BYM338 (Bimagrumab) for Inclusion Body Myositis – New cure or next dud?

Posted by Jeffrey Schneider, MSIV, Drexel University College of Medicine

There has recently been a flurry of news articles about a new treatment in clinical trials for Inclusion Body Myositis. Novartis has announced that BYM338 (Bimagrumab) has recently received FDA breakthrough status for the treatment of inclusion body myositis. What does this mean and what are the implications? Is this a cure or sensationalist hype? What do we need to know about BYM338 other than a sorely needed name change. Before we get to that let’s talk a little about inclusion body myositis.

What is Inclusion Body Myositis?

Inclusion Body Myositis (IBM) is a progressive disease of muscle weakness. Myositis, derived from Greek as many of our beloved medical terms are, is aptly named as it is a disease characterized by inflammation of the muscle. This disease most commonly presents insidiously with weakness of the fingers and quadriceps (thigh). This leads to difficulty with everyday activities like walking or holding objects. Some may also develop dysphagia (difficulty swallowing). The disease may occur sporadically (sIBM) and rarely as Hereditary IBM. It is not a fatal disease but the progressive muscle weakness means that many will rely on assistance for walking and everyday activity within 5 years.  This condition can often be difficult to diagnosis and can be aided with the help of a muscle biopsy.

Epidimiology

IBM is an age related disease that typically affects those 50 and older. Men are more often affected It is the most common of the inflammatory myopathies but is still a relatively rare condition

Differential Diagnosis

A common laboratory finding of myositis is an elevated in Creatine Kinase (CK).  CK, however, is not specific for just Inclusion Body Myositis and many conditions may also have this abnormal laboratory finding. More commonly cholesterol lowering drugs like Statins and Fibrates may lead to myositis. IBM may be mistaken for the other inflammatory myopathies, polymyositis and dermatomyositis. Polymyositis and dermatomyositis are treated with steroids and other immunosuppressive drugs of which have little effect on IBM which can sometimes be the clue that you might be dealing with IBM.

Pathology

The cause of IBM is not fully understood. What is evident is that there is an element of muscle inflammation and an element of muscle degeneration. A muscle biopsy will show the architecture of muscle at the microscopic level. Some of the key features that help to identify IBM are of course the inclusion body itself which are abnormal clumps of protein and tubules. Another feature are rimmed vacuoles which are empty pockets found within the cells. They are found in other inflammatory myopathies but occur in greater numbers in IBM.

Here is another biopsy slide showing some of the characteristic vacuoles and also the inflammatory cells in the endomysium (the layer that surrounds each individual muscle fiber).

Current Treatment

Unlike dermatomyositis and polymyositis there is currently no effective treatment of IBM.  Studies have shown the failure of steroids and other immunosuppressive agents.  Therefore it is approached symptomatically with physical therapy and exercise.

Where does that leave us now?

Novartis’ recent announcement is quite an interesting one. BYM338 (Bimagrumab) is a monoclonal antibody targeted to a very specific receptor on muscles cells. Monoclonal antibody therapy is a very field based on the human body’s own immune system.  B cells, a type of white blood cell, produce millions of variations on a common antibody to target infection. When the right antibody is found to bind to an infectious particle that B cell will undergo a series of interactions leading to cloning of that cell. This is the monoclonal proliferation that leads to a highly specific response. Researchers  have taken advantage of this concept to create highly targeted drugs.

