Friday, October 19, 2018

Trial Shows Positive Initial Results for IGF-1

This is a follow-up article written by Lucy Piper on the IGF-1 trials that is written more for the layperson. It was published in Medwire News. Click on the link below to read the article at Medwire.


Positive initial results for IGF-1 pathway as treatment target in spinal and bulbar muscular atrophy

medwireNews: The insulin-like growth factor-1 (IGF-1) pathway may be a suitable treatment target for patients with spinal and bulbar muscular atrophy, suggest preliminary findings.

“By targeting the IGF-1 pathway in spinal and bulbar muscular atrophy, we aimed to replenish the reduced IGF-1 concentrations found in this disease, to stimulate downstream Akt activity to reduce the toxicity of the mutant androgen receptors, and to increase anabolic activity to prevent muscle loss”, the researchers explain.

They examined the tolerability and preliminary efficacy of the IGF-1 mimetic BVS857 in 27 patients, of whom 18 who were randomly assigned to receive the drug while nine were assigned to placebo.

The patients, aged at least 18 years, were ambulatory, had symptomatic weakness and had serum IGF-1 levels of 170 ng/mL or below.

The patients given BVS857 0.06 mg/kg intravenously once a week for 12 weeks showed a significant improvement from baseline in thigh muscle volume – a marker of muscle wasting and denervation – on magnetic resonance imaging scans, compared with placebo, with a geometric mean ratio of 1.04 in favour of the treatment.

Specifically, thigh muscle volume remained stable in the patients taking BVS857, whereas it declined in the placebo group over the course of treatment.

Improvements in the Adult Myopathy Assessment Tool score were seen in both groups, at 7.0% in the placebo group and 4.9% in those taking BVS857, but there was no significant difference between the two. There was also no change in lean body mass in either group.

There was a similar positive change in EQ-5D score for the two groups and a significant improvement with BVS857 over placebo in SF-36 Mental Component Score.

The researchers, led by Christopher Grunseich (National Institutes of Health, Bethesda, Maryland, USA), note in The Lancet Neurology that there was no treatment effect on muscle function, which may be “a consequence of the small effect on muscle volume.” And there was no increase in Akt signalling in monocytes or muscle biopsy samples possibly as a consequence of “the short duration of the increase in total IGF-1 equivalency”, they propose.

In a related commentary, Atsushi Hashizume and Masahisa Katsuno, both from Nagoya University Graduate School of Medicine in Japan, say that the discrepancy between a positive drug effect on thigh muscle volume and clinical outcomes “suggests a need for identification of novel biomarkers that reflect both biological and clinical effects of IGF-1 mimetics and related drugs.”

They add that “extension of the half-life of IGF-1 is key to improving the biological effects of this therapy in patients with spinal and bulbar muscular atrophy.”

BVS857 was otherwise generally well tolerated, with no cases of hypoglycaemia, Bell’s palsy or serious adverse events. However, immunogenicity was detected in 72% of patients taking BVS857, which “limits its use as a therapeutic drug”, note Grunseich and team.

They conclude that the findings are “encouraging” and call for further trials with sufficient power and longer duration to better assess the effects of IGF-1 targeting on muscle strength and function.

“Activation of the IGF-1 pathway by other means, perhaps in combination with anti-androgen drug[s], might be worth pursuing in future trials,” they suggest.

By Lucy Piper

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

Image:  https://www.alpco.com/role-igf-1-growth-hormoneigf-axis

Thursday, October 18, 2018

Update on the Use and Cost of Orphan Drugs

If a treatment or cure for Kennedy's Disease (SBMA) is found, the orphan drug act will be helpful. Below is an update from NORD.

Updated Study Analyzes Use and Cost of Orphan Drugs

Median annual cost for top 10 rare disease therapies is less than $10,000 per year

Washington, D.C., October 18, 2018— Despite a record-breaking number of new approvals, orphan drugs remain a nominal part of overall drug spending, accounting for only 9.6% of total sales in the U.S. in 2017, according to a new study released today by the IQVIA Institute. The study was commissioned by the National Organization for Rare Disorders (NORD) for the second year in a row to show trends in orphan drug usage and costs.

