Phase II clinical trials with Reldesemtiv (CK-2127107) in Patients with Spinal Muscular Atrophy (SMA II-III)

presented in an oral presentation by John W. Day, MD, Ph.D., Professor of Neurology and Paediatrics (Genetics), Stanford University.

This hypothesis-generating study met its primary goal. It fulfills the effect and safety profile.

In collaboration with Astellas, Cytokinetics is developing reldesemtiv as a potential treatment for people with SMA and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue.

The study showed dose- and concentration-dependent increases in time to muscle fatigue as measured by changes from baseline in Six Minute Walk Distance (6MWD), a sub-maximal exercise test of aerobic capacity and endurance, and Maximal Expiratory Pressure (MEP), a measure of strength of respiratory muscles, after eight weeks of treatment with reldesemtiv.

The study enrolled 70 patients, 39 in Cohort 1 and 31 in Cohort 2. Ambulatory and non-ambulatory (Type II or Type III) patients 12 years of age and older were randomized 2:1, stratified by ambulatory ability, to receive reldesemtiv or placebo dosed twice daily for eight weeks. The first cohort of patients received 150 mg of reldesemtiv or placebo and the second cohort received 450 mg of reldesemtiv or placebo twice daily. Enrollment in this study was stopped short of the targeted 72 patients after blinded analyses of the variability around the changes from baseline of several efficacy measures demonstrated that the study had sufficient statistical power to detect clinically relevant differences versus placebo in efficacy endpoints with the 70 patients already enrolled.

The study, which examined two dose levels of reldesemtiv, 150 mg or 450 mg twice daily, demonstrated dose-dependent increases in 6MWD in ambulatory patients as measured at both post-baseline time points, week four and week eight. In the 150 mg twice daily group, the increase vs. placebo was 10.86 meters (p=0.2531) after four weeks of treatment with reldesemtiv and 7.72 meters (p=0.4684) after eight weeks of treatment. In the 450 mg twice daily group, the increase vs. placebo was 35.63 meters (p= 0.0037) at week four and 24.89 meters (p= 0.0584) at week eight. There was also a statistically significant correlation between Cmax, or peak concentration of reldesemtiv, and change from baseline in 6MWD, with a slope estimate of 9.53 meters/(µg/mL). (p=0.0086).

The study also showed increases vs. placebo in MEP. In the 150 mg twice daily group, the increase in MEP was 5.95 cm H2O (p=0.2276) after four weeks of treatment with reldesemtiv and 11.69 cm H2O (p=0.0378) after eight weeks of treatment. In the 450 mg twice daily group, the increase in MEP compared to placebo was 9.17 cm H2O (p=0.0855) after four weeks of treatment with reldesemtiv and 13.15 cm H2O (p=0.0298) after eight weeks of treatment. Other assessments in the study, including the Hammersmith Functional Motor Score – Extended, Revised Upper Limb Module, Timed Up-and-Go and Forced Vital Capacity did not demonstrate meaningful differences between reldesemtiv versus placebo

Adverse events were similar between groups receiving reldesemtiv and placebo. The most commonly observed adverse effects were headache, constipation and nausea. Four patients had serious adverse events reported that resulted in early termination of study drug treatment, all considered to be unrelated to reldesemtiv.

 

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Mia

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Mamma till tre barn och tvillingarna, en av tvillingarna min äldsta son har SMA Type I-II. Jag arbetar som undersköterska inom akutsjukvården

7 Responses to Phase II clinical trials with Reldesemtiv (CK-2127107) in Patients with Spinal Muscular Atrophy (SMA II-III)

  1. Klinische Studie Phase II mit Reldesemtiv bei Patienten mit spinaler Muskelatrophie (SMA II-III)

    präsentiertmvon John W. Day, MD, Ph.D., Professor für Neurologie und Pädiatrie (Genetik), Stanford University.

    Diese hypothesengenerierende Studie hat ihr primäres Ziel erreicht. Es erfüllt den Effekt und das Sicherheitsprofil.

