Outline of DMD Research Strategies *
In the last five years, DMD research has accelerated. We now know more about the role of Dystrophin and have an increased understanding about what happens to a muscle cell lacking the Dystopin protein. Based on this increase in information, researchers around the world are investigating a number of different treatment strategies - all with the goal of slowing or stopping muscle degeneration.
 

Parent Project Muscular Dystrophy has developed the following outline to help families understand specific strategies, what needs to be understood before such strategies can be tested in individuals with DMD and an approximate timeline.
 

We will provide quarterly updates. It may be helpful to bookmark our site to make it easy to return every three months to find our most up-to-date DMD research findings.
 

STRATEGY TIMELINE APPLICATION COMPANY Concerns/ Hurdles/ Toxicity BENEFITS
Therapeutics: (slow/halt degenerative process)
Calpain/Protease Inhibitors
Calpain Inhibitor
MYODUR		 Orphan Drug Status Granted

Anticipate Phase I/II Clinical Trial
APRIL _ 2006		 ALL DMD Ceptor Animal studies are ongoing.
  1. slow muscle degeneration
  2. oral agent
  3. toxicity unknown
Calpain Inhibitor
SNT- MC17		   ALL DMD Santhera Pharmaceuicals   11/07/2005 - Santhera Pharmaceuticals AG announced the start of a collaborative clinical trial with the US National Institutes of Neurological Disorders and Stroke (NINDS) at the National Institute of Health (NIH) to evaluate SNT-MC17 (idebenone) in patients affected by Friedreich's ataxia (FRDA), a devastating life-threatening neuromuscular Importantly, this study also aims to analyze changes in several neurological and functional parameters as a result of treatment with SNT-MC17. These parameters will be secondary endpoints of the study. Data obtained from this study will be used as part of the development program for SNT-MC17 (idebenone) both in the US and in Europe; Santhera plans to start a pivotal Phase III trial in Europe later this year. disease
BBIC Anticipate Phase I/II clinical trials in 2006 ALL DMD In Discussion In Phase 2 studies for cancer. Minimal side effect profile
  1. slow muscle degeneration
  2. oral agent
  3. low toxicity
Anti-inflammatories
Cyclosporine A Phase I/II trial in Germany

Trial is ongoing		 150 boys - 5 year trial
10 days pred/10 cyclosporine A		 Novartis Widely used for whole organ transplantation. Inhibits the production of T lymphocytes. There is some data to suggest cyclosporine A may be detrimental. Drug has high toxicity profile
  1. oral medication
  2. slow muscle degeneration
Enbrel No Trials Planned at this time

Meeting scheduled to discuss anti-inflammatorie agents Dec. 2005		 Potentially all boys Wyeth - (not interested in dmd - concern about negative results eroding market) Tumor Necrosis Factor (TNF) is one of the major pathways in the immune response. Enbrel binds and deactivates TNF. Major concern: Serious infections and sepsis. Two large clinical trials with Enbrel on heart failure were terminated because of lack of efficacy
  1. potentially expected to slow muscle degeneration
  2. delivered by injection
  3. possible cardiac complications
REMICADE Animal Studies (grounds/ hoey) in progress

No Clinical Trials are planned at this time
Meeting scheduled to discuss anti-inflammatorie agents Dec. 2005		 Potentially all boys Centocor

Centocor is not interested in developing a trial at this time - concern about negative results eroding market)		 TNF inhibitor.
Contraindicated for individuals with heart failure.
  1. anticipated results- slow muscle degeneration
  2. delivered by injection
  3. Centocor states that Remicade does not work against mouse TNF2 therefore published data needs to be validated.
NFkappaB - this is a major anti-inflammatory pathway Animal studies
George Carlson(Mo) and Dr. Vita (sicily)In progress

No trials are planned at this time		 Potentially all boys IMS Heath, England Agents would stabilize the NFkappaB pathway to enhance survival and improving resting membrane potential. Concern that these agents may be highly toxic with chronic administration
  1. anticipated results - muscle degeneration
  2. injection or oral
  3. unknown long-term toxicity
Albuterol(ak - Ventolin, Proventil)