The major findings of the report are as follows:

  • The Orphan Drug Act remains successful in encouraging the development and approval of orphan drugs. In 2017, the Food and Drug Administration approved 80 orphan indications and 57 just within the first eight months of 2018 -- shattering previous records. 
  • The Orphan Drug Act has not been a major driver of drug pricing in the U.S. In 2017, the median price of the top 10 rare disease therapies used by the greatest number of patients was less than $10,000 per year. 
  • In 2017, orphan drugs remained a small part of the overall medicine budget. Total drug spending in the United States in 2017 was $451 billion, with almost 56% spent on non-orphan traditional drugs, 34.7% spent on non-orphan specialty drugs and 9.6% spent on orphan indications of approved orphan drugs. That is a 1.7 percentage point increase over 2016, which is in line with increased FDA approvals. 

“2017 was a year of innovation and advancements in rare diseases, with more FDA approvals of treatments for rare diseases than ever before,” said NORD President and CEO Peter L. Saltonstall. “The recent IQVIA Institute study highlights the enduring importance of the Orphan Drug Act in making that progress possible.”

“It is critical to note that orphan drugs remain a sliver of overall drug spending in the U.S.,” Saltonstall said. “NORD remains committed to shining a light on the simple truths that illustrate how the Orphan Drug Act continues to be vital to the future of rare disease drug research and development.”

About 7,000 rare diseases have been identified, affecting approximately 30 million Americans. Many affect only a few hundred or a few thousand individuals. Rare diseases tend to be chronic, serious and life-threatening. More than 80 percent are believed to be genetic.

Information on the report, including a link to the study, is available on the NORD website at www.rarediseases.org/rareinsights.

Tuesday, October 16, 2018

IGF-1 Clinical Trial for Kennedy's Disease



The Lancet – Neurology published the following article yesterday on the IGF-1 clinical trial for Kennedy’s Disease (SBMA). Below are excerpts of the Summary. The full Summary can be read at the link below and the article can also be purchased on the website.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial


Summary


Background


“Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. …”

Methods


“In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). …”

Findings


“31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. …”

Interpretation


“TMV (thigh muscle volume) remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. …”

Note:  There is an accompanying article also noted:


Image:  http://www.hgh-pro.com/igf-1.html

Saturday, October 13, 2018

Biomarkers of Spinal and Bulbar Muscle Atrophy

This report was published in Frontiers of Neurology three days ago. Excerpts are below and the entire report ban be read by following the link.


Biomarkers of Spinal and Bulbar Muscle Atrophy (SBMA): A Comprehensive Review

Biomarkers in SBMA


A biomarker is a parameter that can be measured accurately and reproducibly and used as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (WHO definition, 1998). An ideal biomarker should have a predictive value and capture subtle changes over relatively short periods of time. Additional requirements to biomarkers include cost-effectiveness, non-invasiveness, and reproducibility. It is generally agreed that no single biomarker is suitable for diagnostic, prognostic and monitoring roles and a panel of several markers may be better suited as multirole indicators. SBMA is a rare and slowly progressing condition, therefore the development of sensitive outcome measures would enable smaller sample-size and shorter duration of pharmaceutical trials.

Biomarkers of Neurological Involvement in SBMA


In recent years, an unprecedented interest has developed in the standardized assessment of neuromuscular performance in SBMA, evaluation of novel therapeutic strategies and in the launch of national SBMA registries. Many of the commonly used instruments, such as the MRC score, respiratory function parameters, the modified Norris scale, ALSFRS-r, Quantitative Myasthenia Gravis Score etc. are non-specific to SBMA, yet remain widely utilized. As these tools have been developed for other conditions, new batteries of tests have been recently proposed to specifically appraise disability in SBMA.


