AAV8-mediated exon skipping gene therapy in subjects with mutations amenable to exon skipping in the Duchenne muscular dystrophy (DMD) gene

Advice was sought on the design of a planned open-label, first-in-human, phase I/II clinical trial and associated pre-clinical studies. The committee gave input and advice on the pre-clinical programme including on animal studies, use of SOPs, early regulatory engagement and go/no-go criteria. 

After discussion about clinical aspects, advice was given by the committee including regarding patient-burden, dose-selection, safety and outcome measure selection.

Name of applicant: Alexandra Bowden

Phase 2 Study to Evaluate Single and Multiple-Doses of AOC 1001 Administered Intravenously to Adult Myotonic Dystrophy Type 1 (DM1) Patients

TACT recognised that the applicant’s collaborators and co-investigators have a global presence and are highly experienced in clinical trials for NMDs. The applicant has developed a new antibody oligonucleotide conjugate aimed at the treatment of myotonic dystrophy type 1 (DM1). At the time of the review, pre-clinical studies were underway, and the applicant expected to initiate a combined Phase I/II clinical study. TACT made comprehensive recommendations that included responses to the applicant’s questions on: study population, the choice of exploratory endpoints, protocol feasibility and the patient perspective.

Name of applicant: Elizabeth Ackerman

GSK3439171 for DMD – Non-clinical and Phase 2 Clinical Development Planning

The applicant is a well-established large pharmaceutical company with a long history of successfully bringing novel therapeutics to the global market. If successful, the development of GSK3439171 will be therapeutic in DMD by inhibiting the synthesis of PGD2, which is believed to play a role in inflammation-driven muscle necrosis. The panel felt that this was a clearly presented rationale for clinical study. From the patient perspective, this was seen as an interesting trial that looks to help preserve muscle function rather than replace dystrophin. TACT made recommendations in response to the applicant’s questions: on pre-clinical aspects including regarding additional animal studies, use of SOPs and independent validation of results. Clinical suggestions, included those on clinical trial design (e.g. selection of outcome measures and inclusion/exclusion criteria).

Name of applicant: Victoria Ballard

Application of novel ClC-1 modulators to neuromuscular disease

This application focuses on developing a small molecule inhibitor of the skeletal muscle specific ClC-1 chloride ion channel to treat weakness and fatigue in clinical conditions in which neuromuscular transmission is impaired. Advice was sought for a proposed Phase 1 study to examine the safety, tolerability and pharmacokinetics of the lead compound in healthy male and female subjects.

The panel gave advice on all aspects in the application including on selection of animal models and additional pre-clinical studies, risk-benefit considerations, cohort selection, outcome measures and trial design.

Name of applicant: John Hutchinson

Dynacure came to TACT with their Unite-CNM Phase 1/2 study of our investigational therapy, DYN101. TACT discussed the interesting application and was also able to point the applicant towards relevant experts such as biostatisticians, hepatologists and physiotherapists to assist in the study design.

Phase 3 clinical development considerations for SRP-5051 in patients with Duchenne muscular dystrophy

Sarepta’s application for advice sought to gain input on the development of a new candidate therapeutic, SRP-5051, a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), for exon 51 skipping in eligible patients with Duchenne muscular dystrophy. SRP-5051 has demonstrated increased delivery in cell culture and animals, and improved exon skipping and dystrophin production in cardiac and skeletal muscle. Preclinical studies in animal models show target engagement, efficacy, and tolerability.   TACT welcomed the opportunity to review this application and stressed the importance to also refer back to advice given in 2018. Suggestions were given by the panel for additional pre-clinical studies, learnings from Phase 1 and 2 and for the design of Phase 3.

Name of applicant: Jon Tinsley

Vertex proposed a novel CRISPR/Cas9 based therapy designed for patients with DMD who have mutations amenable to exon 51 skipping. The committee felt that this application represents a novel and exciting technology with substantial potential benefit for DMD and broad implications to the entire neuromuscular field, supported by promising pre-clinical data in the DMD mouse and dog models. TACT provided recommendations and advice on follow-up work for pre-clinical experiments. Advice was also included on the planned clinical trial including powering, dosing, inclusion/exclusion criteria and regulatory assurance for the proposed study. This was a well-constructed application for TACT advice that resulted in fruitful discussion. The committee appreciated the opportunity to consider this application.

Name of applicant: Alison McVie Wylie

Clinical trial design of anti-myostatin for neuromuscular disorders

Roche requested advice on clinical trial design focusing an anti-myostatin agent, which is considered as future potential treatment for neuromuscular disorders.
TACT offered comprehensive advice on the proposal, including discussion of functional benefit linked to muscle mass increase and variation threshold feasible to be assessed in MRI, validation of animal studies, stratification of patient cohorts based on plasma myostatin level, outcome measure selection, trial design and regulatory considerations.
TACT welcomed the opportunity to give advice on this potentially interesting and novel approach for various neuromuscular disorders, independently of the underlying genetic defect.

Name of applicant: Ksenija Gorni

MYODA clinical program in Duchenne muscular dystrophy innovative trial adaptive seamless design and composite score

Biophytis proposed a small, orally bioavailable compound (BIO101) to treat Duchenne muscular dystrophy (DMD) and improve muscle function, mobility, and respiratory function. Three phases to the phase 1/3 study are planned:

• Part 1- multiple ascending dose (MAD) safety, tolerability and PK study
• Part 2- proof of concept (POC) study
• Part 3- confirmatory study to investigate efficacy and safety/tolerability.