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In the case of BYM338 (Bimagrumab), it is targeted to Type II Activin receptors on muscle tissue. This receptor normally binds an enzyme called Myostatin which inhibits muscle growth. By blocking this receptor the drug is blocking the effect of Myostatin and in theory allowing muscle growth. It is a novel approach to muscle degeneration seen in IBM.An interesting side note is that there is a breed of cattle with a defect in the gene for myostatin. The Breed is called Belgian Blue, their mutation leads to non-functioning Myostatin. They also look like this…

So is this the cure to IBM that we have been looking for. Currently the data has not been published so it is impossible to say. What we do now is that the FDA has approved BYM338 for “breakthrough” status. What this means is that the FDA is going to expedite the review of BYM338 based on what it has seen so far. This does not mean that it is a new breakthrough therapy that has passed all of its tests but rather that the FDA is intrigued by its prospects. It is also important to know that BYM338 has only gone through Phase II of Clinical trials. Phase I assesses the safety of a drug. Phase II trials are compared against placebo with a relatively small sample size (100-300). Phase 3 trials and FDA review will most likely take several more years before we will find out whether BYM338, or rather endearingly BYM338, lives up to its expectations. Could this drug be expanded to treat muscle wasting in cancer patients or the elderly? That is something developers are probably interested in but we currently don’t have the published data to support it. Could this effectively treat IBM? Maybe. Could this be a dud? Possibly. Will it be expensive? Most definitely.

Brain-to-Brain Interfacing: Next Step… Mind Control

Post written by Anne Verlangieri, MS IV at Drexel University College of Medicine, Class of 2014

Obi

Step aside Obi-Wan Kenobi, this is not the mind control you’re looking for. A recent study conducted by researchers at Harvard University has demonstrated a method for non-invasive, functional linkage of brain activity from human volunteers and Sprague-Dawley rats. The method, dubbed brain-to-brain interface (BBI), utilizes electroencephalographic steady-state-visual-evoked potentials (SSVEP) and transcranial focused ultrasound (FUS). The goal of the process is to allow human volunteers to use visual stimuli to elicit motor responses from the tail’s of rats. To understand how BBI works, we’ll need some background on the SSVEP and FUS segments.

SSVEP

Numerous neurophysiological studies have shown that there is increased neural activity elicited by a visual stimulus with directed attention. In other words, observer attention on a specific visual stimuli is more important that the stimulus itself, in producing measurable spikes in neural activity. SSVEP utilizes EEG based brain-to-computer interfacing (BCI), to take advantage of this idea. In practice, a human volunteer is equipped with an EEG and instructed to gaze on a designated visual stimulus. The EEG reads the pre-synchronized neural activity, linking the volunteer’s brain with an SSVEP computer.

FUS

Transcanial focused ultrasound has been used clinically as a non-invasive therapy for certain brain disorders, (ex. Deep brain stimulation in Parkinson’s Disease) as well as thermal ablation of brain tumors. This technology allows for region-specific brain stimulation, and when set at low acoustic energy, has been shown to excite or suppress rabbit motor/visual cortices; effectively creating a computer-to-brain interface (CBI).

How BBI works

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(Figure 1. The schematics of the implemented brain-to-brain interface (BBI). The implementation consists of steady-state visual evoked potential (SSVEP)-based brain-to-computer interface (BCI: on the left column) and focused ultrasound (FUS)-based computer-to-brain interface (CBI) segments (on the right column). [doi:10.1371/journal.pone.0060410.g001]

The set-up shown in figure 1, demonstrates how SSVEP and FUS are utilized to link the human volunteer and with the rat’s brain. The volunteer is instructed to look at a specific visual target, creating an increase in EEG bandwidth corresponding to that specific visual stimulation frequency. A SSVEP detector reads the increase in EEG bandwidth and triggers the activation’s of the FUS, which stimulates specific motor area’s of the rats brain, resulting in a twitch in the rat’s tail. Here’s the experiment in action:

What can we do with this technology?

Certainly, the possible applications of BBI are far reaching. The studies authors proposed that this technology could one day be used for indirect sensory/somatomotor communication allowing an increased degree of understanding during verbal communications between speaker and listener.
Other’s have suggested “Hive mind” like problem solving, via a linked think-tank. And of course there is the potential for further human-to-animal interaction; pet owners would jump at the chance to know just what Fido is thinking.
Another recent study used this technology for one student to control another student playing a video game at a remote location.
Regardless of the application, it will be important to look at the legal, ethical, and privacy concerns involving technology that has the potential to transmit thought from one individual to another. The study is free to download and read here.

