Clinical trials for MND at King’s: an update

Jemeen Sreedharan

van Geest Post Doctoral Fellow in Neurodegeneration Research, KCL

Honorary Consultant Neurologist, KCH

Jemeen.Sreedharan@kcl.ac.uk

Different types of clinical study

• Observational studies – often questionnaire based

• Technology

• Clinical trials – development of disease modifying treatments

Observational studies

Questionnaire based

• Current

• Trajectories of Outcome in Neurological disease (TONiC)

• A Programme for Amyotrophic Lateral Sclerosis in Europe (ALS CArE)

• Upcoming

• June/July 2018 - COMMEND, PROSEC3

Starts June 2018

Introduction Symptoms of excessive thick and/or thin oral secretions in MND population treated in great variety of ways NICE noted a need for a prospective cohort study evaluating therapies for thick and thin secretions in MND patients:

• to understand how specialists are using these treatments • to inform future comparative studies

Sheffield previously studied the acceptability of a new patient-reported outcome measure for saliva problems in MND, the Clinical Saliva Score in MND (CSS-MND)

• demonstrated to be acceptable to patients and had validity and correlated well with patient reported symptom impact

Study Aims

1. Describe how common problems with saliva are in people with MND

2. Describe how saliva problems are currently treated

3. Identify which and how often drugs for saliva problems cause side effects

4. Identify the effectiveness of each treatment for saliva problems

5. Further develop an assessment tool for the severity of saliva problems in

MND patients (the amended CSS-MND)

Hope to recruit 500 patients across the UK in order to achieve these aims.

Methodology

Once study explained to patient and informed consent given, complete the following: 1. Case report form (paper or database) 2. ALSFRS-R (as per normal clinic visit) 3. Clinical Saliva Score (CSS-MND) 4. Modified Likert scale 5. Global change questionnaire 6. Patients in stable state with stable treatment

assigned to the reliability arm

COMMEND Site Training

A feasibility study of Acceptance and Commitment Therapy for people with motor neuron disease (COMMEND)

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Rebecca Gossage-Worrall, The University of Sheffield

Kirsty Weeks, University College London

Central Team

Rationale

• Prevalence rates of 44% for depression and 30% for anxiety have

been observed, with MND being found to be the most frequent

cause of assisted suicide

• Guidance on improving the psychological health of people with

MND is lacking

• COMMEND aims to develop a manualised psychotherapy

intervention, based on Acceptance and Commitment Therapy

(ACT), for those with MND

• Feasibility and acceptability of ACT within this population, within the

NHS, will be investigated during the uncontrolled feasibility study

• A randomised controlled trial (RCT) is scheduled to start July 2019

to evaluate effectiveness and cost effectiveness of ACT.

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ACT

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Acceptance and Commitment Therapy is a form of talking therapy that helps people to learn how to live with difficult or distressing thoughts, feelings or bodily sensations, while still doing things that really matter to them.

Six core clinical processes:

i. acceptance - accepting or opening up to difficult or unpleasant emotional experiences rather than avoiding them;

ii. cognitive defusion - stepping back or detaching from unhelpful thoughts, images and memories as opposed to being fused with them;

iii. contact with the present moment - being in the here and now in contrast to ruminating about the past or worrying about the future;

iv. self-as- context - observing oneself as distinct from the content of one's experiences; v. values - re-engaging with one's personal values and what matters rather than losing

contact with them; and, vi. committed action - committing to doing what matters in contrast to avoidance or

inaction.

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Delivery of ACT

• Therapist delivers up to eight 1-hour 1:1 sessions over three months

• A minimum of four face-to-face sessions should be delivered - within

the MND clinic, GP surgery or participant's home or via

videoconferencing (patient preference and therapist availability)

• Up to four sessions can be delivered via online videos/ DVDs

(followed by therapist support via video-conferencing, instant

messaging, telephone or email).

• Hard copies of video-based sessions will be used for those unable to

operate or access equipment, or where there are compatibility issues

between communication platforms and videos.

Biotelemetry

Clinical trials

• Levosimendan - calcium sensitiser. LEVALS (completed), REFALS (phase 3 upcoming)

• Tirasemtiv - fast skeletal muscle troponin activator

• Interleukin 2 – immune modulator, MIROCALS (phase 2 ongoing)

• Arimoclomol – heat shock protein inducer (upcoming)

• C9orf72 gene therapy – phase 1 (upcoming)

Clinical trials basics: Phases 0-4

• Phase 0 – very small numbers, very small dose

• Phase 1 – still small numbers but slightly bigger than phase 0. Dose escalation, safety, tolerability

• Phase 2 – larger numbers, control group, identification of side effects, possibly randomised

• Phase 3 - large study, comparison with current best treatment

• Phase 4 – study after the drug has been licensed. Longer term follow up of consequences of drug

26.9.2014 Mikko Kuoppamäki/ R&D

Some background info on Levosimendan

• Levosimendan i.v. has been on the market in >50 countries (not in US) for over 10 years • Indicated for a short-term treatment (24 h) of acutely decompensated severe heart failure

• Clinical i.v. program has included about 3400 patients with almost 2000

patients receiving Levosimendan • About 380 patients (heart failure and stroke/TIA) and 260 healthy subjects

have received oral levosimendan (no MAs for oral formulation) • Largest study (n=307) with oral formulation has been PERSIST in heart

patients. Daily Levosimendan doses were 1 and 2 mg, dosing up to 180 days.