Discussion and Future Perspectives


Interest in SBMA biomarkers has grown steadily in recent years, fuelled both by accruing knowledge about pathogenesis and novel therapeutic strategies. SBMA is now widely recognized as a multisystem syndrome. A multitude of studies focus on multi-organ involvement, and the systemic phenotype is now considered just as relevant as the neurological manifestations. It is increasingly recognized that non-neurological features of the disease have an equally important impact on the patients' quality of life. Until now, clinical trials on SBMA focused almost exclusively on the treatment of motor symptoms, but a shift to targeted molecular therapies and focus on systemic processes are likely to be witnessed in the near future. From a clinical trial perspective, ideal biomarkers should undergo robust validation, sensitivity and specificity profiling, and sampling and measurement harmonization across different centers. Crucially, candidate markers should be able to detect the subtle changes expected after the administration of a specific treatment. Given the particularly slow progression rates observed in SBMA, the definition of an effective outcome measures is challenging. The integration of neurological, metabolic, and endocrine indicators seems essential into composite biomarker panels in addition to functional scales. Serum creatinine levels appear to correlate strongly with motor impairment and HOMA-IR index with disease duration. The convincing validation of these parameters and their use as effective outcome measures in clinical trials will require robust multicenter study designs.

Wednesday, October 10, 2018

Beyond motor neurons

This is a pretty good recap of what we know and what else might be of importance in finding a treatment or cure for Kennedy's Disease.

The entire post can be found here: 

Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease

The conclusions are shown below:

Conclusions

In SBMA, as in other genetic conditions caused by mutations in ubiquitously expressed genes, the clinical picture is the result of a complex interplay between differentially affected tissues, which struggle to cooperate to maintain homeostasis.

Extra-motor neuron features in SBMA, such as primary muscle atrophy or hormonal abnormalities, are emerging as clinically highly impactful in patients’ quality of life and disease progression. Their thorough investigations are proving critical for a number of reasons. First, they may provide important insights into common mechanisms of pathogenesis. Second, the peripheral abnormalities may offer the opportunity for direct functional assessments and repetitive samplings, therefore representing potentially exploitable biomarkers to track disease progression and/or response to therapy. Lastly, disentangling the underlying molecular mechanisms of this highly integrated inter-tissues cross-talk may offer unparalleled opportunities for therapeutic interventions in the near future.

Monday, October 8, 2018

Planning for Long-Term Care: The Costs and Potential Issues


A special "thank you" to Hazel Bridges who has written another informative article on long-term care. 

Long-Term Care


Planning for long-term care can be tricky, to say the least; you never know what might happen in the next five or 10 years, and it can be difficult to think about financial planning when you’re unsure of what the future may bring. For seniors, however, it’s imperative to start thinking about how you might pay for your care should you need to stay in a hospital or nursing facility for an extended amount of time. Health insurance and Medicare are wonderful resources, but they only cover so much of the cost associated with long-term care.

For now, think about how to boost your savings and ensure that you are doing everything in your power to prevent issues down the road. This means making your health and mobility a priority and making changes to your home to make it more accessible. This will ensure that you are able to live in it longer, even if your health should fall into decline, and that you will stay safe.

Keep reading for some great tips on how to plan for long-term care.

Turn Your Home Into a Safe Haven


Prevention is one of the best ways to ensure that your health and safety are a priority. Making changes to your home is a great way to start, as it will help you remain there longer without the need for an assisted living facility. For example, you might add grab bars in the shower, place sturdy railings on both sides of the stairs, widen doorways to allow for medical equipment, add lighting to prevent falls, or remove loose rugs or carpeting that can be trip hazards. Think about what each room in your home needs in regard to safety and comfort, and do a little research to figure out what the cost will be to make the changes. Check out this guide for some great tips on which changes you should make and how to get started.

Know Your Policies


You may have a health insurance policy that will help pay for care down the road, but how much will it cover in the long term? Take a good look at your policy, and carefully read over your Medicare or Medicaid paperwork to see exactly what you will be responsible for should you need long-term or daily care due to an injury or major health issue.

Consider Selling Your Life Insurance Policy


If you need a large sum of money to cover care costs, or if you just want to pad your savings account, consider selling your life insurance policy or see if your policy offers a cash value option that would allow you to take money from the total benefit amount now. This will reduce the amount that your loved ones would receive in the event of your death, but it could be a viable option if you need cash to pay medical bills or to put aside for your future needs.