Do you take an antidepressant medicine? – If the answer is yes, you should know about serotonin syndrome

Post written by Dr. Hadi Razjouyan, PGY III Internal Medicine Resident at Monmouth Medical Center

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Introduction

Serotonin syndrome is a rare and potentially life-threatening toxic state caused by excessive serotonergic activity in the nervous system.
It was first described in 1960s in studies of antidepressant medications and classically consists of a triad of mental status changes, abnormalities of muscle tone, and autonomic hyperactivity. However, clinical manifestations can be diverse and nonspecific, leading to misdiagnosis. Most reported cases are in patients using multiple serotonergic drugs, or who have had considerable exposure to a single serotonin-augmenting drug:

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Medications that may contribute to serotonin syndrome. (Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1; 81(9):1139-42).

Epidemiologic features

It can happen in all age groups.
Its incidence is rising as the number and use of available serotonergic drugs are increased in clinical practice.

Mechanism

Potential mechanisms include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation. Addition of drugs that inhibit the cytochromes (e.g. CYP 2D6 and/or 3A4) to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs) could be another mechanism.
The majority of cases are iatrogenic from synergistic medication use, although cases of self-poisoning with serotonergic agents also occur.

Diagnosis

Diagnosis can be made using the Hunter Serotonin Toxicity Criteria:

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Hunter’s rules for diagnosis of serotonin syndrome. (Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1; 81(9):1139-42).

Symptoms can include anxiety, restlessness, confusion, sweating, muscle spasm or rigidity, rapid back and forth eye movement, shaking, fever, rapid heart rate, vomiting and diarrhea.

Symptoms can develop rapidly, within minutes of taking the drug, however, most patients present within couple of hours after a medication change or overdose.

Differential Diagnosis

The primary differential diagnosis of serotonin syndrome includes malignant hyperthermia, neuroleptic malignant syndrome, and anticholinergic syndrome. A complete history of the drugs or substances is helpful in ruling out these conditions. It is necessary to rule out initiation or change of dosage of dopaminergic drugs and other possibilities, such as infection, metabolic disorder, substance intoxication, or withdrawal. Other potential diagnoses include heat stroke, overdose of sympathomimetic drugs, delirium tremens, meningitis, encephalitis, thyroid storm, sepsis, or tetanus.

Treatment

First, Recognize the disease
Next, Stop the offending agent(s)
In the meantime, Supportive care (treat hyperthermia, autonomic dysfunction)
Benzodiazepines may be used to treat agitation and tremor.
Sometimes may administer serotonin antagonists, cyproheptadine or chlorpromazine.
Patients with moderate or severe cases of serotonin syndrome require hospitalization.
Critically ill patients may require neuromuscular paralysis, sedation, and intubation.

Prognosis

If serotonin syndrome is recognized and complications are managed appropriately, the prognosis is favorable. The severity of the disease can range from mild to life-threatening situation. However, most cases are mild and do not require hospitalization and generally resolve within 1 to 3 days by withdrawal of the offending agent and supportive care. Patients with moderate and severe cases may require hospitalization.

Prevention

Awareness of physicians and patients of the potential for toxicity from serotonergic drugs.
Always tell any doctor who prescribes you about all medications, herbal products and street drug you take.
When starting new medicine, have the pharmacist check for drug interaction
Avoiding the combined use of serotonin-augmenting drugs.
If you are already on medicine, do not take a new herbal or over-the-counter medicine without first checking with your doctor

Warning

If you have any symptoms of serotonin syndrome, please call your primary care physician and inform him/her of your suspicion before taking any steps.

Most stroke patients are not getting treated with t-PA!

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We have already blogged about acute stroke, thrombolytic therapy with t-PA, and the importance of getting to the hospital right away for early treatment.

