Tag Archives: small molecule

Potential Myotonic Dystrophy Drug Fails! – Ionis Myotonic Dystrophy Drug fails to reach minimal therapeutic value

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In a instant news email the Myotonic Dystrophy Foundation (MDF) released information that the Ionis Pharmaceutical Drug DMPK-2.5Rx research project has been canceled. The drug DMPK-2.5Rx did not work, and did not get the correct amount of therapeutic drugs into the cells of the patients with myotonic dystrophy. The company may still continue research on a more potent combination but the current trial is halted.

This is hard to hear news for the myotonic community. This is the second drug in development to fail. This new drug is part of a number of new generation of interest drugs  in trying to find a drug to treat the disease. There are still a number of drugs in development but the Ionis one was the most advanced. Perhaps the information in this trial will be of help to the other drugs in development.  For those in the late stages of the disease the length of time to find a treatment that is FDA approved in unlikely now.

There continues to be some “off label” treatments including erythromycin and some NSAIDS as well as Actinomycin-D but none have had any proven human effect.

More information below.

Ionis Pharmaceuticals Reports on
DMPKRx Phase 1/2 Clinical Trial

Ionis Pharmaceuticals recently concluded a Phase 1/2 clinical trial to evaluate IONIS-DMPK-2.5Rx in myotonic dystrophy patients. IONIS-DMPK-2.5Rx was designed to target the toxic DMPK RNA in muscle that is responsible for myotonia or muscle dysfunction in DM1 patients. The clinical trial used dose escalation to assess safety and explore biomarkers for target engagement in muscle biopsies.

Ionis reports that small but encouraging trends in biomarker and splicing changes were observed during the trial, and that this study provided a much better understanding of how future clinical trials and improved clinical endpoints may be used. However, drug levels measured in biopsy tissue from trial participants indicated that the amount of target engagement would not achieve the desired therapeutic benefit to treat this disease.

Without the desired drug levels in muscle, Ionis has decided not to advance IONIS-DMPK-2.5Rx. It will instead pursue the discovery of a more potent drug to target DMPK using new muscle-targeting LICA chemistry made at Ionis.

The company sincerely thanks everyone in the DM community that participated in the study – patients, caregivers and physicians, noting, “we are committed to the DM patient community and we hope to advance a new, more potent drug into development that will benefit people living with DM1.”

Ionis invites DM community members to submit questions regarding the above announcement via this email address. MDF will collect questions through January 12th and then work with Ionis to get answers out to the community as soon as possible.

Case study report of experimental use of approved FDA drugs to reverse myotonic dystrophy symtoms (DM1)

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Encinitas, CA Two recent published studies reviewed the use of FDA approved drugs in Mice that reversed some myotonic dystrophy symptoms.  The mice showed improvement in muscle strength after a regime of using these approved rugs in appropriate dosages.

My son Chris has Congential Myotonic Dystrophy with a repeat count of about 1700. He is severely affected being non-verbal, cognitive delays, autistic spectrum disorder, and some muscle involvement. Chris also has the adult form of the disease as he reached puberty and has a level 1 heartblock, excessive sleepiness and other adult symptoms.

He has had 3 bouts of respiratory collapse. This initially involved a Hospital Stay, MSRA pneumonia. Within a very short period of time of initial symptoms he was in the ICU on a respirator and full dosages of heavy antibiotics including vancomycin. Recovery was uncertain and very slow. Tracheotomy was performed as weaning from the respiratory was difficult and dangerous. Full recovery was accomplished at 120 days. USA Hospital costs was approximately $750,000 for this. Two other bouts of respiratory collapse related to pneumonia occurred with similar outcomes.

We decided to pursue an experimental course of treatment with these FDA approved drugs due to concerns that he might not survive another bout of respiratory collapse.

In April 2016  we initiated a course of treatment on Erythromycin after consultation with pneumologist, cardiologist, cardiology expert in DM, and primary care Physician. The Primary care physician wrote the script for erythromycin. The cardiology team was involved as there is a contraindication for erythromycin with cardiac arrhythmia’s. The course was 2X daily 125mg of Erythromycin orally.

In May 2016 we added a daily dose of 80 Mg of Ketoprophen as this drug was found to have a positive effect on mice as well in ameliorating the myotonic dystrophy symptoms.

Results: We did not use any formal metrics in evaluating the results of the trials. The main reporting point was discussions with caregivers to see if there was any improvement in cognitive or strength related improvement in the patient. These conversations were all convergent in :

Overall Muscle strength               NOT IMPROVED
Overall Cognitive Abilities             NOT IMPROVED
Chest Congestion                        DECREASED SOUNDS
OF SECRETION CLEARING

# of Pneumonia Infections           IMPROVED

Overall the results of this 8 month trial did not replicated the information in the two mice studies. There was no increased muscle strength noted by caregivers. There did seem to be a significant improvement in clearing secretions in the lungs which is a critical factor in this patients Quality of Life (QOL). No Pneumonia infections were reported. this is a significant improvement over the last 12 months.

