CurityMD

A service to identify, evaluate, and share expertise in rare diseases to benefit patients, advocates, and qualified health centers

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Atypical Hemolytic Uremic Syndrome (AHUS):  The Who, What, When, Where, and Why of Genetic Testing

A part of CurityMD’s partnered Hospital Series

At CurityMD, we are constantly identifying and evaluating hospitals with our own unique, data-driven analysis to identify centers with world-class expertise.  Sometimes we work with these hospitals to help them understand and share their rare disease expertise with the global community.  We find that sometimes, even the best centers may be surprised at how much experience they have with certain rare diseases.  

This post features one rare disease where we have partnered with an expert hospital to help communicate and share new innovations and discoveries.

Complement Tests

One important tests to understand is the test for “Complement” activity.  “Complements” are proteins that are part of normal function, but which are over-active in AHUS.

Uncontrolled activity of these complement proteins is a major cause for several rare kidney diseases -  Dense Deposit Disease (DDD) and C3 glomerulonephritis (C3GN), and AHUS (Atypical Hemolytic Uremic Syndrome).  Because these complement factors are important in AHUS, hospitals with experience in rare kidney diseases will use tests (also called “assays” to study the levels of complement proteins and related products, all of which can provide evidence for definitive diagnosis. In this way, tests of complement protein levels serve as a biomarker for disease, and as a way to study the momentum of the disease.  In some cases, these complement tests can help predict the likely response to anti-complement therapies as treatments.

Genetic Tests Used In AHUS In aHUS a patient may show abnormal levels of anti-factor H autoantibodies.  These autoantibodies bind to factor H produced normally in the body, preventing them from working in a normal way.  This can be tested to help clinicians decide how to approach their treatment plan. The test may be ordered by doctors when seeing an aHUS patient between the ages of 5-13, and in aHUS patients who show signs of severe hemolysis (bleeding) and kidney failure.  

Research suggests that Factor H autoantibodies appear in about one in ten aHUS patients. Most but not all of these aHUS patients have a specific gene mutation (“polymorphism”), called CFHR3-CFHR1. This mutation, which results in the deletion of the functional gene, occurs in 15% of aHUS patients.  Patients with autoantibodies are likely to have increased frequency of symptoms in areas other than the kidney such as the liver, brain, and GI (most commonly with diarrhea).  

Testing for these antibodies can help to tell apart an aHUS with anti-factor H deficiency from patients with complement gene mutations, which can help doctors anticipate these differences in symptoms. More than 60% of children with anti-factor H autoantibodies also have low levels of C3.

Finding Hospitals with Diagnostic Testing Facilities Required For Diagnostic Testing Most hospitals offering genetic testing that is used to help diagnose and understand AHUS have special facilities called clinical diagnostics labs.  These labs are regulated by a national body, and must be approved to operate (this is called CLIA approval), being reviewed frequently by a government group.  For Factor H autoantibodies, a test called an “enzyme-linked Immuno-Sorbent Assay (ELISA) is used, which uses a sample of a patient’s blood (this blood is processed to isolate the plasma, which is used in the test).  

This test is complex, and can take some time - 1-2 weeks - to run and get a result.  The cost of the test can range from $300-$500, and may not be covered by your insurance.  To review if your plan covers this test, you can request information from your insurance provider about the “CPT Code” for the assay, which is 83516.  If you pay without insurance, make sure to ask your local hospital for pricing information.

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review CurityMD results for Benign Schwannoma - all our top experts, hospitals, and research in the condition: view results

This work was made possible through an article published by Carla Nester, MD, MSA, Assistant Professor, Director, Pediatric Glomerular Disease Clinic, University of Iowa Hospitals and Clinics; Phone: [phone]; e-mail: [email protected]

Visit the Foundation for Children with aHUShttp://www.atypicalhus.net/

Learn more about Thrombocytopenia -https://www.uichildrens.org/Adam/?/HIE%20Multimedia/1/000586

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About Rare Diseases - Atypical Hemolytic Uremic Syndrome (AHUS), Part 2

A part of CurityMD’s partnered Hospital Series

At CurityMD, we are constantly identifying and evaluating hospitals with our own unique, data-driven analysis to identify centers with world-class expertise.  Sometimes we work with these hospitals to help them understand and share their rare disease expertise with the global community.  We find that sometimes, even the best centers may be surprised at how much experience they have with certain rare diseases.  

This post features one rare disease where we have partnered with an expert hospital to help communicate and share new innovations and discoveries.

PART 2 - Assessment, Treatment, Conclusion

AHUS (Atypical Hemolytic Uremic Syndrome) is a rare syndrome that involves an unnatural  of hemolysis, thrombocytopenia, and renal insufficiency. Genetic mutations in the alternate pathway of complement are well recognized as the cause in more than 60% of patients, but many patients develop the disease without a known genetic cause. aHUS as known to be tightly linked to a biological pathway/process called the alternate pathway, which is active in all people but dysfunctional in AHUS patients. Because aHUS shares many characteristics with other and more common diseases, genetic testing is often required to diagnose patients with confidence.  This can delay diagnosis, and may lead to our limited current understanding of the epidemiology, genetics, and clinical features of aHUS across all patients.  This introduction (split into two posts) is designed to help patients discuss their disease with doctors, and to learn more about how to identify symptoms and consider treatments.  In this second post, we focus on clinical assessment and treatment options.

Assessment of AHUS

Because there are no specific acute markers that can immediately distinguish aHUS from the other diseases, a genetic screening and treatment strategy for AHUS is often required, but hard to complete without past experience and laboratory resources.  Almost all laboratory tests use plasma that is isolated from a sample of the patient’s blood.