Primary Objective

• To investigate the efficacy of oral levosimendan on respiratory function in patients with ALS

Secondary objectives

• To evaluate the efficacy of oral levosimendan on hand grip strength and endurance, patients’ QoL and daily functions

• To collect preliminary data on tolerability and safety of levosimendan in this patient population

• To determine PK of levosimendan and its metabolites

• To evaluate the effects of levosimendan on plasma trough concentrations of riluzole

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Presenter / Department

Objectives of LEVALS

End-of-study visit 2

Levosimendan

1 mg

Levosimendan 2 mg 1

(1 mg b.i.d.)Screening

visitLevosimendan

2 mg

Placebo

Levosimendan

2 mg

Levosimendan

1 mg

Placebo Levosimendan

1 mg

Levosimendan

2 mg

Placebo

- 2 0 1 2Week 5 6 7 10 11 12 16 20 24 28

Double-blind part Open-label part

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Screening4-14 d

TC = telephone contact

1 1 mg in the morning for first 2 weeks

2 14-25 d after last study treatment intake

3 ± 2 days

4 ± 4 days

Period 1 14 d

Post-treatment period 14-25 d

V1

Wash-out19-23 d

Follow-up extension6 months

Wash-out19-23 d

Period 3 14 d

Period 2 14 d

V2 3 V3 3 V4 3 V5 3 V6 3 V7 3 V8 3 V9 3 V10 4 V11 4 V12 4TC 3

LEVALS design: Double-blind, Cross-Over + Open-Label follow-up

1. Database lock 2. Database lock

• Much appreciated by the experts

• Likely to help recruitment

• Possibility to collect long-term data (uncontrolled)

Compassionate use → Open-label follow-up for 6 months in the protocol

24 36 40

LEVALS Phase 2 outcome

• Statistically significant results which showed improvement in supine svc

• Sitting svc results not positive.

• Proceeding with Phase 3 next few months in Europe (already been opened in USA).

• This new study will have more patients and 100 sites!

• Cytokinetics results negative (completed open label phase) .

• New compound already being tested in USA and some European countries.

MIROCALS Phase 2

MIROCALS

Efficacy and safety of low‐dose IL‐2 (ld‐IL‐2) as a Treg enhancer for controlling neuro‐inflammation in newly diagnosed Amyotrophic Lateral Sclerosis (ALS)

patients: A randomised, double‐blind, placebo‐ controlled, phase‐II Proof of Concept/

Proof of Mechanism Clinical Trial

Remarkable features of MIROCALS Focus on biomarkers alongside clinical evaluation

3 lumbar punctures at different timepoints IL-2 subcut injection – a treatment used for other conditions that could potentially be

repurposed for MND While Cytokinetics and Levosimendan trials focus on lower motor neuron system,

MIROCALS may have more widespread effects

Experimental treatment overview

• Interleukin-2 • Recombinant human protein • Marketed and indicated for metastatic kidney cancer – (Proleukin – Novartis Pharma) • Used at high doses (18 to 30 million IU/m²/day) in cancer • Therapeutic objective: boosting effector T cells (Teff) anti-cancer activity • However: Cytokine essential for the survival and activation of Tregs

New strategy with low dose IL-2 (0.2 to 3 MIU/day) • Objective: specifically boosting regulatory T cells (Treg) suppressive effect on Teff

• Anticipated Benefits in ALS

• Decrease in neuro-inflammatory induced motor neuron damage • Reduction in the rate of decline in motor function • Prolongation of survival

• Risks • Much milder than high doses (see next slide) • Acceptable in ALS patients (IMODALS study)

MIROCALS – Adverse Events – Ld-IL2 From Data Published (10 studies – 195 patients) and

unpublished (IMODALS)

MOST COMMON:

Injection site reactions: 53%

Flu-like symptoms (myalgia, arthralgia, fever, chills): 25%

Fatigue: 14%

Gastro-intestinal symptoms (nausea, vomiting, anorexia, diarhhoea): 12%

Headache: 7%

LESS THAN 5% (1-2 cases):

Infection, dyspnoea, hypertension, allergic rhinitis, nasal congestion, asthma flare, skin reaction, irritability, dizziness, cold sweat

Thrombocytopenia, creatinine increase, TSH increase, Hyperglycaemia, CRP increase

MIROCALS Clinical case

• Male patient in 60s

• Limb onset ALS <2y

• Mobile with stick

• Not on NIV

• Not on Riluzole

• Suitable for MIROCALS

MIROCALS Clinical case

• 1st visit “inclusion”. History, obs, full examination, sVC, bloods, LP and CSF, CXR, ECG

• 2nd visit “randomisation”. Bloods, LP and CSF.

• 3rd visit – declined. Aware that has continued to deteriorate, thinks has been given the placebo

MIROCALS: progress so far

• Managed to recruit 10 patients at KCH

• Work in progress – criteria being modified as problems arise

• Plan to extend study til end of year?

• Bloods, DNA, CSF will all be invaluable resource in post-hoc analyses

C9orf72

ASO trials on the horizon

SOD1 in MND

Huntingtin in HD

Tau in Alzheimer’s

Currently Active ASO trials in UK

Antisense drug delivery through a lumbar puncture

ASO drugs licensed in UK

SpinrazaTM in SMA (Nusinersin)

Gene therapies with ASO : “Shoot the messenger”

TDP-43WT +/+ ATXN2 -/- TDP-43WT +/+

Antisense to ATXN2

WT TDP-43 overexpressing mice survive no more than 30 days A remarkable increase in survival was observed by reducing ATXN2 in a model of sporadic MND

Conclusions/personal opinion

• MND trials team busier than ever

• Some genuinely interesting drugs/gene therapies in the pipeline

• Need to consider every patient for trials

• Need more staffing for trials unit