TACT provided feedback and advice on all areas of the application including on biomarker studies, pre-clinical data, dosing and trial design. In addition, the applicant’s specific questions were addressed. This were around scales to be used, meeting the concerns of patients, patient selection and any additional needs in the pre-clinical plan for a clinical program.

Name of applicant: Mounia Chabane

Santhera is developing omigapil, an investigational medicinal product with anti-apoptotic properties, as a potential therapy for two forms of congenital muscular dystrophy (CMD) based on both in vitro and in vivo pre-clinical data.

The Phase 1 clinical study (CALLISTO, NCT01805024) in patients with CMD has been completed. In response to the application, TACT gave an evaluation of a proposed clinical trial to investigate the efficacy of omigapil in patients with CMD, answered several specific questions about trial design and made recommendations about the need for further pre-clinical studies and suitable biomarkers to be used in a future study.

Name of applicant: Irinel Coserea

The research group led by Dr Aránega proposed a novel approach – the use of miR-106b inhibitors as a potential therapy to increase the regenerative capacity of the dystrophic satellite cells in Duchenne muscular dystrophy (DMD). If successful, this treatment would not be dependent on the type of mutation in DMD and could potentially be used for other muscle wasting conditions.

However, this was a very early application and the panel felt that a suitable lead compound needed to be identified before advice could be given on the development of a clinical trial. The panel posed questions at a pre-clinical level with recommendations that experiments use the standard operating procedures available from the TREAT-NMD website. The advice also recommended further pre-clinical work including the replication of data in an independent lab with a robust power analysis informing the optimal number of animals that should be used.

Name of applicant: Amelia Aranega

Fulcrum is developing small molecules that modulate targets responsible for regulating gene expression. Fulcrum plans to submit regulatory filings in early 2019 for lead compound FTX-1821 to treat facioscapulohumeral muscular dystrophy (FSHD), a disease caused by dysregulated expression of double homeobox 4 (DUX4). Unpublished in vitro data show FTX-1821 inhibits DUX4 expression, prevents cell death and restores function in muscle cells from FSHD patients. TACT reviewed Fulcrum’s proposal for its lead program to treat FSHD with FTX-1821 via the reduction of DUX4. The committee felt that this was a well thought out plan with a number of de-risking activities already in place or underway to evaluate and standardize drug development tools and assessments prior to initiating the clinical trials. The committee made a number of recommendations regarding the interpretation of the preclinical data, design of the proof of concept clinical trial and considerations for go/no-go decisions prior to and after the proof of concept clinical trial.

Name of applicant: Diego Cadavid

This is a proposal from Dr Vallejo and colleagues to slow down the progression of Duchenne muscular dystrophy (DMD) with new chemical entities, known as Ahulken compounds (AHK). This proposal is based on successful pilot studies that indicate these compounds regulate calcium in vitro in dystrophin-deficient human myotubes. In vivo pilot studies have also shown improvements in muscle function in mice.

The committee welcomed the opportunity to review this application at an early stage of development and recognises that this is a possible way to reduce disease progression. TACT suggests more preclinical studies to confirm the compound’s safety and superiority. The report makes further recommendations on performing independent validation of mdx studies in collaboration with experts in the DMD field.

Name of applicant: Ainara Vallejo

Duchenne muscular dystrophy: Investigating corticosteroid adverse effects (DEDICAtE) study

This is a proposal from Dr Hawcutt and colleagues to carry out a study to investigate which side/adverse effects of corticosteroids should be prioritised for investigation. Strengths of the proposal include the fact there is little information currently on some adverse effects such as adrenal suppression (AS) or an understanding of cortisol levels in the Duchenne muscular dystrophy (DMD) population. The committee felt that it was important to establish whether the study would have impact on the management of AS in patients.

The TACT review makes several recommendations including a pilot study and to approach other DMD expert groups working on the impact of steroids to share data.

Name of applicant: Dr Hawcutt

This is a proposal from Audentes Therapeutics to treat Pompe disease using gene therapy. The proposal aims to evaluate safety, preliminary efficacy, and dose selection in patients with infantile and late onset Pompe disease (IOPD and LOPD). The proposal is based on promising preclinical results which have shown improved muscle pathology and proof of concept.

The committee felt this was a well-planned clinical trial proposal, and made recommendations including those regarding further pre-clinical studies, safety considerations, control groups and end-point selection. Inclusion of patients in the study design was also supported strongly.

Name of applicant: Sal Rico

This is a proposal from Dr. Peter Arthur and colleagues at the University of Western Australia to develop Taurine as a potential therapy for the treatment of Duchenne and Becker muscular dystrophy. The proposal seeks to establish blood and urine biomarkers that respond to Taurine treatment and use these biomarkers in a dose-escalation clinical study to identify an optimal taurine dose. The primary goal is to demonstrate improvements in muscle function and echocardiography in a cohort of boys with DMD in a longer-term clinical trial.

TACT welcomed the opportunity to review the proposal at this stage where discussion impacts not only the design of the clinical study, but also considered the potential for additional studies to aid biomarker selection. The committee felt that the program demonstrated a plausible basis for expecting a beneficial effect in DMD patients and generally supported the further investigation of taurine in the clinic. The report makes recommendations on further pre-clinical studies that include an examination of potential biomarker candidates in animal models as part of the biomarker selection process. TACT also makes recommendations on the consideration of the wide availability of Taurine and its presence in the background diet, manufacturing controls, IP protection and regulatory advice.