The other laboratory tests to consider when assessing patients for possible AHUS are:

ADAMTS13,

Levels of “complement” proteins such as C3, C4,

Complement factor H

Complement factor I

Methylmalonic acid

Homocystine

Antiphospholipid antibody

Direct antiglobulin

Many of the genetic tests above can take a long time to come back with results, which has led some doctors to look for tests that are either more common or which can be read more quickly.  Some of these other common indicators of this disease pathway that doctors may look for include:

Increased plasma lactate dehydrogenase (LDH)

Reduced plasma haptoglobin

Increased indirect bilirubin

Increased plasma aspartate aminotransferase (AST)

Increased plasma-free hemoglobin

If the patient is young, a streptococcal infection test may be performed to see if this may have been a trigger for the AHUS symptomsTreatment of aHUS

Plasma therapy

Plasma therapy, also called plasma exchange or plasma infusion, has been a major aHUS therapy for decades.  In plasma therapy, doctors seek to deliver normal levels of proteins deficient in AHUS patients through infusions, through a procedure called apheresis. Unfortunately, there is not extensive data on the safety and efficacy of plasma therapy in AHUS.  Data from patient registries suggests that the treatment is effective, however, in in achieving hematologic remission (where blood levels return to a normal range) for a majority of patients. The ability to achieve Renal remission is slightly different and less certain.Choosing plasma exchange is based on several factors, including the genetic profile and testing levels of blood proteins and enzymes, which vary in different AHUS patients. The size of the patient and the degree of kidney damage are also factors in choosing infusion.Infusion therapy may be started immediately once a diagnosis is made, and may last for several days before being decreased slowly over time as a patient starts to show response.  This often happens before genetic results have come in, as this can take weeks.  Infusions will start to be tapered off when platelet count, LDH, and hemoglobin levels improve and approach normal levels. After this, doctors will follow a patient, tracking blood levels and looking at kidney function.

Eculizumab (aka “Soliris”)

The activation “complement pathway” is essential to develop aHUS symptoms. The drug Eculizumab (also called Soliris; made by Alexion Pharmaceuticals) is a monoclonal antibody drug that prevents the creation of the membrane attack complex that leads to the damaging symptoms of AHUS. Eculizumab, was approved in Europe and in the US in 2011 for the treatment of aHUS after successful trials in adults and adolescents.  The drug is initially given weekly for a short period, which is followed by infusions every other week.  So far, clinical data supports the use of Eculizumab in patients before end-stage kidney disease and after kidney transplantation.  There are safety concerns with eculizumab. Treatment by infusion does carry a risk for infection, which can be increased as a result of the drug.  Patients often receive vaccinations and antibiotics before being treated. 

Kidney Transplantation

aHUS can be a progressive disease, with the kidneys gradually becoming more impaired over time.  In late stages, AHUS patients can develop late stage kidney disease, which is a serious complication that can require kidney dialysis and eventually kidney transplants.  In AHUS, patients may reach this late stage of kidney disease (sometimes called “end stage renal disease” or “ESRD”) because of delayed diagnosis, misdiagnosis, or an insufficient response to drug therapies.Kidney transplants in AHUS vary from center to center, and often require significant preparation and conditioning of a patient’s case to minimize the risk of repeated kidney failure (which is a serious risk in AHUS patients, especially those with severe disease).  Patients will often go through extensive genetic testing and blood work before transplantation is approved.  The kidney transplant itself often happens while a patient is undergoing eculizumab therapy, and sometimes after several sessions of plasma therapy and pre-transplant vaccinations will be used.  This helps to improve the patient’s state prior to receiving the new kidney, and may reduce the risk of infection.

Liver transplantation

Many of the proteins that stop working normally in AHUS are made by the liver.  Based on this, some patients may receive a liver transplant, which may help with symptoms by replacing AHUS liver function with more normal function. Liver transplants are still rare in AHUS treatment, and because transplanting an organ is a very serious procedure, doctors must first help patients prepare with conditioning. The recommendation of a liver transplantation requires consideration of the risks and benefits, including the experience of the transplantation center.  Sometimes, liver transplantation is only considered when patients are already experiencing end stage kidney disease and must receive a kidney transplant as well.   

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review CurityMD results for Benign Schwannoma - all our top experts, hospitals, and research in the condition: view results

This work was made possible through an article published by Carla Nester, MD, MSA, Assistant Professor, Director, Pediatric Glomerular Disease Clinic, University of Iowa Hospitals and Clinics; Phone: [phone]; e-mail: [email protected].

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About Rare Diseases - Atypical Hemolytic Uremic Syndrome (AHUS)

A part of CurityMD’s partnered Hospital Series

At CurityMD, we are constantly identifying and evaluating hospitals with our own unique, data-driven analysis to identify centers with world-class expertise.  Sometimes we work with these hospitals to help them understand and share their rare disease expertise with the global community.  We find that sometimes, even the best centers may be surprised at how much experience they have with certain rare diseases.  

This post features one rare disease where we have partnered with an expert hospital to help communicate and share new innovations and discoveries.

PART 1 - Introduction, Disease Biology, and Clinical Presentation

What Is AHUS?

AHUS (Atypical Hemolytic Uremic Syndrome) is a rare syndrome that involves an unnatural  of hemolysis, thrombocytopenia, and renal insufficiency. Genetic mutations in the alternate pathway of complement are well recognized as the cause in more than 60% of patients, but many patients develop the disease without a known genetic cause. aHUS as known to be tightly linked to a biological pathway/process called the alternate pathway, which is active in all people but dysfunctional in AHUS patients.

Because aHUS shares many characteristics with other and more common diseases, genetic testing is often required to diagnose patients with confidence.  This can delay diagnosis, and may lead to our limited current understanding of the epidemiology, genetics, and clinical features of aHUS across all patients.  This introduction (split into two posts) is designed to help patients discuss their disease with doctors, and to learn more about how to identify symptoms and consider treatments.

AHUS is in a class of diseases called thrombotic microangiopathies (TMAs), where arterioles and capillary walls grow thicker.  These conditions show swelling and thickening of the cardiovascular system, resulting in blockages developing in the blood system and tissue ischemia (where parts of the body don’t receive enough oxygen and nutrients normally carried in the blood).  