Discussion: Overall it appears that this therapy may have had an positive  impact on the patient. Overall the results of this one case did not replicate the studies that used mice in terms of improvements in muscle strength. this may be due to a number of reasons including dosing strength. It could also be that the mice that are created to have myotonic dystrophy are not the ideal method to test drugs the the DM in these mice may be more susceptible to disruption that the actual DM gene in human patients.

Patients with Congenital Myotonic Dystrophy and certain other patients (older than 57) are currently excluded from clinical new drug trials. Myotonic Dystrophy is slowly progressive until an exponential event occurs. Because of the risk of sudden death and pneumonia with these cases is ongoing looking for alternatives to reduce risk of death may be warranted by patients health care team.

 

Phenylbutazone & NSAIDS – Another potential treatment(s) for Myotonic Dystrophy

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Orudis KT

Another paper has been published and revealed another potential treatment for myotonic dystrophy, Phenylbutazone PBZ.. Interestingly this study was also done in Japan………… now a hotbed of repositioning drugs for treatment of myotonic dystrophy.   some info from the study

“Using the drug repositioning strategy, we found that PBZ markedly elevated MBNL1 expression in myogenic cells(Fig. 1 and Supplementary Fig. S1) as well as in skeletal muscles in HSALR mice model (Fig. 2 and Supplementary Fig. S2). PBZ mitigated muscle pathology (Fig. 2d,e) and improved the running wheel activity and grip strength
in HSALR mice (Fig. 2c and Supplementary Fig. S2d).”

This summary above  showed that in mice this drug helped mice with myotonic dystrophy run on the wheel better and had better grip strength. More info below

PBZ is an NSAID with anti-inflammatory, antipyretic, and analgesic activities. PBZ was approved in humans for rheumatoid arthritis and gout in 1949. Although incidental adverse effects of fatal liver disease and aplastic anemia markedly lowered the use of PBZ, PBZ is still used as an alternative drug for ankylosing spondylitis32,33.
Interestingly, another NSAID, ketoprofen has been reported to suppress CUG-induced lethality in Drosophila34, and we also found that 50 μ M ketoprofen upregulated the expression of Mbnl1 mRNA 1.2-fold in C2C12 cells, which was lower than the 1.3-fold increase of Mbnl1 mRNA by 50 μ M PBZ (Supplementary Fig. S6). Ketoprofen
and some other NSAIDs may have beneficial effects on a mouse model of DM1, as well as on DM1 patients.

Editors Note: This drug (PBZ) approval was removed for humans in 2003 in the USA and Canada. It is available for use in animals only. The drug Ketoprofen was not studied in depth but is an approved NSAZID drug in the USA. We have choosen the image of Ketoprofen as this is an approved drug in the USA.

Full study is Here.. Phenylbutazone Treatment DM1 mice

Common Antibiotic Might Help Treat Myotonic Dystrophy Type 1 – Promising Therapy

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In a study published in December 2015 in a peer review journal researchers from Japan and Poland found that a commonly used antibiotic might assist in the treatment of Myotonic Dystrophy. This is a sort of interesting  discovery as there is no treatment identified to treat the disease. Treatment now consists of reducing symptoms. There are several other approaches that are in development maybe as soon as the end of this year. Here is a link to another promising therapy as well Cagumycin

The researchers first began by screening antibiotics. In a screen of 20 antibiotics 2-3 were found to have some potential with the disease.When screening the drugs they first used mice cells and lab equipment to find the most promising compounds (drugs). . Erythromyicin was found to have the highest attraction to the RNA CUG expansion (The opposite of CTG repeats in the DNA) Erythromycin was the drug that the researchers chose to study. Click here for the screening graph Muscleblind and Various antibiotics and compounds

Continue reading →

FDA approved Chemotherapy Drug Might Treat Myotonic Dystrophy

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In a stunning development The Berglund lab in Gainsville, FL has identified a potential treatment of myotonic dystrophy of a Chemotherapy drug Actinomycin D. In Both Cells and mice that were created to have myotonic dystrophy the drug used at or below levels that are used in human chemotherapy pushed back the Foci that are associated with the disease.

In theory this might be a treatment for myotonic dystrophy. This has not been tried in humans and would be highly risky but for people near end of life this may be a vector for them and their doctors to consider.

Researchers have previously identified what they think is the cause of the disease.In Myotonic Dystrophy the repeat expansion mutation is made into RNA but it does not get out into the cytoplasm. It remains trapped in the nucleus where it sticks to various proteins and appears as spots or foci that can be observed down the microscope. Because these proteins are stuck to the repeat RNA they cannot perform their normal functions correctly within the cell.

Researchers have found that to make progress with this disease, they need to “unstick” the proteins. This drug appears to do this in mice and cells.

Previously to the publication of this article there was no even theoretical treatment available. There are several drugs in development but this takes years of development. For those near end of life with this disease there is now a potential treatment. A copy of the article is here. This is something you may want to discuss with your medical team. Its untried and potentially risky with side effects. More information will be available shortly.

Myotonic Dystrophy Treatment

Please note the study is very technical. We are not recommending this to anyone but bringing all the current information to your attention