Name of applicant: Peter Arthur

Mesoangioblast-mediated exon skipping for genetic correction of exon 51 mutation

This is a proposal from Professor Giulio Cossu and colleagues at Manchester University to develop mesoangioblast-mediated exon skipping for genetic correction of exon 51 mutation as a therapy for Duchenne muscular dystrophy. The proposal aims to use mesangioblasts (MABs) treated ex vivo with a virally-mediated strategy to exclude exon 51 into the final DMD transcript. The study will focus on safety and measuring functional improvement in patients’ thumb muscles.

The committee valued the previous experience of the investigator and the accomplished team associated with this proposal. They also welcomed the wealth of data from a previous clinical trial.

The report makes recommendations and suggestions on the development of important additional pre-clinical data, and for the clinical trial, the benefit of accompanying vascular imaging, precision in dystrophin quantification by multiple analytic methods, and on the use of double-blinded analysis of muscles injected with cells or only physiological solution.

MTB-1, a selective modulator of PPARdelta(δ), for the treatment of Duchenne muscular dystrophy

Mitobridge Inc. proposes the study of a new drug candidate, MTB-1, in a human clinical trial for the treatment of Duchenne muscular dystrophy (DMD). MTB-1 is a novel, potent and selective gene regulator that increases mitochondrial respiration and biogenesis. It is suggested that MTB-1 will activate multiple pathways linked to muscle health, which will lead to improved muscle endurance capacity.
This proposal builds on various studies (Scholte and Busch, J Neurol Sci., 1980; Rybalka et al, PlosOne, 2014; Chen et al, JCB, 2000 and Baron et al, PlosOne, 2011, among others), which have demonstrated mitochondrial dysfunction in DMD patient tissues and cultured muscle cells as well as animal models, suggesting there are fundamental, intrinsic problems with mitochondria in dystrophic muscles. Thus, the mitochondria in DMD boys would be a good target for therapy with MTB-1, which aims to enhance mitochondrial function.

A range of pre-clinical data was presented, including tissue culture and in vivo studies using the dystrophic mdx mouse (which is a model of DMD).  The clinical proposal is general and at an early stage. The applicants sought advice from TACT regarding many aspects of the clinical trial that they propose would start in 2018.

The TACT panel felt that a clear advantage of the compound was its potential to have relevance for all DMD patients irrespective of ambulatory status and the underlying disease mutation. There was good pre-clinical evidence presented that the compound is highly specific and activates gene expression in model systems. In addition, TACT commended that the application’s functional studies were carried out in two separate laboratories.

TACT offered advice and recommendations including suggestions that could further support the pre-clinical hypothesis for MTB-1 and to help clarify the precise mechanism of action in DMD. In addition, the panel advised the applicant to seek regulatory guidance from the FDA and EMA early in the process and in advance of an investigational new drug (IND) application.

Name of applicant: George Mulligan

This proposal is to conduct a 12 month dose escalation trial of simvastatin (a specific inhibitor of HMG-CoA reductase) in non-ambulant DMD patients aged 10 years and older. The proposed primary outcome measure is cardiac MRI. In this study, initial pharmacokinetic measurements will also be obtained from 16 subjects (8 treated and 8 placebo) to ensure appropriate exposure in DMD boys.

The rationale supporting the trial is based on the preclinical work performed at the University of Washington (Whitehead NP et al., Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12864-9). These results showed beneficial effects of simvastatin on specific muscle force, decreased fibrosis and decreased inflammation in the mdx mouse. Importantly, they showed beneficial effects of simvastatin in mdx mice with treatment at 3 weeks, 12 weeks and 52 weeks of age.  The proposed mechanism of action includes reduced oxidative stress and normalized autophagy.

Simvastatin is a ready to use drug that is already approved for use in man. There is clinical evidence of safety in a paediatric population (for familial hypercholesterolaemia). TACT felt that the pre-clinical mdx mouse data for skeletal and diaphragm muscle was very strong.

The TACT panel agreed with the applicant that the overall rationale for use in DMD is promising and recommended confirmatory pre-clinical studies conducted by an independent laboratory. In addition, suggestions were made about additional animal models that be considered. Advice was given on outcome measures (primary and secondary) to be selected. TACT strongly recommended early pre-IND engagement with regulatory authorities.

Name of applicant: Jorge Quiroz

PhaseBio Pharmaceuticals Inc. proposes the development of PB1046 (Vasomera), as an adjunctive therapy for the treatment and prevention of cardiomyopathy associated with dystrophinopathies; Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-dCMP). PB1046 (Vasomera) is a long-acting analog of the neuropeptide vasoactive intestinal peptide (VIP).  PB1046 has been evaluated in several heart failure animal models, which have suggested positive effects on cardiac function. Although the specific mechanisms of action are unknown, the preclinical studies have demonstrated positive lusitropy (early diastolic relaxation); improved inotropy secondary to changes in intracellular calcium mobilization; peripheral vasorelaxation, which is thought to be due to enhanced nitric oxide synthase activity; and attenuation of inflammation and fibrosis, likely due to modulation of inflammatory cell activity, based on the known mechanisms of VIP. More limited studies have been performed in the mdx mouse, and a small number of studies have been performed in the mdx:utrophin double knockout mouse.

TACT welcomes the research into cardiomyopathy in dystrophinopathy, because it is a significant cause of morbidity and mortality in patients. TACT would encourage PhaseBio to conduct further preclinical studies to support the rationale for a clinical trial of Vasomera as an adjunctive treatment for cardiomyopathy in the dystrophinopathy population. A study with similar time-points and outcome measures in mdx mice with ACEi alone, and ACEi+Vasomera treatment groups compared with untreated mdx mice was also suggested. TACT recommended that the potential for the production of antibodies should be a focus of the upcoming clinical studies; and that consideration should be given to limiting the study to a much more clinically homogenous population, such as DMD patients or BMD patients with a similar degree of skeletal and cardiac muscle impairment.