AHUS is often clinically identified by looking at a “constellation” or pattern of multiple symptoms.  These include seeing a patient who shows one or more of the following conditions:

Thrombocytopenia

Hemolysis

Schistocytes

Kidney failure

Because AHUS can lead to significant organ damage (especially the kidney), patients often end up in the hospital, often for kidney dialysis to filter out toxins in the blood that are normally controlled by the kidneys.  Many diseases can cause this same health issue, and the symptoms of AHUS can be confused with other, more common diseases.  That is why it is important to understand the biology of the disease, and how genetic tests may help experts tell an AHUS patient apart from a case of a more common disease that may require different treatment.  

Disease Biology - Learning about the “Complement” Pathway The alternate complement pathway (AP) is a part of the human immune system that is constantly active in our bodies. Tight control of this pathway is required to regulate how much of an enzyme called “C3 convertase” is present in the body.  The C3 convertase enzyme helps the body assemble a complex of proteins called the “membrane attack complex,”  which causes endothelial cell damage, platelet activation, and thrombus formation.

The effects of this “membrane attack complex” are important, but can become over-active in AHUS patients.  Normally, this complex serves an important role in protecting the body from infectious agents and diseases.  However, when one of the genes involved in the alternative component pathway is missing or cannot function at normal levels, dysregulation can lead to dangerous side effects.

Multiple different genes in this pathway can be mutated in aHUS patients.  

Mutations in genes that control the alternative component pathway may account for about 2 out of 3 of aHUS cases.  Complement factor H mutations are among the most common and are thought to be present in 1 of 4 patients based on patient registry studies. Membrane cofactor protein (MCP), Complement factor I (CFI), complement component C3 (C3), and thrombomodulin are other common mutations, seen in about 1 in 20 aHUS patients. respectively.  While this insight has helped to better understand the disease, there are still many patients (about 1/3) who will present with aHUS symptoms but not test positive for mutations in known genes associated with the disease.  Much still remains unknown about how gene expression and other factors may lead to aHUS for large portions of the patient population.

Clinical Presentation of aHUS AHUS may develop either in childhood or adulthood, and are equally likely to be male or female.  Often, AHUS first appears in an episodic way, where symptoms may come and go over time.  Sometimes, these symptoms can be triggered by another health event.  Particularly common is a trigger of AHUS symptoms after an infection (such as an upper respiratory tract infection or gastroenteritis). For women, the first episode of AHUS symptoms may occur around the time of a pregnancy, often after birth.

Patients with aHUS often appear pale, experience low appetite, nausea and vomiting, fatigue, and drowsiness. Some patients may also have edema (swelling caused by blood cell buidup, often in the ankles and feet) or hypertension due to kidney injury or ischemia, which can be severe enough to cause heart failure. The majority of patients, both adult and children, may need dialysis and hospital admission. Also, symptoms showing an impact on the disease in the liver or brain may be seen in 1 out of 10 patients. These can include irritability, drowsiness, seizures, partial blindness, confusion, and even coma.

The development of aHUS can be unpredictable;  patients may have symptoms that fluctuate for months, and may show kidney dysfunction before or after the symptoms that lead to diagnosis.  

Learn More

Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review CurityMD results for Benign Schwannoma - all our top experts, hospitals, and research in the condition: view results

This work was made possible through an article published by Carla Nester, MD, MSA, Assistant Professor, Director, Pediatric Glomerular Disease Clinic, University of Iowa Hospitals and Clinics; Phone: [phone]; e-mail: [email protected].

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INTRODUCTION TO COMPASSIONATE USE

A Lesser - Known Way for Patients to Access Experimental Treatments

(CurityMD’s educational series on clinical research, part 7)

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

Decoding research can be challenging, especially when patients are trying to understand and access new treatments, including experimental treatments that are not yet FDA approved, but which are being studied in partnership with patients and hospitals in “clinical trials.”  Towards the end of clinical trials (see our earlier posts for descriptions on Phase 1, Phase 2, Phase 3 and Phase 4 studies), something called compassionate use may become an option.  This is an FDA-permitted process where a single physician can petition both the FDA and the company who makes the drug or treatment to provide access for a single patient to an experimental therapy even though the patient is not a candidate or cannot get enrolled in any clinical trial.  

Compassionate Use (also called “named patient programs”) are closely-monitored ways for a physician to request an experimental (pre-approval) drug for a specific (“named”) patient for a specific period of time.  This is often selected as an option when the condition or the patient has an immediate, severe health risk and/or no other therapeutic options (for example, a patient may have already failed other approved treatments, or may not be eligible for an ongoing clinical trial for one or more reasons).  

In compassionate use, a drug company often pays for all costs of treating the patient, in part because the company cannot charge for the drug if it is not FDA approved to treat that patient.

There is a significant amount of paperwork required for compassionate use, and it may not be accessible to all patients or physicians in all cases where a drug is in development or not approved.  It is also important to note that compassionate use is not a way for large numbers of patients to access an experimental drug;  because there is so much work involved, it is challenging for all parties - hospitals, doctors, regulators and drug makers - to support large numbers of patients in compassionate use programs.  Still, it may be worth talking with your provider to learn more about whether this is an option to pursue.

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EPIDEMIOLOGY - A Simple Introduction

(CurityMD’s ongoing research series - Part 8)

Decoding research - What is “Epidemiology”?

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.   This is the next post in a series to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.

You might have seen epidemiology discussed in a paper or website about rare diseases.  Experts and researchers consider epidemiology as an important tool to understand a disease, and to interpret results on potential new treatments that might help patients in the future.  What is usually not explained, though, is what they mean by epidemiology, and why it is important for patients to have a sense of where the term is relevant to them.

Epidemiology is the study of how a disease presents itself in the general population.  This means that people studying the epidemiology of a disease are looking at some of the following:

How many people are affected in a country or around the world

When a disease usually starts (for example - is it present at birth or before birth?  Does it affect people in their 60s?  like Alzheimer’s, is there a version of the disease that affects people at a younger age, and then another version that commonly affects people who are older?)