    In Zusammenarbeit mit Astellas entwickelt Cytokinetics Rleddesemtiv als eine mögliche Behandlung für Menschen mit spinaler Muskelatrophie und möglichen anderen Krankenheiten von Muskelschwäsche

    Die Studie zeigte dosis- und Zunahmen der Stärke der Muskeln bis zur Muskelermüdung. Es konnten eine 6-Minuten-Gehstrecke erreicht werden.
    Stärke der Atemmuskulatur, nach acht Wochen der Behandlung mit Reldesemtiv

    Die Studie umfasste 70 Patienten. Ambulante und nicht-ambulante (Typ II oder Typ III) Patienten im Alter von 12 Jahren und älter

    Zweimal täglich für acht Wochen, erhielt die eine Gruppe ein Placebo.
    Die anderen Patienten mit SMA erhielten 50 mg von Reldesemtiv oder ein Placebo und die zweite erhielt 450 mg von Reldesemtiv oder Placebo zweimal täglich.

    Die Studie zeigte auch Erhöhungen gegenüber Placebo in MEP. In der Gruppe mit zweimal täglich 150 mg betrug der MEP-Anstieg 5,95 cm H2O (p = 0,2276) nach vier Wochen Behandlung mit Reldesemtiv und 11,69 cm H2O (p = 0,0378) nach acht Wochen Behandlung. In der Gruppe mit 450 mg zweimal täglich betrug der Anstieg der MEP im Vergleich zu Placebo 9,17 cm H2O (p = 0,0855) nach vier Wochen Behandlung mit Rledesemtiv und 13,15 cm H2O (p = 0,0298) nach acht Wochen Behandlung. Andere Bewertungen in der Studie, einschließlich der Hammersmith Functional Motor Score – Erweiterte, überarbeitete Obere Gliedmaßen-Modul, zeitgesteuerte Up-and-Go und Forced Vital Capacity zeigten keine sinnvollen Unterschiede zwischen Reldesemtiv versus Placebo

    Unerwünschte Nebenwirkungen waren ähnlich zwischen Gruppen, die Reldesemtiv und Placebo erhielten. Die am häufigsten beobachteten Nebenwirkungen waren Kopfschmerzen, Verstopfung und Übelkeit.

    Bei vier Patienten wurden schwerwiegende unerwünschte Ereignisse berichtet, die zu einer vorzeitigen Beendigung der medikamentösen Behandlung der Studie führten, die alle als nicht mit der Behandlung in Zusammenhang stehen.

  2. Fas II-klinisk undersøgelse af Reldesemtiv for patienter med spinal muskelatrofi (SMA II-III)

    præsenteret af John W. Day, MD, Ph.D., Professor of Neurology and Pediatrics (Genetics), Stanford University.

    Denne hypotesegenererende undersøgelse har opnået sit primære mål. Det opfylder effekt- og sikkerhedsprofilen.

    Cytokinetik udvikler i samarbejde med Astellas Reldesemtiv som en potentiel behandling for personer med spinal muskelatrofi og mulige andre typer muskelsvind

    Undersøgelsen viste dosis og forøgelse af muskelstyrken til muskel træthed. Det kunne opnås en 6-minutters gå. Styrken af ​​respiratoriske muskler efter otte ugers behandling med Reldesemtiv

    Undersøgelsen omfattede 70 patienter. Kliniske og ikke-ambulante (type II eller type III) patienter 12 år og ældre

    To gange om dagen i otte uger modtog en gruppe en placebo.
    De øvrige patienter med SMA modtog 150 mg Reldesemtiv eller placebo, og den anden modtog 450 mg Reldesemtiv eller placebo to gange dagligt.