Name of applicant: Lynne Georgopolous

BioBlast Pharma Ltd. brought their proposal BBRM2 (intrathecal Azithromycin) for the treatment of spinal muscular atrophy to TACT. Based on their preclinical data they proposed to start a phase 1b open label study to assess the safety, tolerability and pharmacokinetics of single intrathecal administration of BBrm02 in paediatric patients with SMA type2. Azithromycin is an approved antibiotic and potential read-through agent for the stop codon located at exon 8 of the SMNΔ7 protein. The compound has a well established risk/benefit profile and therefore is an interesting candidate for this indication. It was pointed out by TACT that the compound is not currently approved for continuous administration, which is likely required in the treatment of SMA, which has potential safety and also regulatory implications.

TACT welcomed the proposal but advised that more pre-clinical work would be beneficial before moving into clinic to ensure successful clinical trials. Advice was given on suitable animal models and relevant pre-clinical dosing experiments and readouts that should inform the design of the clinical study.

Name of applicant: Dr. Gliko-Kabir

TACT reviewed an application from Dr Marti and his team from the Vall d’Hebron Research Institute (VHIR) who are developing an in vivo gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), TACT was asked to provide input in preclinical development and clinical trial design. Patients with MNGIE do not have enough thymidine phospohorylase and the abolition of the enzyme activity leads to accumulation of thymidine and deoxyuridine in body fluids and cells. The build-up of thymidine and deoxyuridine results in damage to mitochondrial DNA, which leads to a severe clinical phenotype that is fatal in more than 80% of patients before the age of 40 years.  Development of a gene therapy product is very well adapted to treat this very rare disease. This gene therapy consists of an AAV2/8 (a serotype already used clinically in human for haemophilia) vector carrying a liver restricted human TYMP expression cassette. The promoter used is liver specific. The TYMP gene is responsible for the production of the Thymidine Phosphorylase (TP). There are promising results in the preclinical studies already available but need to be confirmed in a larger pivotal study. The proposed clinical trial is very interesting but should be adapted in terms of future preclinical results especially for the primary outcome measure. It well integrates the specifics related to gene therapy products. The TACT recommended that the applicant works with the most experienced centers. A limited understanding of the natural history of the disease, because we are in the case of an ultra-rare disease, will be a challenge for the determination of the clinical efficacy. The TACT recommends that the applicant get in touch with the agencies to discuss the clinical development of this product. This gene therapy has been granted orphan drug designation in Europe (August 2014) and in USA (September 2014) for MNGIE.

Name of applicant: Ramon Marti

The NHE-1 (sodium-hydrogen exchanger 1) blocker KR-33028 for the treatment of muscular dystrophies

Peacock Pharma are investigating the use of a selective NHE-1 (Na/H-exchanger-1) blocker, KR-33028, as a potential therapeutic for the treatment of dystrophin-deficient muscular dystrophies. Calcium overload of skeletal and cardiac muscles is a key contributor to the pathophysiology of muscular dystrophies, and overactivation of NHE-1 may contribute to calcium overload. Consequently, inhibiting NHE-1 may reduce calcium overload and improve muscular function in patients with muscular dystrophies. The applicant has generated some encouraging but limited preclinical pilot data with KR-33028 in the mdx mouse model. These data indicate a possible beneficial effect of KR-33028 on intracellular calcium uptake and grip test performance. Nevertheless, this project is at a relatively early stage of development and the preclinical package is not fully complete. Peacock Pharma are planning additional preclinical work and are developing plans for the First In Man (FIM) study in healthy adult volunteers, and a short duration (14 days) pilot phase 2A study in 15 adult Becker muscular dystrophy (BMD) patients. Overall, TACT advise that the applicant recruits a preclinical and regulatory expert advisory committee to address their preclinical work-package status and planning, and to develop an adequate dossier for obtaining scientific advice, guidance and regulatory input from the regulatory authorities. It is advised that such input be obtained prior to moving forward, to make sure that all data generated in any further work contributes to the design and execution of the next steps, and also contributes to a development/regulatory perspective in case of a positive outcome.

Name of applicant: Stefan Schäfer

EspeRare proposes to reposition Rimeporide, an inhibitor of Na/H-exchanger-1 initially developed for heart failure, for development in Duchenne muscular dystrophy (DMD) and other muscular dystrophies. The proposal is based on preclinical data including research with in vitro primary cultures of myoblasts and in vivo studies covering progressive cardiomyopathy and muscular dystrophy in various rodent models including mdx mice. It has been demonstrated that Rimeporide regulates sodium, pH, calcium overload, reduces inflammation in a number of muscles; decreases skeletal, diaphragm, and cardiac fibrosis as well as muscle cell degeneration. The preclinical data package has allowed Orphan Drug Designation granting by the European Medicines Agency in April 2015. Non- invasive biomarkers qualification to measure intracellular pH and sodium concentration with Magnetic Resonance Spectroscopy (MRS) is ongoing. Safety and Pharmacokinetics (PK) have already been established in several phase I trials in adults. EspeRare plans a 4-week multiple ascending dose phase IB trial in 6-14 year old Duchenne boys investigating safety, tolerability, PK and pharmacodynamic action as measured by MRS and multiple biochemical and immunological biomarkers.