How a disease is distributed in the population - for example, are people of a specific ethnicity more at-risk or protected from developing a disease?  Are patients in urban areas more affected?

How does the disease population rect to different treatments for the disease?

How can patients with a disease be segmented to better understand the different ways a disease develops?  For example, are there genetic mutations that define a particular group of patients with a disease form the rest of their fellow patients?

So why care about epidemiology studies?  Epidemiology studies are more powerful and informational than ever, thanks in large part to the ability of researchers to study genetic differences within a patient population )even a rare disease patient population, which may be quite small compared to other conditions!)  In rare disease, epidemiology can help to determine whether a patient is a good candidate for a clinical trial, or whether a patient has the predisposition for a better response to a new treatment.  While not all rare disease have been studied at the epidemiological level to have this kind of information and evidence, those that do can provide patients with more choices, more accurate predictions of how a patient will respond to a treatment, and a better understanding of how their disease is likely to develop in the future.  

It is important to remember that none of this work is set in stone; epidemiology research is early evidence  that can suggest things to a trained expert.  The more epidemiology work that is done, the better this evidence becomes, and the more accurate the predictions that doctors make from epidemiology studies will be.  But there can always be unexpected surprises, and it is worth talking to a clinical expert to better understand how strong a given piece of epidemiology research is.  

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Search for expertise, clinical trials, and research in thousands of different diseases oncurityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review a general introduction to “Clinical Research”

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Clinical Trials By the Phases:

PHASE 4 TRIALS

(CurityMD’s series in decoding clinical research, Part 6)

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

This series of posts is written to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.

Phase 4:   A Phase 4 trial starts after a drug is approved, and involves a company or organization (often a university or advocacy group) doing further clinical study on patients in the same condition.  These trials are also sometimes called “follow on” studies, and can range from being short-term to long-term trials, either in a large population of patients or a small sub group.  Phase 4 trials may be required by the FDA when a drug is approved based on the clinical data shown in Phase 4, or may be performed by the company for their own research purposes.

Have you seen trials and wondered why one is a Phase 4 and not a Phase 3 (or the other way around)?  Think of it this way - a Phase 4 trial is collecting more data in the same condition after approval, while a Phase 3 trial may be going on for a drug that is FDA approved if the drug is being tested for a new indication.  For example, many drugs that the FDA has approved for rheumatoid arthritis (RA) have recently completed new Phase 3 trials in another condition called ankylosing spondylitis (AS).  Because it is a new condition, the makers of the drugs had to complete new Phase 3 trials, instead of being able to use Phase 4.

Phase 4 studies may be carried out by individual experts at hospitals or by consortium groups (as opposed to earlier stages of trials, which may be more likely to be sponsored by drug companies), and be focused on improvements in how approved interventions are given to patients, whether additional steps can help outcomes when patients take the drug, and other ways to improve the standard of care without the use of a new molecule.

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review a general introduction to “Clinical Research”

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Clinical Trials By the Phases:

PHASE 3 TRIALS

(CurityMD’s series in decoding clinical research, Part 5)

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

This series of posts is written to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.

Phase 3:     A Phase 3 trial, also called the “Pivotal” trial in clinical development, is the largest, and often longest, clinical trial before a drug is evaluated by the FDA for approval in a specific condition.  In the Phase 3 trial, the goal is to reinforce the signs of efficacy seen in previous trials, and to establish a comprehensive sense of common side effects in patients taking the new drug candidate.  Phase 3 trials are more likely than prior trials to be placebo controlled (at least to begin with), and to be “blinded” (so that patients enrolling in the trial do not know whether they receive the drug candidate or a placebo).  

Phase 3 trials may take years to complete, and years to analyze, interpret, and submit regulators for review and potentially for approval.  Depending on the results of the first Phase 3 trial, another one may be required by regulators (in the US, the regulatory body is the FDA).  Occasionally, while this data is being analyzed and assessed, a drug company and the FDA may work with doctors to make a drug available to individual patients on a program called “compassionate use,” where the drug company covers the cost of delivering the drug to individual patients whose doctors petition to get early access to the drug. 

For rare diseases:  Phase 3 trials in rare disease may differ greatly in rare diseases.  Because many rare diseases have either extremely serious symptoms or very few eligible patients (or both), Phase 3 trials may be much smaller, and use a large number of centers to enroll even a single patient at a hospital.  A Phase 3 trial for a common condition may recruit thousands, or even tens of thousands of patients across many centers around the world.  A phase 3 trial in a rare disease may enroll fewer than 50 patients.

While the Phase 3 trial may lead to approval and the ability for physicians to prescribe a medicine to patients, there is usually ongoing clinical tiral research for a drug even after it has been approved.  We will cover that in the next post, Phase 4 clinical trials.

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review a general introduction to “Clinical Research”

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Clinical Trials By the Phases: 

PHASE 2 TRIALS

(CurityMD’s series in decoding clinical research, Part 4)

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

This series of posts is written to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.

Phase 2:   A Phase 2 trial is often the first time that researchers, clinicians, and manufacturers see signs of how effective a drug is in real patients.  The phase 2 trial differs from most Phase 1 trials (which generally recruit healthy patients to test safety at different drug doses) by recruiting patients living with the disease, and by doing so across more than one hospital/university.  The physicians will usually use the best dose seen in their Phase 1 trial (based on the best mix of safety and the ‘signal’ they saw that suggested the drug was active in the Phase 1 group).  

In Phase 2, physicians are often looking for signs of efficacy - reduction in symptoms, slowing the progression of an advancing disease, or otherwise modifying the typical evolution of a condition.  These efficacy signs are often called primary endpoints, which the trial must meet to be considered a success.  Safety is also monitored, but is often called a secondary endpoint, meaning that the trial may be considered a success without showing a specific profile of safety.

Phase 2 trials are often “controlled” - meaning that there is at least one group of patients that does not receive drug, instead getting a placebo - and “blinded” - meaning that patients don’t know whether they are getting placebo or drug.  This may be different in rare diseases (see below).