PPMD supporting project on Clembuterol (Beta2 agonist)		 Pilot trial complete
Developing Phase III - date for trial not identified		 Potentially all DMD GSK ?2 agonist thought to slow muscle degeneration. Animal studies in currently in progress. Current thinking- pulse dose may be more useful to sustain benefit. Clinicians have concerns about effect on heart because it also stimulates ?1 receptor in the heart
  1. anticipated results - slow muscle degeneration
  2. should be combined with ?1 blocker
nNos upregulation
(Judy Anderson, PhD)		 Preclinical studies

No trials are planned at this time		 Potentially all DMD Dr. Anderson is working with a company. She is unable to disclose specifics until data is complete. The absence of Dystrophin results in a cascade of pathological biochemical processes to include decreasing Nitric Oxide Synthase (nNos). Loss of nNos causes vascular constriction, thus decreasing blood supply and oxygen to the muscle cell.
  1. anticipated results - slow muscle degeneration
  2. method of delivery unknown
Pentoxifillin Pilot Trial Phase I/II In progress CINRG

No longer seeking patients for enrollment		 Potentially all boys   Pentoxifillin is a mast cell stabilizer. Sweeney lab is re-investigating the effect of Pentoxifillin in the mdx mouse.
  1. expected to slow muscle degeneration
  2. oral agent
  3. toxicity unknown
GROWTH FACTORS
MYO-029
Myostatin inhibitor		 In trial FSH, Myotonic and Becker MD

Anticipated that Wyeth will expand trials to DMD trial if results suggest benefit

CALLING ALL PATIENTS WITH BECKER MD

Trial having difficulty recruiting Becker patients.		 Potentially ALL DMD patients Wyeth-Ayerst Myostatin is a negative regulator of muscle size. Concerns raised about 'wearing out' the regenerative process. Anticipated to be used in combination with other therapies
  1. anticipated results - increase muscle mass.
  2. MYO-29 antibody is delivered by vein (IV)
IGF-1 In Phase III trials for ALS

DMD Trials are not planned at this time		 Potentially all patients Cephalon, Inc IGF-1 appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues
  1. expectation is to stimulate regeneration
  2. promote survival of motor neurons (ALS)
Inducing Production of Dystrophin
Read-through of nonsense mutations Phase I (healthy volunteers complete)
Phase II planned for the third quarter of 2005

Candidate enrollment will begin late November, 2005		 DMD with confirmed Premature Stop codons (10-15% of patients) PTC Therapeutics Study in Healthy volunteers did not demonstrate adverse effects.
Phase II study will include 24 boys ages 5+ with confirmed premature stop codons. Trials expected in 3 sites:
Children's Hospital of Philadelphia
Cincinnati Children's Hospital Medical Center
University of Utah
  1. promote 'read through' - produce full length dystropin
  2. Stop muscle degeneration
  3. oral agent
GENE CORRECTION

Exon Skipping (AON)

Research teams:

The Netherlands
J. VanDeutekom
G-J van Ommen

Australia
S. Wilton

US
Qi Lu

France
T. Partridge
Luis Garcia		 Proof of principal Phase I/II trials (single muscle)
Exon 51
Followed by
Exon 46
The Netherlands first quarter 06.

Phase II trials are expected to involve injections into arms/legs - date will depend on results of single muscle injection

Regulatory agencies will require Phase I/II trials for any change in chemistry (each different exon(s)