TACT welcomes the pathophysiological concept and the scientific approach to first verify that in a Golden Retriever Muscular Dystrophy (GRMD) study and then to repeat this in a first human phase IB trial together with dosing and safety investigations.  However, TACT advises to ensure appropriate statistical power of the GRMD study to secure translatability of data to DMD boys. For further drug development, the MRS data and other biomarkers will necessarily have to be validated with functional clinical outcome measures as the latter are required for marketing authorisation. At this time to strengthen the positioning of Rimeporide as a cardiac and/or skeletal muscle disease modifying agent, the TACT proposes further preclinical explorations addressing complementary PK and dose-dependent effects on muscle function in mdx mice.  This will contribute to strengthen the rationale for the primary efficacy outcome criteria for a pivotal clinical trial in patients with DMD.

Name of applicant: Florence Porte-Thomé

FibroGen has developed FG-3019, a human monoclonal IgG1 Kappa antibody directed against CTGF (connective tissue growth factor). FG-3019 is being developed as an anti-fibrotic agent. To date, FG-3019 has been administered to more than 300 human subjects in clinical trials conducted by FibroGen, including trials for adults with idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, with promising preliminary results. Results in IPF suggest that FG-3019 reverses fibrosis in a subset of human subjects.  The rationale for using FG-3019 in DMD is based on observations that CTGF levels are increased in DMD and that fibrosis is a major contributor to muscle dysfunction in DMD.  Morales et al. (Hum Mol Gen 2013) examined mdx mice with a genetic reduction in CTGF and found reduced disease progression, with results demonstrating a reduction in creatine kinase (CK), fibrosis, embryonic myosin, and myogenin. A small cohort of mdx mice, treated with FG-3019 for two months, showed increased myofibril size, reduction in fibrosis and serum CK, and improved strength in the gastrocnemius muscle. Based on this published data and on newer mdx mouse data,  FibroGen proposed a clinical trial in boys with DMD. Overall, TACT felt that there was compelling evidence from a variety of approaches − including genetic, pharmacologic, and immunological − to support the use of anti-fibrotic agents in DMD and to support the potential use of FG-3019 as one of these agents. The committee also felt there were a number of aspects in the proposed clinical trial design that would benefit from greater input from experts in DMD clinical trials, and recommended that FibroGen enlist the consultation of clinical advisors with experience in DMD clinical research or design.

TACT reviewed an application from Audentes Therapeutics (http://www.audentestx.com/) who are developing an adeno-associated viral vector (AAV8.Des.MTM1) for use in X-linked myotubular myopathy (XLMTM) patients. Audentes Therapeutics plan to use AAV8.Des.MTM1 in a Phase-2, single-arm, open-label study in male XLMTM children.  TACT was asked to provide input regarding the appropriateness of a variety of secondary outcome measures, including both motor functional and ventilatory (e.g., ventilator-free survival). Overall, there was a great deal of enthusiasm for this application for several reasons. First, the preclinical efficacy data including both the Mtm1 knockout mouse and the XLMTM dog model (with a missense mutation), were promising.  Second, the proposal makes use of AAV8, a serotype that has been used clinically in man (haemophilia), with a good safety profile. Third, this is a devastating disorder, for which no other therapy is available.  Fourth, significant preclinical data suggesting safety has already been generated, and pre-IND interactions with the FDA have occurred, outlining an acceptable approach to development. The limitations of the proposal were largely recognized by the applicants themselves and are generally consistent with the challenges of drug development in an ultra-rare disease. These include a limited understanding of the natural history of the disease, limited understanding or availability of outcome measures to support determination of clinical efficacy, the lack of a non-invasive biomarker, and the lack of a concurrent control and blinding of trial which will confound the interpretation of some of the functional efficacy outcomes.

Name of applicant: Suyash Prasad MD

TACT reviewed an application from Professor Azzouz who has developed a AAV9 viral vector (AAV9-) expressing DNA for the human Survival Motor Neuron (SMN) transgene for the treatment of spinal muscular atrophy. To date, Professor Azzouz’s group have (i) performed studies to scale up GLP and GMP AAV9 vector production; (ii) preliminarily demonstrated that scAAV9-SMN can extend the lifespan in SMNΔ7 mice; (iii) worked on dose-response efficacy studies to determine the optimal dose for future preclinical studies; (iv) planned regulatory GLP toxicology and biodistribution studies in rodents; and (v) worked on a dossier submission for a Biologics Licence Application (BLA) to initiate a phase I trial in SMA patients. Overall, TACT believes this is a promising approach to treat a devastating disease. However, TACT recommended that several issues should be considered before moving into the clinic. Specifically, planning for the preclinical toxicology studies will depend on identifying the preferred dose range for the clinical trial. Therefore, generating additional data to support dose selection should strategically best occur as one of the next steps.

Name of applicant: Prof Mimoun Azzouz

Pfizer Inc. submitted an application to TACT for review, which focused on Pfizer’s PF-06252616 experimental asset, a humanized monoclonal antibody directed against the myostatin protein (growth and differentiation factor 8, GDF8).  The asset is being considered by Pfizer for  potential future clinical trials in Duchenne muscular dystrophy (DMD). Preclinical data from Pfizer indicated that PF-06252616 effectively inhibits myostatin signalling in vitro assays and in animal models. Subsequent preclinical studies also indicated that PF-06252616 was observed to significantly increase total lean mass and muscle mass in a dose-dependent manner in wild-type mice and non-human primates. PF-06252616 has been submitted by Pfizer in an Investigational New Drug (IND) filing, inclusive of necessary pre-IND toxicity, pharmacokinetics (PK), formulation and other studies.  As part of Pfizer’s evaluation of potential indications for PF-06252616, Pfizer requested TACT review of Pfizer’s proposed Phase 1b/2 studies in DMD. Overall, TACT was enthusiastic about the maturity and breadth of the Pfizer program at this stage.