For rare diseases:  Phase 2 clinical trials may look different for rare diseases.  Sometimes, the initial human trial (phase 1) can be combined with a Phase 2 efficacy trial, resulting in a “Phase 1/Phase 2” trial.  This may happen when there are especially few patients available to test (rare or ultra-rare diseases), or when the risk of going untreated is so high for a specific condition that both patient and clinician agree to taking on the risk of treating patients with an earlier-stage molecule.

Rare disease Phase 2 trials may be much smaller than Phase 2 trials for common conditions (the common condition Phase 2 trial may include hundreds of patients, where a rare disease Phase 2 could be in as few as 10).  Depending on the condition, more than 1 Phase 2 trial may be completed before moving on to the next and final stage in clinical trials, Phase 3

Next time - Phase 3!

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review a general introduction to “Clinical Research”

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CLINICAL TRIALS BY THE PHASES:

CurityMD’s series in decoding clinical research (part 3)

Phase 1 Clinical Trials:   These trials are often the smallest in a drug’s development.  A molecule will be extensively studied in animal models and in the research lab before starting a Phase 1 trial.  When the trial begins, hospitals will generally recruit healthy adult patients and give a series of different doses of the new molecule (this creates data called a “dose-response curve”), and then observe the healthy adults over a period of time to look at signs of toxicity, side effects, and other safety risks.  It is challenging to predict how the entire human body will react to a new molecule at different dose levels - how the liver and kidneys will metabolize it,  how it will circulate through the bloodstream and in the brain, and how it will affect the heart, lungs, and other organs.  

Phase 1 trials may also be “uncontrolled” or “unblinded” - meaning that there is no ‘control’ group of people getting a ‘placebo’ (uncontrolled), and that patients know that they are getting an experimental drug (unblinded).

For rare diseases:  drug development in rare and severe conditions may allow the inclusion of patient fighting the disease in a Phase I trial.  These trials may also be called “Phase 1/Phase 2” trials, meaning that the molecule is being tested for both basic safety and a preliminary sense of efficacy in a single trial.  This may be an option when there are few patients available (the condition is rare) or when the disease is extremely severe (and the patients and physicians and regulators are willing to allow patients to try an earlier-stage drug because of that severity).

Next time - Phase 2!

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Search for expertise, clinical trials, and research in thousands of different diseases on curityMD

Search the US Government clinical trials website - clinicaltrials.gov

Review a general introduction to “Clinical Research”

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What is “Clinical Research”?

CurityMD’s Series Decoding Research in Medicine (part 2)

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

This series of posts is written to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.

Clinical Trials are the only way that new molecules, devices, and interventions can be studied and considered safe to use in patients battling a disease.  The clinical trial process can take over a decade, and can cost over 1 billion dollars - making it a huge undertaking for companies trying to improve patient health.  In the US and around the world, clinical trials have evolved into a very structured process (and there are event specific rules for drugs in development to treat rare diseases), which break clinical development up into different phases - typically phase 1, phase 2, phase 3, and phase 4.  Drugs are approved after Phase 3, either by the FDA (in the US) or EMA (in Europe).  The approval rules are slightly different for medical devices, so we will start by focusing on new drugs in development (often called “candidates”).

Clinical Trials - Who, What, When, Where, Why:   Because clinical trials are one of the most important ways that rare and complex condition patients gain access to new approaches to treatment, we want to explain where these trials come from, who organizes them, and how they progress.  Our hope is that this information helps to empower patients to find trials that are relevant to them, and hopefully make well-informed decisions about enrolling.  

What:   Clinical trials are a formal, structured, long-term process of evaluating safety and efficacy of a newly-discovered molecule thought to have potential in helping patients with a disease.  Clinical trials are separated into phases (Phase 1,2,3,4 being the main ones).  During each phase a different aspect of a molecule is tested, either in healthy volunteers or in patients fighting the disease.  These trials eventually produce the data that will be used to evaluate whether a drug is suitable for approval by a regulatory group such as the FDA.

Why:   Clinical trials are an important process in drug discovery and development because they help minimize the risks of patients taking dangerous compounds or molecules without a good sense of the benefit/risk tradeoff between efficacy and safety.  A drug may help to reduce symptoms or delay the onset or advancement of a disease but be unsuitable as a drug because of serious safety risks.  It may also be very save, but not effective enough to add on top of the other medications often being taken by patients.  

Who: Clinical trials for new medications and interventions are often sponsored by a drug company or medical device company.  New drugs require years and hundreds of millions of dollars to take from their discovery (often in academic hospitals or labs) through to submitting safety and efficacy data to regulators such as the FDA.  Because it is so costly, hospitals and advocacy groups cannot bring drugs “to market” (to the point where they are manufactured and sold legally).  

Drug companies are increasingly focusing on rare and complex diseases, which now present some of the greatest unmet need in medicine.  While drug and medical device companies lead and fund clinical development, they do it in partnership with hospitals, advocacy groups, and sometimes patients.  More than ever, drug development in rare and complex diseases is a team effort.

Clinical trials are led by a Principal Investigator (also called a “PI”) at that center, and are typically coordinated by a research coordinator (often a nurse or nurse practitioner).  The coordinator monitors enrollment and helps evaluate patients over the course of their trial, working with drug company sponsors to make sure all procedures are being followed.  The PI has a similar role, but also treats and evaluates patients throughout the clinical trial, and evaluates whether a patient is a suitable candidate for clinical trials.  PI’s may also be the originators of a clinical trial, having thought of the idea to use a particular drug in a particular way within a specific disease.  

When:   New treatments are typically developed for years or decades before they are approved.  While the FDA may help to fast-track review and clinical trial design in the case of new medicines for rare diseases, this process still takes a long time.  Unfortunately, this may leave patients unable to access new therapies quickly, leading to frustration.  This occurs because efficacy and safety must be tested extensively to minimize the risk of serious side effects or expensive drugs that do not provide enough clinical benefits.  