Make Lifestyle Changes


Along with the changes to your home, you can make changes to your lifestyle that will allow you to stay healthy, which, in turn, can possibly reduce the risk that you will need long-term care down the road. This includes eating right, getting daily exercise, and eliminating bad habits, such as smoking or using substances such as alcohol to excess.

Planning for long-term care does not have to be stressful. By starting now, you are on the right track toward ensuring that your healthcare needs won’t be overwhelming in the future. Make the necessary changes to help your body and mind stay healthy, and remember to ask for help when you need it.
Photo via Pixabay by Sabinevanerp

Monday, October 1, 2018

Symptoms of Kennedy's Disease (SBMA)

Any time I list the potential symptoms of Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy (SBMA), there is a tendency for someone to comment, “I have that. Do you think it’s Kennedy’s Disease?”

My answer is always the same. “I don’t know. You need to see your primary care doctor and discuss your symptoms with her/him.”

When my symptoms started, there was no DNA test for Kennedy’s Disease (SBMA). Most doctors and many neurologists did not know about SBMA. Neurologists put you through a series of tests, some not very pleasant, to help determine the cause of the symptoms. Most often, it was an educated guess based upon available evidence. In my case, I was diagnosed with ALS.

Several years later, another doctor diagnosed it as SBMA and sent me to see Dr. Fischbeck for a second opinion. I still remember walking into Dr. Fischbeck’s office that morning. He saw my gate, nodded his head, and said, “You have the walk.” He performed a DNA test and confirmed Kennedy’s Disease.

Today, because of the DNA test, a doctor can draw a little blood and send it off to a lab. Within a few weeks you will have an answer as to if you have Kennedy’s Disease. If not, you will still have to go through more testing, but at least SBMA is ruled out.

In regards to the list of symptoms below, those of us living with Kennedy’s Disease normally do not have all of them. We will have several and some might not appear until later in the progression. The most common early symptoms are severe cramping, hand tremors, unexplained fasciculations, and gynecomastia.

Please note there is a wealth of information available on the Kennedy’s Disease Association website (http://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease).



SYMPTOMS

(I apologize for the formatting problem below)
Neurological:

Bulbar Signs
The Bulbar muscles are those supplied by the motor nerves coming off the brain stem. They control breathing, swallowing, talking and other functions of the throat. Bulbar signs are problems with these functions.
Dysphagia
Trouble swallowing. (One of the Bulbar signs.)
Intention Tremor
Hand tremors when trying to do something.
Normal Babinski
Normal plantar response, ie., when the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward bending of the toes indicating a problem in the brain itself.
Lower Motor Neuropathy
The lower motor nerves are those that run from the spinal cord to the muscles that they stimulate to move. Loss of that nerve leads to weakness and wasting of the muscle.
Primary Sensory  Neuropathy
Numbness over certain areas. Loss of sensation.
Decreased or Absent Deep Tendon Reflexes
When a doctor taps the knee with his hammer there is no response.
 Muscular:

Fasciculations
Twitching of small muscles without purposeful movement. These can be seen through the skin.
Cramps
Large muscle spasms.
Postural Tremor
Shaky muscles with certain positions.
Muscular Atrophy
Wasting and shrinkage of muscles that occurs when the lower motor nerve does not stimulate the muscle adequately.
Hypertrophied Calves
Calf muscles that become thicker because of cramps.
 Thoracic:

Gynecomastia
Enlarged breasts.
 Endrocrine

Androgen Deficiency
Loss of masculinizing effect (qualities that are perceived as masculine).
Estrogen Excess
More of an apparent estrogen effect because of the lost of masulinizing effect.
 Genito-Urinary:

Impotence
Erectile dysfunction.
Reduced Fertility
Low sperm count.
Testicular Atrophy
Testicles become smaller and less functional.
 Miscellaneous Characteristics:

Late Apparent Onset
Symptoms could become apparent in 20's or 30's, but might not appear until the 60's or 70's.
Slow Progression
Near-normal lifespan.
Asymmetry of Clinical Signs
Muscles of one side may be more affected than the same muscles on the other side.
 Laboratory:

Elevated Serum Creatine Kinase
Elevation of CPK enzyme in the blood test.  Can be confused with the enzyme released during a heart attack.