    Undersøgelsen viste også stigninger over placebo i MEP. I den 150 mg to gange daglige gruppe var stigningen i MEP 5,95 cm H2O (p = 0,2276) efter fire ugers behandling med Reldesemtiv og 11,69 cm H2O (p = 0,0378) efter otte ugers behandling. I 450 mg to gange daglig gruppe var stigningen i MEP sammenlignet med placebo 9,17 cm H2O (p = 0,0855) efter fire ugers behandling med Reldesemtiv og 13,15 cm H2O (p = 0,0298) efter otte Uge behandling. Andre undersøgelser viser → herunder Hammersmith Functional Motor Score – Avanceret, Revideret Upper Limb Module, Timed Up-and-Go og Tvinget Vital Kapacitet, viste ingen meningsfulde forskelle mellem kognitiv via placebo

    Bivirkninger var ens i grupper, der fik Reldesemtiv og placebo. De hyppigst rapporterede bivirkninger var hovedpine, forstoppelse og kvalme.

    Fire patienter rapporterede alvorlige bivirkninger, der førte til for tidlig seponering af undersøgelsen, som alle ikke blev betragtet som relateret til behandling.

  3. Fas II kliniska studien av Reldesemtiv vid patienter med typ II, II IV , spinal muskelatrofi

    kliniska studie av Reldesemtiv för patienter med spinal muskelatrofi (SMA II-III)

    Presenterad av John W. Day, MD, Ph.D., professor i neurologi och pediatrik (genetik), Stanford University.

    Den här hypotesgenererande studien har uppnått sitt primära mål. Det möter effekten- och säkerhetsprofilen.

    Cytokinetik utvecklas i samarbete med Astellas Reldesemtiv som en potentiell behandling för personer med spinal muskelatrofi och möjliga andra typer av neurologiska muskelsjukdomar

    Studien visar dos och ökning av muskelstyrkan till respiratorisk muskel. Det kan gå 6 minuter. Styrkan i respiratoriska muskler efter åtta veckors behandling med Reldesemtiv

    Studien omfattade 70 patienter. Kliniska och icke-ambulerande (typ II eller typ III) patienter 12 år och äldre

    Två gånger om dagen i åtta veckor fick en grupp en placebo.
    Övriga patienter med SMA fick 150 mg Reldesemtiv eller placebo, och den andra fick 450 mg Reldesemtiv eller placebo två gånger dagligen.

    Studien visade också ökningar i placebo hos MEP. I 150 mg två gånger dagligen, ökningen i MEP 5,95 cm H 2 O (p = 0,2276) efter fyra veckors behandling med Reldesemtiv och 11,69 cm H2O (p = 0,0378) efter åtta veckors behandling. I 450 mg bid grupp, ökningen i MEP jämfört med placebo 9,17 cm H 2 O (p = 0,0855) efter fyra veckors behandling med Reldesemtiv och 13,15 cm H2O (p = 0,0298) efter åtta veckors behandling. Andra studier visar → inklusive Hammersmith Funktionell Motor Score – Advanced reviderade Upper Limb Module, Timed Up-and-go och Tvinget vitalkapacitet, visade inga betydelsefulla skillnader mellan kognitiv via placebo

    Biverkningar liknade i grupper som fick Reldesemtiv och placebo. De vanligast rapporterade biverkningarna var huvudvärk, förstoppning och illamående.

    Fyra patienter rapporterade allvarliga biverkningar som ledde till för tidig avbrytande av studien, vilka alla inte ansågs relaterade till behandlingen.

  4. Peter says:

    👍

  5. That’s the next hope, big steps forward. 🙂

  6. Phase 2 Study of Reldesemtiv in Patients with SMA
    Showed Potentially Clinically Meaningful Effects
    on Six Minute Walk Distance and Maximal Expiratory Pressure

    “We made substantial progress in the second quarter of 2018 advancing programs in both our cardiac and skeletal muscle verticals,” said Robert I. Blum, Cytokinetics’ President and Chief Executive Officer. “Following the recent presentation of positive data from our Phase 2 study of reldesemtiv in patients with SMA, we are now working with our partner, Astellas, as well as advocacy partners and clinical advisors, to consider a potential path forward in this indication, and potentially others, as we expect additional results this year. In the past quarter, we also received feedback from FDA regarding the planned second Phase 3 clinical trial of omecamtiv mecarbil in patients with heart failure, under our collaboration with Amgen; we are working toward the objective of initiating this trial before the end of the year. Finally, we continued the preclinical development of several new compounds, independently and within our collaborations, and we expect to move one or more potential drug candidates into Phase 1 clinical studies later this year.”