While the wait is long and frustrating, clinical trials examining new drugs provide an opportunity for patients to be considered for early access to these medications, under strict conditions (called inclusion and exclusion criteria).  Additionally, patients may be able to request some medications on a compassionate use basis, where drugs that are not yet approved are given to patients at the specific request of the expert.  

Where:   Clinical trials often begin at a single academic center, one where there is a multidisciplinary team of experts in the condition, and one where there are administrative resources to help coordinate the completion and reporting of data throughout the clinical trial.  

Because of this relationship, and because rare diseases may be challenging to enroll (patients may be very hard to find around the world when there are very few of them) clinical trials may take place in a large number of centers around the world.  This often means centers are enrolling in the US, Europe, Central America.  

We have found that centers enrolled in clinical trials are often experienced at evaluating patients, and have the diverse resources required to successfully enroll patients in trials, deliver the treatment carefully, and provide the right follow up care.

Next time - learn more about Phase I, the first time a new candidate reaches the clinic for human trials.

Learn More:

Search for conditions of interest in CurityMD, and see where trials are happening in conditions that matter to you

Review the US Government’s site for clinical trials (we try to make this information more easy to navigate on our site)

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Decoding research - What is “Translational Research”?

At CurityMD, we are always busy analyzing and studying research in thousands of different rare diseases.  This is work being done by some of the most innovative physicians, scientists, and teams in the world, who have spent years (or even decades) trying to better understand the risks, causes, and pathways of rare conditions.  Since they live at the frontier of medicine, many times their work can leave patients, family members and advocates slightly behind in the trail of new science.  

This is the first post in a series to help you better understand this research at an introductory level.  We apologize if some of this is old news, but we want to start at square one.  

“Translational research” is work that bridges the gap between tests and experiments done in a lab with smaller, more controlled testing environments, and experiments that test the same hypotheses and questions but in a way that is more closely tied to humans.  For example, “basic research” - which comes before translational research - could test how two molecules interact in a petri dish, or within a cell;  “translational research” might be designed from the results of this petri dish experiment to see how this interaction of molecules affects animal models of diseases (such as flies, mice, rats, or other animals traditionally studied to better understand a variety of diseases).

Translational research is often done by universities and hospitals, and helps to connect individual scientific concepts that work in an artificial setting created by scientists into a living system, where there are more variables but also more direct connections to human diseases.  Sometimes this work is done in partnership with Pharmaceutical and biotechnology companies, who fund scientists and physician experts to perform translational research that could lead to new, more effective drugs.  This is why you might see “conflict of interest statements” or “disclosure statements” when you read scientific articles or see physicians give presentations - it means that a drug company has given a grant to help further medical research in universities and hospitals.    

Translational research can help show early signs of toxicity, binding properties, effects on organs and cells, and more.  

A great deal of work in translational and preclinical research needs to happen before a new discovery starts being developed as a drug, and that includes moving early-stage research from a university (where the translational research began) to a drug company.  When development moves into a drug company setting, more in-depth preclinical research is performed on the molecule, testing it as a potential drug target in many ways.  If this goes well, the company may even start to do “first-in-man” trials that study the general effects of a molecule on human beings (usually healthy volunteers at first).  This makes translational research a critical point in developing new medications and interventions for disease.

In our next post, we will discuss what happens after translational research - the first step in clinical trials.  

Learn More:  

Read an introduction to Translational Research from the Children’s Hospital of Philadelphia

See an example of a Translational research center at the University of Iowa

Meet the research experts at the Translational Research department at the Penn Medicine Cancer Center 

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Resources for Ongoing Care in Spina Bifida - Neurogenic Bladder

Spina bifida (and myelomeningocele, MMC, the most severe type of spina bifida) is a type of open neural tube defect that can occur with problems with the early development of a fetus.  Spina bifida results when the tissue at the bottom of the spinal cord fails to close completely. Spina bifida usually results in a variety of medical problems including nerve damage and motor function deficits, and abnormalities of the brain.  Learn more about Spina bifida experts here.

While we have written about the MOMS trial, one of the definitive clinical trials testing a new surgical approach to treating Spina Bifida and MMC, the reality is that much of the attention and care in the condition is focused on prenatal and infant care.  So much comes after that, as our own Patient Writer Nicole tells us.  In this post, we highlight a few of the resources that some hospitals offer, and provide a few links to hospitals which actively have resources for growing patients.

Ongoing Care  in Spina bifida/MMC:  Neurogenic Bladder

One of the most common conditions in Spina Bifida and MMC is called neurogenic bladder. Because MMC and spina bifida involve spinal cord malformation, often the nerves controlling the bladder are incompletely connected. This can result in difficulty storing urine and emptying the bladder.  Periodic catheterization becomes a common practice in these cases, which can protect the kidneys and prevent urinary tract infection and allow a higher quality of life.  Spina Bifida patients also frequently require a bladder medicine from the anticholinergic class of medications, that helps relax their bladder so that it may store more urine.

For patients who are not controlled by the medical treatments listed above, some surgical options are also available.  These treatments can include some of the following:

Vesicostomy:  A vesicostomy is an opening in the lower abdomen into the bladder.  This opening allows urine to continuously drain out of the body (reducing the need for catheterization, and potentially helping protect kidney health). The opening is created by a surgical procedure where a small incision is made through the skin and into the bladder. A small part of the bladder wall is turned inside out and sewn to the abdomen. It appears as a small slit, surrounded by pink tissue. The vesicostomy is a temporary and reversible option.

Bladder Augmentation, which can make catheterization less frequent, improving independence and overall quality of life.

Appendicovesicostomy, a procedure brought to North America by the Children’s Hospital of Philadelphia, involves creating a connection between the outside of the body and the bladder.  This allows children and adults with neurogenic bladder to independently empty their bladders, which can help improve independence and overall quality of life.

MACE (Malone antegrade colonic enema) where an opening is made in the GI system to allow patients to self-deliver enemas directly to the colon.

