases the human safety database for this investigational drug. The trial also measured enzyme biomarkers of muscle damage, such as creatine kinase. In this modified diet study there was no change in the enzyme levels when patients received SMT C1100 compared to when they received a placebo. The Company plans to evaluate creatine kinase as well as additional biomarkers over a longer duration of exposure to SMT C1100 in the upcoming Phase 2 open-label trial. Summit plans to commence the Phase 2 open-label trial during the fourth quarter of 2015. The trial will evaluate the longer-term benefits of SMT C1100 on muscle health, function and safety. Further details of the trial will be provided at a future date. * On February 20, 2015, Summit Therapeutics announced that the first patients with DMD have been enrolled and dosed in a Phase 1b modified diet clinical trial of the orally administered, small molecule utrophin modulator SMT C1100. The company now looks forward to reporting data from this study in Q3 2015. The trial is being conducted in the UK and is enrolling a total of 12 patients aged between 5 and 13 years, divided equally into three dose cohorts. The trial will include three randomised 14-day treatment periods during which each patient will receive two different doses of SMT C1100 and a placebo control. There will be a 14-day wash-out period between each of the three treatment periods. * On December 11, 2014, Summit announced that it has received approval from the UK Medicines and Healthcare products Regulatory Agency and the Ethics Review Committee to initiate a Phase 1b modified diet trial of SMT C1100. This new trial aims to increase the plasma levels of SMT C1100 by providing patients with specific dietary guidance intended to improve drug absorption. The trial will also evaluate the potential impact that SMT C1100 is having on enzyme markers of muscle health. Top-line data from the Phase 1b modified diet trial are expected to be reported in mid-2015. If this trial is successful, it will be followed by a Phase 2 open label trial that will seek to generate longer-term efficacy and safety data on SMT C1100. It is expected that patients participating in the Phase 1b modified diet trial will be eligible to join the Phase 2 open label trial. * On October 8, 2014, Summit reported clinical data on SMT C1100, highlighting its safety profile and further detailing the observed reduction in enzymes associated with muscle damage in a Phase 1b study in boys with DMD. In addition, Summit is unveiling new positive preclinical data on its second generation utrophin modulator programme for the treatment of DMD. The data on the second generation programme comprise results from in vivo and in vitro studies that highlight the promising profile of two lead candidates as potential disease modifying treatments: Significant improvement in systemic exposure in vivo compared to first generation utrophin modulator SMT C1100 with blood plasma levels 10-40 times higher following oral dosing; Modulation of utrophin expression in vivo with an increase in protein levels observed in skeletal muscle, diaphragm and heart compared to the control; Significant improvement in disease pathology with reduction in muscle fibre fibrosis ('scarring') and membrane damage; Improvement in muscle health indicated by a significant reduction in the number of regenerating muscle fibres; Protection of muscle function with the increased utrophin protein levels resulting in significant improvement in muscle membrane stability and resistance to damage. These studies were conducted as part of the UtroDMD Alliance, a collaboration to develop utrophin modulator drugs for the treatment of DMD. Overview of WMS Presentations: Utrophin modulators to treat Duchenne Muscular Dystrophy (DMD): Phase 1b clinical trial results of SMT C1100. Francesco Muntoni, Stefan Spinty, Helen Roper, Imelda Hughes, Valeria Ricotti, Alison Bracchi, Bina Tejura, David Roblin, Kay Davies, Jon Tinsley A review of the Phase 1b clinical trial results that showed SMT C1100 was safe and well tolerated at all doses tested and a reduction observed in plasma levels of three enzymes associated with muscle damage; these reductions were statistically significant. Inter-patient variability in the blood plasma levels of SMT C1100 were also observed and will be explored in future patient clinical studies. New orally available compounds which modulate utrophin expression for the therapy of Duchenne Muscular Dystrophy (DMD). Simon Guiraud, Sarah E. Squire, Ben Edward, Nandini Shah, David T. Burns, Huijia Chen, Graham M. Wynne, Angela J. Russell, David J. Elsey, Francis X. Wilson, Jon Tinsley, Kay E. Davies Positive preclinical data on second generation utrophin modulators reporting their enhanced bioavailability compared to SMT C1100 and their ability to increase expression of utrophin, improve the disease pathology, reduce muscle regeneration and protect muscle function. Development of a multifaceted biomarker strategy to support clinical development of utrophin modulators for Duchenne Muscular Dystrophy (DMD) therapy. Jonathon Tinsley, Francis X. Wilson, Narinder Janghra, Jennifer Morgan, Caroline Sewry, Francesco Muntoni, Kay E. Davies Feasibility data on the quantification of utrophin protein in muscle biopsies and data on a biomarker measuring the level of muscle fibre regeneration are reported. These two projects have been supported by Joining Jack and form part of Summit's wider programme developing exploratory biomarkers for use in future patient clinical trials. * On