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However, even now that t-PA can be administered to most stroke patients within 4.5hrs since the onset of their symptoms, only around 5% of acute stroke patients receive the clot busting drug in the USA, more (7-8%) at certified stroke centers.

 

The #1 reason for not receiving t-PA is missing the time window for safe administration.

The drug must be administered within 4.5hrs (or 3hrs for some patients) since the onset of stroke symptoms in order for the benefits of the drug to exceed the risk.

Why don’t stroke patients get to the hospital in time?

Uncertain time of stroke onset.

In many cases, stroke happens during sleep, patients go to bed normal and wake up many hours later with a stroke.

We don’t know exactly what time the stroke occurred, and we have to go by the time when they were last known to be normal, which often put them outside that 3-4.5hr window.

Lack of knowledge.

However, there are still many patients who could get to the hospital in time to receive t-PA but don’t.

This is a failure of public education.

Studies have shown that as many as 1/3 of people surveyed cannot name a single symptom of stroke, and that 1/10 of people surveyed are not aware there is a time sensitive treatment available.

Only 2/3 stoke patients choose to call 911 and come to the hospital by ambulance – those that do are 50% more likely to get t-PA.

Stroke

time is brain

This is the reason for the ad campaigns like the AHA’s “act FAST” and “Time is brain”.

 

Even if they do get to the ED in time, most stroke patients still don’t get t-PA

Only 1/3 of acute stroke patients who do get to the hospital in time get t-PA!

Many have a definite contraindication, like taking blood thinners or having had recent major surgery, that does make the treatment too risky.  These are a subset of stroke patients who should be considered for interventional procedures to directly retrieve blood clot from the cerebral arteries at comprehensive stroke centers.

However, as many as a 1/3 of acute stroke patients seen within that 3-4.5hr time window do not receive t-PA because their neurologic deficit is considered to be “too mild or rapidly reversing”.  Obviously, this is a statement that is so hard to define, and yet still considered by many physicians to be contraindication to the use of the drug.

Many of us would argue that to the patient, there is no such thing as  a “mild” stroke.

Image 1 in Holland-TREC

Some affected patients just get a quick screening examination lying on a gurney, and are quickly dismissed as having had “mild stroke” even though they can’t stand and walk because this was never tested.

Furthermore, there is increasing evidence that patients who truly have minimal stroke symptoms can still benefit from t-PA administration.

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Our own research from our certified stroke center at Monmouth Medical Center has corroborated these concerns:

We reviewed the charts from all acute stroke patients seen at Monmouth Medical Center from 2008-2012:

8% got t-PA.

75% were excluded because came outside the 3-4.5hr time frame for administration of t-PA.

9% were seen in time for t-PA, but either refused treatment or couldn’t get it because if a definite contra-indication.

8% did not get t-PA because of a “mild or rapidly improving deficit” – of those, 13% needed rehab placement, so there deficit wasn’t so mild after all!

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Obviously, our goal is to give more t-PA to stroke patients who can benefit from the clot busting treatment.

We are working hard on public education events to get stroke patients to come to ED sooner, and we are also going to be treating more patients with “mild” deficits as long as they meet eligibility criteria.

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What can you do?

Know the warning signs of stroke.

If you, or anyone you know, shows any of these signs call 911 and get them to the hospital right away.

Be a participant in your own or your loved one’s medical decision making – if there seems to be any residual stroke symptoms (however mild) ask about t-PA treatment for stroke.

Find out more about Monmouth Medical Center’s certified stroke center here.

A Simple Device to Detect Concussions

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Preventing, evaluating and managing sports related concussions is a hot topic right now.

For example, Monmouth Neuroscience Institute, in association with the  Matthew J. Morahan III Health Assessment Program, offers baseline cognitive screening events and concussion evaluations for local school and college athletes.

Like most programs around the country, we use the ImPACT computerized testing to measure reaction times and assess concussions.  However, this type of computer testing requires specialized equipment and staff training.

Investigators are still looking for a more simple and cost effective assessment tool that can be used to asses athletes’ reaction times right on the side lines, to allow immediate return to play decisions during the actual game.