Cecostomy buttons (where a tube is implanted to help children with stool incontinence flush their colon).

Learn More:

Review top experts, multidisciplinary clinical teams, and hospitals with experience in spina bifida and myelomeningocele on CurityMD:

A description of neurogenic bladder

Spina Bifida and Myelomeningocele

Spina Bifida Aperta

Spina Bifida Cystica

Children's hospital of Philadelphia neurogenic bladder team

UCSF's neurogenic bladder program 

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Resources for Ongoing Care in Spina Bifida - Bladder Exstrophy

Spina bifida (and myelomeningocele, MMC, the most severe type of spina bifida) is a type of open neural tube defect that can occur with problems with the early development of a fetus.  Spina bifida results when the tissue at the bottom of the spinal cord fails to close completely. Spina bifida usually results in a variety of medical problems including nerve damage and motor function deficits, and abnormalities of the brain.  Learn more about Spina bifida experts here.

While we have written about the MOMS trial, one of the definitive clinical trials testing a new surgical approach to treating Spina Bifida and MMC, the reality is that much of the attention and care in the condition is focused on prenatal and infant care.  So much comes after that, as our own Patient Writer Nicole tells us.  In this post, we highlight a few of the resources that some hospitals offer, and provide a few links to hospitals which actively have resources for growing patients.

Specialty Care for chlidren/adolescents in spina bifida/MMC:  Bladder Exstrophy

Bladder complications are extremely common in MMC.  This may adversely affect urinary continence and quality of life, and can also lead to deterioration of the urinary tract over time, and even kidney disease (Source - UpToDate.com). 30-40% of children with MMC develop some degree of renal dysfunction, and this can lead patients and families to consider surgical correction.  “Bladder Exstrophy” refers to the bladder developing outside of the body, a condition that may require rapid correction. Some centers will prefer multiple procedures, while others show a preference for repairing bladder exstrophy in a single operation.  In Spina Bifida and MMC cases, this will generally be an additional, post-birth procedure (or procedures), and will often include surgeons from a hospital’s department of urology.

After the procedure, we recommend seeking out programs that have a dedicated team of physicians, nurse practitioners, and other care providers to provide ongoing clinical, emotional, and social support with the condition.  Post-operative treatment involves learning a lot about ongoing and lifelong care, so an experienced team can be very valuable.

In 2010, The Children’s Hospital of Philadelphia started a consortium of three centers - theirs, Boston Children’s Hospital, and the Children’s Hospital of Wisconsin.  Each of these programs, surgeons and caregivers share their experience with the goal of improving immediate, and long-term outcomes.

Learn More:

Review top experts, multidisciplinary clinical teams, and hospitals with experience in spina bifida and myelomeningocele on CurityMD:

Spina Bifida and Myelomeningocele

Spina Bifida Aperta

Spina Bifida Cystica

CHOP describes bladder exstrophy team

Boston Children's describes blader exstrophy team

Children's Hospital Wisconsin describes their bladder exstrophy team

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Resources for Ongoing Care in Spina Bifida

Spina bifida (and myelomeningocele, MMC, the most severe type of spina bifida) is a type of open neural tube defect that can occur with problems with the early development of a fetus.  Spina bifida results when the tissue at the bottom of the spinal cord fails to close completely. Spina bifida usually results in a variety of medical problems including nerve damage and motor function deficits, and abnormalities of the brain.  Learn more about Spina bifida experts here.

While we have written about the MOMS trial, one of the definitive clinical trials testing a new surgical approach to treating Spina Bifida and MMC, the reality is that much of the attention and care in the condition is focused on prenatal and infant care.  So much comes after that, as our own Patient Writer Nicole tells us.  In this post, we highlight a few of the resources that some hospitals offer, and provide a few links to hospitals which actively have resources for growing patients.

How To Define A Powerhouse Spina Bifida Team? One of the most common elements of a successful Spina Bifida / MMC team is a mature, multidisciplinary team.  These teams will see patients before birth or after birth (whether or not the patient had their initial procedures and surgeries with their team), will often offer both prenatal and post-natal surgery options, and will provide comprehensive care for the entire patient (not just the spinal cord area).

Some key aspects of multidisciplinary Spina Bifida/MMC teams:

urology

neurology

neurosurgery

orthopedics

nephrology

genetics

orthotics

note - many of the above specialists do more than what we listed, and can be patient champions in many ways.  The above is meant as a general introduction.

Comprehensive evaluation Top teams will often go further than a surgical or medical or prenatal evaluation, offering ongoing evaluations throughout pregnancy, infancy, childhood and adolescence.  The goal of these teams is to constantly address a patient as they experience the immediate recovery after surgery (either prenatal or postnatal), then

Long-term management is another crucial element for Spina Bifida care.  Spina Bifida and MMC affect infants, but after initial interventions (surgeries, consultations and decision support), patients grow up.  That is why clinical support for both children and teens with spina bifida is important.  This care can include support for spinal cord injuries and other spinal cord abnormalities, motor function, cognitive function, and kidney/bladder function (among others).

Learn More:

Review top experts, multidisciplinary clinical teams, and hospitals with experience in spina bifida and myelomeningocele on CurityMD:

Spina Bifida and Myelomeningocele

Spina Bifida Aperta

Spina Bifida Cystica

[curitymd]

Celebrating Rare Disease Day 2015

It’s a statistic heard often in the rare disease community, but one that seems consistently surprising:one in ten people in the United States lives with a rare disease. While individual diseases may seem rare, collectively these disease affect a massive number of Americans.

So on the last day of February each year, in hospitals and homes, across social media and news networks, and throughout the halls of governments and companies, a plea for awareness can be heard: Rare diseases are not so rare.

Rare Disease Day was launched in 2008 by EURORDIS, a European alliance of rare disease organizations, and was adopted in the US in 2009 by the National Organization for Rare Disorders (NORD). With the goal of raising awareness of rare diseases and their impact on patients’ lives, the day has grown spectacularly since its inception. Eighty four countries now participate and thousands of events have taken place reaching hundreds of thousands of people.