July 7, 2014, Summit reported new data from its recently completed Phase 1b clinical trial of the utrophin modulator SMT C1100 for the treatment of DMD. These data are being reported at the 13th International Congress on Neuromuscular Diseases ('ICNMD') being held between 5-10 July in Nice, France. The results of this study showed a statistically significant decrease in key enzymes associated with muscle damage and support the proposed mechanism of action of SMT C1100. The new data reports the impact of dosing with SMT C1100 on blood levels of the enzymes creatine kinase ('CK'), aspartate aminotransferase ('AST') and alanine aminotransferase ('ALT'). The levels of these enzymes are normally very low in healthy people but in patients with DMD, muscle cells are weakened by the lack of dystrophin causing these enzymes to leak out and accumulate in the blood. During dosing with SMT C1100, a statistically significant reduction in CK, AST and ALT levels was observed when compared to pre-dose baseline levels. Blood levels of these enzymes increased towards pre-dosing levels after dosing stopped. These data are consistent with the proposed mechanism of action of the utrophin modulator SMT C1100, whereby its effect would result in lower muscle damage and lead to lower levels of these key markers in the blood. The data from this Phase 1 study are encouraging and clearly support further evaluation in a placebo-controlled study. * On May 21, 2014, Summit announced that SMT C1100 for the treatment of DMD has successfully met its primary endpoint of safety and tolerability in a Phase 1b clinical trial in patients with the disease. The Phase 1b dose-escalating trial was conducted in 12 patients with DMD aged between 5 and 11 years old. These preliminary results show that SMT C1100 was safe and well tolerated at all doses tested in the study, and that there were no issues with patient compliance. All the boys had variable blood plasma concentrations of SMT C1100 with only two of the boys achieving concentrations similar to those of the adult volunteers in the 2012 Phase 1 study. Initial evidence suggests that the variability in drug uptake may be due to differences in diet and to other disease-related factors. The non-placebo controlled trial also measured creatine kinase ('CK') levels, an enzyme that is associated with muscle fibre damage and elevated in boys with DMD. In the majority of patients there was a reduction in CK levels during dosing with SMT C1100. These data are consistent with non-clinical in vivo efficacy studies in the mdx model of DMD that showed SMT C1100 reduced CK levels after only 15 days. These preliminary trial data will be reviewed further by Summit and is expected to lead to a revision of future clinical trial plans in order to determine the optimal way, either through dietary means or drug formulation changes, to address the drug uptake differences between DMD patients and healthy volunteers. The next patient study is now expected to start in Q4 2014. * On December 9, 2013, Summit announced that the first DMD patient has been enrolled and dosed in a Phase 1b clinical trial of the oral, small molecule utrophin modulator SMT C1100. * On November 1, 2013, Summit has announced that its Phase 1b Clinical Trial Application for SMT C1100 has received approval from the UK Medicines and Healthcare products Regulatory Agency (‘MHRA’) and the Ethics Review Committee. * On March 21, 2013, Summit has outlined its future plans for the continued development of utrophin modulators for the treatment of DMD. The company has announced that its lead candidate SMT C1100 is expected to enter clinical trials in patients during H2 2013, and earlier-stage next generation utrophin modulators are being developed to add further value to the programme. The proposed proof of concept patient trial will include two components: a dose-finding study in DMD patients to confirm translation of safety, tolerability and pharmacokinetics from an adult to a paediatric population, followed by a Phase 2 trial that will include clinical markers of muscle health as well as levels of utrophin expression and other novel biomarkers. The biomarker programme has commenced and includes the collaboration with Children’s National Medical Center of Washington DC, funded by the DMD organisation, The Foundation to Eradicate Duchenne, which was announced by Summit in February 2013. Summit is now engaged with the regulatory authorities and expects the dose finding study to start in H2 2013. In preparation for the clinical studies, drug material manufacture and long-term regulatory toxicology studies will be commissioned. Summit has selected a specialist contractor capable of manufacturing and formulating GMP grade drug material for use in the long-term toxicology studies, the patient proof of concept trials, and ultimately any potential future registration trials and market use. * On November 7, 2012, Summit has announced that the repeat dosing of the utrophin upregulator SMT C1100 for the treatment of Duchenne Muscular Dystrophy (DMD) has successfully met the endpoints as part of a Phase 1 clinical trial in healthy volunteers. The trial evaluated a new formulation of SMT C1100 and the results showed that upon repeat dosing, concentrations of the drug achieved in the blood plasma, stabilised at levels that from preclinical studies are expected to significantly increase utrophin protein production. The previously reported results from the single ascending dose cohort showed SMT C1100 to be safe and well-tolerated at all doses. These new