The TACT application submitted for review by Dr Schmidt addresses the potential development of a therapy for inclusion body myositis (IBM). Preclinical data from Dr Schmidt and others has shown a unique interplay between inflammatory and degenerative mechanisms in IBM pathology. Cell culture models showed that exposure of muscle cells to IFN-γ and IL-1β induced intracellular up-regulation of amyloid precursor protein and accumulation of β-amyloid). A subsequent study showed that NO is an important mediator of these interactions and that blockade of inducible NO synthase (iNOS) in vitro reduced NO-mediated toxicity and subsequent accumulation of amyloid in muscle cells . Dr Schmidt asked the TACT committee for specific guidance in translating this hypothesis into a clinical trial in IBM patients. Specifically, guidance was requested with regards to the identification of a lead compound, with plans to take this compound into eventual human trials. Different compounds were discussed, among them the iNOS blocker 1400W. Overall, the TACT committee recognized the unmet need for therapies for IBM, but showed little enthusiasm for pursuing drug development of 1400W, which seems unlikely to have a clear route forward to human trials. However, there was significant enthusiasm for further preclinical testing with other potential compounds, e.g. those that are currently in clinical development.

Name of applicant: Dr. Jens Schmidt

The TACT application submitted by Dr Denis Guttridge proposes to use a Nemo binding domain (NBD) peptide coupled to a cell penetrating peptide as a blocker of the NF-κB pathway to treat Duchenne muscular dystrophy (DMD). The NF-κB pathway is strongly implicated in the pathogenesis of DMD. In macrophages, NF-κB promotes inflammation and fiber necrosis, while its activation in damaged muscles inhibits muscle stem cell regeneration. Thus targeting NF-κB should both dampen the immune response and boost new muscle growth. The NBD peptide is a specific blocker of the NF-κB pathway which acts as a competitive inhibitor to block the association of the IKK complex whose kinase activity acts directly upstream to stimulate NF-κB. The applicant has published data showing that NBD treatment leads to a reduction in inflammation and decreased pathology in two mouse models and has similar unpublished data in a dog model of DMD.

TACT was enthusiastic about the targeting of the NF-κB pathway as a potential therapy for all DMD patients. TACT provided advice on the feasibility of using muscle biopsies to assess treatment effect, the use of non-invasive biomarkers, biodistribution and pharmacokinetic issues, patient burden associated with the proposed treatment schedule, assessment of interaction with corticosteroids and the potential for immunogenicity.

Name of applicant: Dr Denis Guttridge

Fate Therapeutics presented a proposal to develop a Wnt-based protein therapeutic as a potential treatment for a broad range of muscular dystrophies and neuromuscular diseases, including Duchenne muscular dystrophy (DMD). The academic work of Dr Michael Rudnicki has characterized the role of Wnt7a signaling in satellite stem cell proliferation and skeletal muscle hypertrophy.Fate therapeutics presented data demonstrating the successful engineering of the Wnt7a protein to analogs with preferred product development characteristics. In support of potential beneficial effects for muscular dystrophy, the Wnt7a analogs were seen to induce a significant increase in the satellite stem cell population, reduced inflammation and fiber damage and significantly improve muscle strength in preclinical model systems. The company proposed a development plan including an initial human proof of concept study with targeted delivery of the Wnt7a-analog protein to specific muscle groups followed by a program expansion to systemic delivery. The TACT committee suggested that while an intramuscular administration may be useful for certain muscular dystrophies or stages of disease, true therapeutic benefit for DMD would require a systemically delivered product.

Summit has developed SMT C1100, a small molecule utrophin modulator drug to maintain the production of utrophin, the foetal form of dystrophin. Studies in mice show utrophin acts as a functional replacement for dystrophin. This strategy is not mutation specific and offers the potential of a broad therapy for DMD and BMD. SMT C1100 has completed Phase 1 trials in healthy human volunteers and has orphan drug status in Europe and the US. The TACT reviewed the preclinical package which importantly included evidence of increased utrophin in the heart, the Phase 1 results, and the plans for Phase 1b and the Phase 2 studies. The Phase 1 data and pre-clinical safety data suggest that SMT C1100 has an appropriate safety profile for acute use. Given the effects observed in the mdx mouse and human cell cultures, the drug is likely to increase levels of utrophin in humans if similar therapeutic blood levels of the drug can be achieved. For the Phase 2, the main challenge will be the development of assays capable of showing consistent and measurable increases of utrophin in patients. The TACT made a number of suggestions regarding additional preclinical studies, metabolism and safety studies, regulatory questions, selection of the patient population in the clinic, and trial design.

Name of applicant: Jon Tinsley

Damaged myofibers, such as those in muscular dystrophy, release ATP into the extracellular space.  Purine nucleotides are recognized as important extracellular signalling molecules and act as agonists for the P2X receptors, including P2X7.   The P2X7 receptor has been referred to as a danger receptor and is up-regulated in mdx muscle.  Reducing P2X7 activity is a proposed target for therapy in Duchenne Muscular Dystrophy.  TACT made recommendations regarding additional preclinical studies to confirm the importance of the P2X7 receptor in Duchenne Muscular Dystrophy and also advised regarding suitable small molecules that may best be able to demonstrate antagonism in the pre-clinical models.  Additionally, TACT provided advice on potential industry relationships to facilitate the preclinical, and ultimately clinical, investigation. TACT also provided guidance on organizing a clinical trial.