Last year was a particularly significant year for Rare Disease Day in the US. Not only did 1,800 organizations become partners and supporters in 95 events in 37 states, but the US Senate issued a proclamation declaring February 28th Rare Disease Day.

Today is Rare Disease Day 2015, and the theme is “Living with a Rare Disease,” with the intention of “paying tribute to the millions and millions of parents, siblings, grandparents, spouses, aunts, uncles, cousins, and friends whose daily lives are impacted and who are living day-by-day, hand-in-hand with rare disease patients.” The day’s ambassador, Sean Hepburn Ferrer, lost his mother, actress Audrey Hepburn, to a rare cancer called pseudomyxoma adenocarcinoma---a disease that affects only one in a million individuals. His video can be viewed here.  

So how can you participate? Check out NORD’s Rare Disease Day US site to partner, donate, find events in your area, create an event, and more. CurityMD is excited to participate, and help draw attention to rare diseases and an important public health issue that cannot be ignored.

And if learning more about expertise in thousands of rare diseases - the clinical trial runners, the translational research innovators, and the multidisciplinary teams that drive the frontier of new medicine in rare diseases - come see us and search for free at curitymd.com 

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Expert Critique of Fetoscopic Surgery for Myelomeningocele 

What Happened:   

In this new opinion article, published by authors at the Children’s Hospital of Philadelphia (CHOP), provided commentary on work done by a fetal surgery team in Germany who provided updated information about fetoscopic treatment of myelomeningocele (MMC).  The authors of the article suggest that, based on this international data, minimally-invasive (fetoscopic means a procedure that takes place through minimal surgical exposure of the fetus) MMC surgery still needs improvements before becoming a possible standard of care.

  What they Found:

The Germany team has worked for over 10 years in fetoscopic surgery, reporting on over 80 patients.  From this data (and a small amount of research from other groups), This type of MMC surgery remains challenging from a technical perspective - it requires multiple points of surgical tool insertion, which can lead to rupture of uterine membranes, a severe complication to fetoscopic surgery.

The author also has some concerns about how the MMC is repaired during the fetoscopic procedure, a question which may be harder to answer when the surgery is performed in this fetoscopic manner.  Overall, the author urges more caution and observation for these types of concerns before considering fetoscopic surgery for MMC.

  Why it Matters:

Spina Bifida and MMC are extremely challenging cases that require interdisciplinary care, and where innovative treatments have led to a fascinating evolution in treatments from interventions after birth to prenatal procedures.  While this evolution has shown promise in improving long-term outcomes, there is still room for improvement.  Because of that, work such as the fetoscopic research from Germany is critically important - but it must be critiqued and analyzed before it can become a new (future) standard of care.

   Learn More: 

Review commentary on the article from CHOP’s website here

Review top experts, multidisciplinary clinical teams, and hospitals with experience in spina bifida and myelomeningocele on CurityMD:

Spina Bifida and Myelomeningocele:

Spina Bifida Aperta

Spina Bifida Cystica

[curitymd]

Fetal Myelomeningocele Repair - Experts Share Their Technical Experience

Abstract from the published article: 

Myelomeningocele (MMC) is one of the most common serious congenital malformations. Typically this condition has been treated with closure of the MMC defect shortly after birth. In general, surgery for MMC aims to provide a multilayered closure to provide protection to the neural elements, prevent leakage of spinal fluid and reduce infection risks. A randomized controlled trial, the Management of Myelomeningocele Study (MOMS), has shown that closure during the fetal period can be performed relatively safely and can result in significant benefit to the child. Whereas the surgical technique of prenatal closure of an MMC defect is similar to a postnatal closure, there are some important technical differences. The goal of this paper is to describe the technique of fetal closure of MMC defects, highlight the unique steps that are needed for this surgery and delineate some potential pitfalls.

  CurityMD Commentary:

The authors of this paper, part of the fetal team at the Children’s Hospital of Philadelphia (CHOP) One of the most valuable segments of this article may be the role-by-role breakdown of the fetal team who reviews and evaluates MMC cases at large-volume hospitals such as CHOP.  Prenatal surgery requires a coordinated effort from a number of people, including:

Anesthesia team with special training in fetal surgery and an understanding of both fetal and maternal anesthesia needs.

Fetal cardiology is present to monitor the fetal heart rate and function using fetal echocardiography, variables that can be affected by fetal manipulation and anesthesia.

A maternal-fetal medicine obstetric team is present to monitor the mother, manipulate the fetus and aid in the selection of the hysterotomy location.

A nursing team prepares fetal resuscitation drugs in case they are needed, and prepares a graft if it is likely to be needed.

Fetal surgeons, who perform the hysterotomy, provide access to the fetal spine and perform the maternal laparotomy and closure.

Fetal neurosurgereons, who perform the MMC closure with a fetal surgeon as co-surgeon

Once the team has reviewed the case and determined that prenatal treatment of MMC is appropriate, the authors go on to describe fetal MMC closure in extreme detail.  There are several images of surgical steps, and a level of detail that is written by and for surgical experts.

Why do they write in such a technical terminology?

This article from CHOP’s fetal surgery team is important because it is sharing highly detailed instructions and guidance for prenatal MMC surgery.  This surgery was innovated across several hospitals over the past several decades, with a significant clinical trial (MOMS) showing that it might be more effective in some cases than closure after birth.  However, the prenatal procedure has evolved over the years, is high-risk and complex, which may leave many fetal teams struggling to understand the finer points of the procedure.  This article helps to address some of those, which could lead to more families able to consider the procedure.

  Learn More: 

Review the full article here - WARNING:  contains surgical imagery which some may find graphic

Learn more about the MOMS trial that helped examine prenatal surgery

Review top experts, multidisciplinary clinical teams, and hospitals with experience in spina bifida and myelomeningocele on CurityMD:

Spina Bifida and Myelomeningocele

Spina Bifida Aperta  

Spina Bifida Cystica