data are being reported from the repeat dosing cohort where the volunteers received 100mg/kg twice daily for nine days. These results show that in all volunteers the blood plasma concentration of SMT C1100 stabilised after four days of dosing above the required level expected to increase utrophin protein production by 50% for at least 14 hours a day in a preclinical model. The plasma levels achieved were equivalent to those that gave significant therapeutic benefit in the gold standard disease model of DMD. These data strongly support the progression of SMT C1100 into the next stages of development that includes biomarker and long-term safety studies, which will be required before a DMD patient efficacy trial could commence. The latest results will be presented at the 2012 Action Duchenne Conference, 9-10 November, London UK. * On October 10, 2012, Summit has announced positive top-line results from a Phase 1 clinical trial of SMT C1100 for the treatment of Duchenne Muscular Dystrophy . These data will be presented at the 17th Annual Congress of the World Muscle Society, 9-13 October 2012, Perth Australia. The Phase 1 dose-escalating trial was conducted in healthy volunteers and evaluated a new aqueous formulation of SMT C1100. The trial met its primary endpoints with results showing the formulation to be safe and well tolerated at all doses. Importantly, the new formulation also demonstrated improved levels of bioavailability (absorption) of the drug that were above those anticipated to be needed to achieve clinical efficacy. These results are strongly supportive for the progression of SMT C1100 into patient clinical trials. Analysis of the multiple ascending dose groups remains on-going and results are expected to be reported later this year. * On June 12, 2012, Summit has announced it has successfully passed a milestone in the Phase 1 trial of SMT C1100 for the treatment of the Duchenne Muscular Dystrophy, which triggered the final payment from a $1.5 million funding agreement with US-based DMD organisations. The Phase 1 dose-escalation study in healthy volunteers was initiated in May 2012 and will now progress to the stage where participants receive multiple doses. Results from the trial are expected by the end of this year. * On February 14, 2012, Summit has outlined its clinical trial plans for SMT C1100, a potential first-in-class disease modifying drug for the treatment of Duchenne Muscular Dystrophy (‘DMD’). SMT C1100 has been extensively evaluated in non-clinical efficacy and safety studies and has demonstrated its ability to restore and maintain the function of muscles. A Phase I clinical trial in healthy volunteers will now be conducted by Summit. The trial will evaluate if the new formulation of SMT C1100 can provide consistent levels of the drug in the blood that non-clinical efficacy studies predicted would be required to confer therapeutic benefit in DMD patients, while also further assessing its safety. The new formulation will be appropriate for use by all DMD patients. The manufacture and formulation of SMT C1100 is currently on-track and Summit expects to submit a clinical trial application (‘CTA’) to the Medicines and Healthcare products Regulatory Agency (‘MHRA’) in Q1 2012. If CTA approval is granted, the Phase I trial would commence with headline results from this study anticipated in Q3 2012. A successful outcome from the Phase I trial could lead to a Phase II study in DMD patients starting in H1 2013. The Phase I clinical trial is completely funded by the $1.5 million agreement signed in December 2011 between Summit and the Muscular Dystrophy Association, Parent Project Muscular Dystrophy, Charley’s Fund, Cure Duchenne, the Foundation to Eradicate Duchenne and the Nash Avery Foundation. * On March 14, 2011, Summit has announced positive non-clinical efficacy results for SMT C1100, an orally available drug that has the potential to be a disease modifying treatment for the fatal disorder Duchenne muscular dystrophy (DMD). New results from studies evaluating the effect of SMT C1100 on dystrophin deficient muscle cells taken from DMD patients have been positive. Dosing of these human myoblast cells with only low concentrations of SMT C1100 resulted in increased utrophin protein levels, which if translated into DMD patients, are anticipated to be of significant therapeutic benefit. These new data showed that SMT C1100: • Increases the amount of utrophin and reduces muscle degeneration, fibrosis and chronic inflammation. • Significantly improves resistance to muscle fatigue in a forced exercise model. This is a surrogate for the six minute distance walk test which is the accepted primary efficacy end-point in human clinical trials. The studies were conducted at Oxford University by Professor Dame Kay Davies FRS, a world-leading expert who pioneered utrophin upregulation as a therapeutic approach for DMD. These results in DMD muscle cells incidate that SMT C1100 could increase utrophin to levels, which if replicated in DMD patients, would make it a disease modifying therapy. In a healthy volunteer clinical trial, SMT C1100 was shown to be safe and well tolerated with no adverse events reported. In addition, blood plasma levels of SMT C1100 did exceed levels that are anticipated to produce a therapeutic effect in some individuals, although there was variability in the results with lower exposure levels reported for others. Summit believe alternative formulations of SMT C1100 can produce consistently higher results and is seeking to evaluate these in future clinical studies