PPMD, GSK, MDA form a funding consortium to insure stable funding to explore AON as a potential treatment for DMD		 Most boys EXCEPT those with duplications or very early or very late (c-terminus) deletions Prosensa (the Netherlands)
  1. specific chemistry - controversy over 20MeAos or Morpholino
  2. delivery- systemic delivery has not been achieved to date
  3. Functional Dystrophin? While shortened versions of Dystrophin have been expressed in human muscle (in culture) it is not yet know if they will be efficient to withstand the burden of muscle contraction
  4. Becker patients with shortened versions of the protein have had the protein onboard since BIRTH. It is not yet known if reinstating the protein at a certain point in time in DMD will be useful.
  5. Maintaining expression. This may be related to dose and trials involving escalated dosing will be required
  6. AON therapy will need to be repeated at intervals of 6 wk. to 2 mo.
  1. Produce a shortened version of Dystrophin
  2. Stabilize muscle
  3. Slow or potentially stop muscle degeneration
  4. Systemic delivery would be by vein
  5. Repeat delivery every 6-10 weeks
Plasmid DNA
(naked DNA)		 Trials in France showed small amount of expression and no immune response. All boys Transgene Systemic Delivery will be attempted in Phase II
  1. Stabilize muscle
  2. Stop muscle degeneration
  3. Systemic Delivery at intervals -unknown at this time
GENE Therapy
Adeno-Associated virus (AAV)
Micro Dystrophin		 Phase I
Single muscle injection planned
Estimated date: 2005/ early 06		 Potentially all boys Asklepios -AAV
  1. Production (currently unable to produce sufficient quantity to treat one individual)
  2. Systemic delivery remains a significant hurdle
  3. Need for comparison between AON and microdystrophin to determine if one is more or less effective
  4. Question on immune response to Dystrophin
  1. Replace Dystrophin with shortened version
  2. Significantly slow or stop muscle degeneration
  3. Systemic delivery by vein - may need to be repeated after unknown period of time.
AAV/U7
(permanent exon skipping)		 Animal work ongoing

Strategy will be incorporated into the business plan for the AON consortium		 Same as Exon skipping Genethon
  1. Production of AAV
  2. Systemic Delivery
  1. Replace Dystrophin with shortened version
  2. Functional protein would dramatically slow and potentially stop degeneration
  3. Systemic Delivery by vein
STEM CELL
USA-
Gussoni
Kunkel
Chamberlain
Italy-Cossu
India =
China		 Animal studies - USA
No trials planned at this time

Trials in India and China do not provide benefit in DMD		 Potentially all boys  
  1. directing stem cells to regenerate/ correct skeletal muscle (concern they may increase scar tissue)
  2. Specific type of stem cell for efficacy
  3. Systemic delivery
  1. Replace Dystrophin
  2. Stop muscle degeneration
  3. Systemic delivery by vein


 
STRATEGY TIMELINE APPLICATION INDUSTRY Concerns/ Hurdles/ Toxicity
NEW DRUG DISCOVERY (small molecules)
PTC Therapeutics (project catalyst)
High throughput screens (HTS) on 5 targets

Goal
To identify new treatments for Duchenne muscular dystrophy (DMD)
Stage 1: Initial Drug Discovery
Stage 2: Lead optimization
Stage 3: Pre-clinical development
Stage 4: Clinical development

Drug Discovery Approach
PTC's GEMS (Gene Expression Modulation by Small-molecules)
Stage 1: PTC will apply its proprietary GEMS technology to five target genes of potential therapeutic relevance to DMD.
Goal: To identify small molecule compounds that can be developed into novel drugs for the treatment of DMD.		 Hits have been identified from each of the five screens
  • Characterization of hits from the five screens is in progress
  • Select hits have shown promising activity and selectivity
  • OPTIMIZATION PHASE In progress, evaluating hits for efficiency and toxicity
 ALL DMD PTC Therapeutics unknown
UCLA- M. Spencer, PhD/ J. Tidball, PhD
-High throughput screens on specific targets such as:
  1. muscle membrane stabilizers
  2. anti inflammatory agents
  3. anti fibrosis agents
  4. upregulate NFAT/Calcineurin pathway
Cell culture-based assay system in development ALL DMD
Attempt to identify small molecules capable of inhibiting degenerative pathway in DMD		 UCLA  
VASTox -Utrophin upregulation (Kay Davies, PhD, Jon Tinsley, PhD)

Conducting high throughput screens -Utrophin upregulation		 Characterization of hits

Toxicity Studies ongoing		 All DMD    
GEMZYME

High throughput screens
Targets: Unknown		 Initial stage of development

Muscle Program in Development. Considering options		      
NOVARDIS Developing program in MUSCLE      

 
* This outline is provided for general informational and educational purposes only, and does not constitute an endorsement or recommendation of any particular research strategy or course of action. Parent Project Muscular Dystrophy (PPMD) will make every effort to ensure that the outline is reasonably complete, accurate, and up-to-date; however, the outline is not intended to be an exhaustive list of all DMD research strategies. PPMD makes no representation, warranty, or guarantee as to the outline's completeness, currency or accuracy, and assumes no liability for actions taken in reliance on the information contained in the outline.