Sports medicine physicians from the University of Michigan have developed a homemade device that could be used in this way.

They stuck a hockey puck to then end of a long wooden dowel marked with centimeter spaced lines along its length.

The evaluator holds it in front of the athlete who is seated with one arm resting on a table. The evaluator lines up the puck with the bottom of the athlete’s hand and lets go.  Once the athlete has caught the falling stick, the evaluator marks where his hand lands, which gives a quantitative measure of reaction time.

A concussed athlete will have a slower reaction time and take longer to catch the stick (catching it further down) than a healthy athlete.

In a study published last year these investigators first used their homemade device to measure pre-season reaction times of football, soccer and hockey players.  Then they waited for these same athletes to get injured with concussions, and had them to re-take the test within at least 48 hours of the head injury.  They found that the concussed athletes took significantly longer (sometimes as much as a full second) to catch the rod than before the head trauma.

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The catch?  You still need a baseline measure for each athlete – but it might be easier to get high school and college kids to do this simple 5min test before the first game of the season than have them go to specialized testing center for a computer based test.  Then, with those baseline test results recorded, any coach can repeat the test on the side-lines after an injury and decide if they should be worried.

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I am sure the use of a hockey puck was no accident!

Read more about the study here.

Read more about concussion and concussion screening.

Find out more about the Matthew J. Morahan III Health Assessment Program at Barnabas Health.

New Brain Tumor Study at Monmouth Medical Center

ZocchiCenter

The David S. Zocchi Brain Tumor Center at Monmouth Medical Center is a research site for the ACT IV study – an international clinical trial evaluating the effects of adding an investigational vaccine to standard treatment in patients with glioblastoma, the most commonly diagnosed cancerous brain tumor.

Approximately one-third of patients with glioblastoma express a particular genetic mutation – the Epidermal Growth Factor Receptor protein variant III (EGFRvIII) – which is linked to increased tumor cell growth.  Rindopepimut  is an experimental cancer vaccine that may act to promote anti-cancer effects in patients who have tumors that express this EGFRvIII protein.

Sumul N. Raval, M.D., is the medical director of the Brain Tumor Center and primary investigator for the study at Monmouth Medical Center. “The ACT IV study, evaluates the survival rate, time to disease progression, and quality of life among patients with this genetic mutation (EGFRvIII) when the investigational vaccine rindopepimut is added to standard chemotherapy treatment ” said Dr. Raval.

The study is open to adults with newly diagnosed EGFRvIII-positive glioblastoma. Potential participants will undergo a screening phase, during which tumor tissue is tested for EGFRvIII. Other tests, including brain MRIs, physicals, blood tests, among others, will also be performed to determine eligibility.

Once a patient is accepted into the study, he or she will undergo one of two treatment regimens – both of which include injections of the standard course of chemotherapy treatment, temozolomide. One regimen will add injections of rindopepimut – the vaccine under evaluation – combined with a low dose of GM-CSF to “activate” the immune system. The other regimen will add injections of Keyhole Limpet Hemocyanin – the control injection. Study participants have an equal chance of receiving either treatment regimen, and neither the patient nor the doctor will know which treatment the patient is receiving.

During treatment, patients will be closely monitored and will be asked to visit the clinic site several times per month for standard medical tests, including blood tests and periodic brain imaging. Participants will be contacted every month to evaluate their health and to see what additional treatments are being used to treat their glioblastoma.

Participation in the ACT IV study is voluntary and may last up to five years or longer. Patients should discuss the study and other possible treatment options with their doctor, family and friends before deciding to participate. Taking part in the study may or may not improve the condition of a patient’s glioblastoma. There may be risks associated with study participation, and patients should discuss these risks with the study doctor.

To learn more about the clinical trial, visit www.GlioblastomaStudy.com. For more information on the David S. Zocchi Brain Tumor Center at Monmouth Medical Center, call 1-877-577-9800.