Name of applicant: Dariusz C Gorecki

Italfarmaco proposes to test the histone deacetylase inhibitor (HDAC), Givinostat, in Duchenne Muscular Dystrophy (DMD). This is an interesting proposal with a novel drug and approach to DMD. Givinostat has been evaluated in inflammatory and oncological diseases in humans including children dosed for up to 6 months with a good safety profile. Published pre-clinical data suggests a benefit of other HDAC inhibitors in the mdx mouse model of DMD. Investigators found that Givinostat increases the size of myofibers, decreases inflammation and prevents formation of fibrosis in the mdx mouse model of muscular dystrophy. Additional pre-clinical data on the mdx mouse model and potentially the canine model including biomarker identification and cardiac effects were encouraged. The committee recommended adding a placebo control group to both the safety and POC/efficacy studies of Givinostat, consideration of alternative or additional proof of concept outcome measures other than muscle histology, and consistency in the duration of dosing within treatment groups.

Name of applicant: Paolo Bettica, MD PhD

The applicant presented a program to evaluate the non-selective HDAC inhibitor sodium phenylbutyrate (NaPB), a compound registered for treatment of urea cycle disorders, in SMA. NaPB is an unpleasant drug (taste and odor) so compliance is poor and a real problem with children. GMP-Orphan proposes a paediatric formulation for treatment of SMA. The FDA and EMA have both awarded Orphan Drug Designation to GMP-Orphan. The proposed preclinical plan is a 28 or 90-day safety/ PK bio-comparison of oral and new formulations of NaPB that will be conducted in juvenile minipigs, according to a design consistent with regulatory guidelines. The clinical target population proposed for the subsequent clinical trial is a sub-group of SMA. This study would dose for a limited period of time with an option to extend on the basis of clinical benefit based on a primary endpoint of a biomarker’s level and a secondary endpoint of improved survival.  NaPB is known to modify that biomarker’s level in patient fibroblasts and human lymphocytes from individuals who have been treated with oral NaPB. The committee felt this was an ambitious plan and identified several challenges, most notably: a) feasibility of identifying the target population; b) the proposed safety package may not support the planned clinical work so early Regulatory interactions were strongly advised; c) preclinical work has not supported changes in brain biomarker level; therefore its use as a primary endpoint in patients may be questionable, although gene copy number is known to correlate positively with survival. A number of recommendations concerned with patient population selection and clinical trial design were made to address these challenges.

Name of applicant: Fred Marin

Tivorsan Pharmaceuticals presented a detailed and well described development plan with specific milestones to advance a recombinant form of human biglycan for treatment of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). They propose to perform a Phase Ia clinical trial with single ascending dose in healthy volunteers to assess safety and pharmacokinetics (PK), followed by a Phase Ib clinical trial with multiple ascending doses in ambulatory patients with DMD. This therapeutic approach is based on published work from Dr. Justin Fallon that shows beneficial effects of recombinant biglycan in young mdx mice treated for up to 3 months. Importantly this work has been replicated in independent laboratories. TACT suggested some additional pre-clinical studies be performed prior to taking this therapy to the clinic, largely based on the requirement to obtain a further understanding of the dose-response relationship. TACT also advised on the selection of outcome measures linking biopsy results to functional changes and suggested a 6-month clinical study for the main outcome measures instead of the proposed 3 months of dosing in order to have greater potential to see functional changes. Consistent with Tivorsan’s plans, TACT further advised that any trials in BMD be sequential to and distinct from studies in DMD.

Name of applicant: Dr. Joel Braunstein

Halofuginone (HT-100) has been shown in experimental animals to possess antifibrotic, anti-inflammatory and muscle regenerative effects. Early clinical studies with topical administration show evidence of an antifibrotic effect in humans, and human studies with oral administration also show evidence of expected biological activity. Investigations in adult healthy volunteers and cancer patients showed frequent nausea and vomiting occurring at high doses, but with no serious toxicity. Clinical studies show that the nausea and vomiting can be managed by dividing daily doses into smaller individual doses. Halo proposes a Phase II, randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study in Duchenne boys. The primary objective is to investigate safety and tolerability. Secondary objectives are the pharmacokinetic profile and several clinical and biological measures of efficacy, including muscle biopsies.

TACT considered the proposal to be ready for the clinic and extraordinarily well prepared, and is enthusiastic about the potential of the compound based on the proposed mechanism. Given the limited amount of long-term tolerability data, TACT advised to start the trial with a dose-escalating tolerability and pharmacokinetics phase, followed by a longer second phase addressing efficacy on a biological and clinical level. While all patients are planned to be on standard treatment with corticosteroids, interaction with other drugs frequently applied in Duchenne MD also have to be considered. TACT agreed with the Sponsor that nausea and vomiting make repeated small daily dosages and/or appropriate drug formulation necessary for avoiding untoward gastro-intestinal interactions. Repeated biopsies seem to be inevitable to quantify fibrosis at the present stage of drug development; however additional less invasive outcome measures, such as standardised MRI, are also recommended. FDA should be approached as soon as possible with the aim to discuss acceptable clinical outcome measures.

Name of applicant: Marc B Blaustein MPP

A 6-month multicenter, randomised, double-blind, placebo-controlled, Phase IIa proof of principle study of naproxcinod (HCT 3012) 750 mg bid in patients with Becker Muscular Dystrophy.