    Recent Highlights and Upcoming Milestones

    Cardiac Muscle Program

    omecamtiv mecarbil (cardiac myosin activator)

    Continued patient enrollment in GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure), the Phase 3 cardiovascular outcomes clinical trial of omecamtiv mecarbil. Enrollment has surpassed 50 percent completion with over 4,000 patients randomized to date having a risk profile consistent with the trial design. We expect completion of patient enrollment into GALACTIC-HF to occur during the first half of 2019.

    Conducted further interactions with FDA and finalized the protocol for a second Phase 3 clinical trial of omecamtiv mecarbil. This trial is intended to evaluate the potential effect of omecamtiv mecarbil on exercise performance in patients with heart failure and will be conducted by Cytokinetics in collaboration with Amgen. We continue to work toward the objective of beginning this clinical trial by the end of the year.
    Skeletal Muscle Program

    reldesemtiv (next-generation FSTA)

    Announced that data from the Phase 2 clinical study of reldesemtiv in patients with spinal muscular atrophy (SMA) were presented by John W. Day, M.D., Ph.D., Professor of Neurology and Pediatrics (Genetics), Stanford University, at the 2018 Annual Cure SMA Conference in Dallas. The study showed dose- and concentration-dependent increases in time to muscle fatigue as measured by changes from baseline in Six Minute Walk Distance, a sub-maximal exercise test of aerobic capacity and endurance, and Maximal Expiratory Pressure, a measure of strength of respiratory muscles, after eight weeks of treatment with reldesemtiv.

    Continued site activation and patient enrollment in FORTITUDE-ALS (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints – in ALS), the Phase 2 clinical trial of reldesemtiv which is designed to assess the change from baseline in percent predicted slow vital capacity and other measures of skeletal muscle function after 12 weeks of treatment with reldesemtiv in patients with ALS. This trial has enrolled over 250 patients toward the objective of 445 patients in the trial and is being conducted by Cytokinetics in collaboration with Astellas. We expect to complete enrollment in FORTITUDE-ALS in Q4 2018 with results from this clinical trial now expected in the first half of 2019.

    Completed patient enrollment in the Phase 2 clinical trial of reldesemtiv in patients with chronic obstructive pulmonary disease (COPD) which is designed to assess its effect on physical function. This trial is being conducted by Astellas in collaboration with Cytokinetics. We expect results from this clinical trial in Q3 2018.

    Continued patient enrollment in the Phase 1b clinical trial of reldesemtiv in elderly subjects with limited mobility which is designed to assess its effect on measures of physical function. This trial is being conducted by Astellas in collaboration with Cytokinetics. We expect Astellas will conduct an interim analysis of data from this clinical trial in Q3 2018.

    Pre-Clinical Research and Development

    Continued research in collaboration with Astellas directed to the discovery of next-generation skeletal muscle activators; jointly advanced a potential drug candidate into IND-enabling studies.

    Continued pre-clinical development of a next-generation cardiac muscle activator in collaboration with Amgen; we expect to submit an IND in 2018 and plan to initiate Phase 1 studies for this potential drug candidate by year-end or in early 2019.

    Continued IND-enabling studies with an unpartnered cardiac sarcomere directed compound and engaged FDA in preparation for potential advancement to Phase 1 studies expected in Q4 2018.

    Continued independent research activities directed to our other muscle biology research programs.

  7. CK-2127107 – Reldesemtiv in Patients with SMA Typ II -IV
    A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple Dose Study of CK-2127107 in Two Ascending Dose Cohorts of Patients With Spinal Muscular Atrophy (SMA)

    Announced that additional results from the Phase 2 clinical study of reldesemtiv in patients with spinal muscular atrophy (SMA) were presented by John W. Day, M.D., Ph.D., Professor of Neurology and Pediatrics (Genetics), Stanford University at the 2018 Muscle Study Group Scientific Meeting in Oxford, UK, showing sustained increases in 6MWD and MEP four weeks after discontinuation of study drug.