NicOx SA submitted a proposal to use naproxcinod (HCT3012) in Becker muscular dystrophy (BMD) subjects in a phase IIa clinical trial. Naproxcinod is an anti-inflammatory proprietary compound synthesized by adding a nitric oxide (NO-donating moiety) to naproxen. It has been used extensively and safely in clinical trials for osteoarthritis (OA) (more than 4000 subjects in studies up to 65 weeks without significant adverse effects). At the time of the submission of the protocol to TACT, HCT 3012 pre-clinical testing was relatively limited in dystrophin-deficient mice (e.g., mdx) and the TACT panel recommended that more data be available before going to clinical trial. The proposed, 6-month, clinical trial in BMD using HCT 3012 was placebo-controlled with diagnosis based on muscle biopsy and DNA analysis. The clinical protocol in BMD was of interest but the review panel suggested that the Duchenne muscular dystrophy (DMD) patient population potentially offered advantages for clinical testing. Two attractive features of the DMD population include a greater number of subjects available for recruitment and better defined outcome measures for clinical trials.

Name of applicant: Fabrizio Dolfi, MD

Tetracycline Derivatives as SMN2 Splicing Modifiers for the Treatment of SMA. Screen of a tetracycline library -identified a group of potential candidates. One of these will be selected as a final candidate

Paratek Pharmaceuticals is at a compound optimization stage in the drug discovery process. The company is targeting spinal muscular atrophy (SMA). Paratek’s strategy involves the identification and development of compounds that mediate the increased inclusion of SMN2 exon 7. Paratek has conducted a Structure-Activity Relationship (SAR) program that began with the identification of a lead compound through the screen of a tetracycline library. They have identified a group of potential candidates. One of these will be selected as a final candidate for intrathecal administration in children with SMA.

Paratek has a strong assay suite that includes cell and mouse models. They have identified compounds that increase the expression of full-length SMN2 mRNA and protein. They have supportive data in the mouse brain, using intracerebroventricuar administration. TACT advised the company to carefully evaluate the feasibility and implications of this route of administration for a chronic disease, although we recognize that, under some circumstances, intrathecal administration to children may be possible. Safety may be significantly defined by dose and the required frequency of administration in the case of direct administration to the CNS. We suggest contacting neurosurgical and safety experts, as well as regulatory experts, SMA clinicians and patient groups to better define the path to the clinic including choice of patient population which will be very important.

Name of applicant: Dr Higgins

Rose Pharmaceuticals proposed GsMTx4 as a peptide therapeutic to reduce the activity of stretch activated ion channels. GsMTx4 has been shown in vitro to decrease Ca2+ uptake associated with eccentric contractions and activation of calpains in dystrophic muscle fibers and hence is likely to reduce the severity of long term muscle damage. Since GsMTx4 has a different target than any other pharmaceutical in development, it could potentially be combined in a drug cocktail with other agents. TACT’s assessment concluded that the development of GsMTx4 is still at an early stage. Although in vitro data show a good safety profile, TACT considered it important that an initial safety screen be conducted in vivo to determine the risk of cardiac arrhythmia as a consequence of possible action on hERG receptors before committing to further development. Assuming an acceptable safety profile, TACT determined it critical to establish an in vivo therapeutic window that changes the disease in animal models of muscular dystrophy, particularly with respect to the ability to reduce damage associated with abnormal activity of the mechanosensitive ion channels, prior to additional pre-clinical pharmacology testing, and Regulatory activities to support a clinical trial application. If the studies above support further development, TACT recommended engaging clinical researchers with expertise in the disease early in the process to help identify the most suitable patient population for initial clinical testing.

Name of applicant: Dr Sachs

Overall, the drug is ready for the clinic and there is an unmet need a drug to treat SEPN1-RM. The biological rationale is good; the preclinical animal data are pending. The investigators are well aware of the challenges in conducting a clinical efficacy trial for SEPN1-RM. TACT is concerned that the small Phase II study as currently planned will yield too little information for the planning of Phase III. Therefore, TACT recommends omitting the Phase II biomarker trial as currently planned and designing a larger Phase II trial with a placebo group and including the investigation of those biomarkers and clinical outcomes that are considered as endpoints for a subsequent Phase III trial.

Obtaining additional historical natural history data and prospective natural history data is also considered of high priority. With regards to clinical outcomes, measures of respiratory function and fatigue hold promise. A limited set of clinical outcomes should be selected and prospectively studied under a rigorous protocol as part of a natural history study.

A subsequent Phase III clinical trial should be of relatively long duration (feasibility permitting). Given that SEPN1-RM is a rare disease, efficiency in trial design is very important, so that the best possible use is made of patient time and observations. TACT recommends formal chart review studies of recruitment feasibility and a detailed written recruitment plan. The partnership with patient groups will be very important to the success of this trial. Regardless of the outcome with regards to NAC treatment, a well-designed trial will be an important step towards trial readiness in SEPN1-RM as it will set up much needed trial infrastructure and provide outcomes data for future trial planning.

Name of applicant: Dr Ferreiro

An open-label, fixed dose, exploratory study to assess the efficacy and safety of P-188 NF on left ventricular volume changes in patients with Duchenne muscular dystrophy (DMD)

In summary, TACT recommended that in order for P-188 to enter clinical trials in DMD additional pre-clinical studies were required using the route, dose and frequency proposed for human acute and chronic studies. TACT considered it important to assess the action of P-188 in conjunction with corticosteroids and compared to ACE inhibitors, as these are currently the standard of care in DMD. TACT concluded that, following the suggested pre-clinical studies and toxicity studies, a dose escalation study was essential to guide further development, to ensure that an effective dose could be determined in DMD and to make a go/no-go decision regarding further development of P-188. Based on the initial safety evaluation and dose selection, the next step would be a randomised placebo controlled dose escalation trial to establish the potential benefit over sufficient time to observe cardiac remodelling.

Name of applicant: Dr Symons