What is Alport syndrome and who does it affect?
Alport Syndrome was first described by a physician called Cecil Alport, back in the late 1920s. It's a genetic disease that affects a certain type of collagen involved in the functioning of the kidney, the ear, and the eye.
Mainly, when people discuss Alport Syndrome, they're thinking about kidney disease, but a number of these patients do also have impaired hearing and impaired vision.
As a genetic disease, Alport syndrome can affect anybody in the genetic inheritance line concerned.
Probably about 75% of the transmission is what we call X-linked, so inherited through the X chromosome. The condition therefore predominantly affects males.
In the remainder of cases, the condition is not X-linked and the inheritance rate is comparable between males and females.
Depending on the nature of the genetic mutation, the age at which the syndrome starts to cause symptoms varies.
Overall, you tend to see patients initially presenting with symptoms of renal disease at some point in their teens. Quite often, they will have hematuria or blood in the urine, but are otherwise feeling well, which is usually the reason they visit the doctor.
There's then a cascade of investigations the doctor undertakes because, so long as no urinary tract infection is present, healthy people should not have blood or protein in their urine.
How much is currently known about the causes of Alport syndrome?
Quite a lot is actually known about the causes in terms of the genetic defect affecting specific collagen molecules. Certain genes code for those molecules, which are very important with regard to the anatomy of the kidney.
The collagen molecules are assembled in an arrangement referred to as the basement membrane, which is critical in enabling the kidney to function as an effective filter of waste products.
In Alport syndrome, because the basement membrane collagen is not constructed correctly, the kidneys basically fail to function properly and, over time, inflammation and consequently fibrosis (scarring) develop.
Why is the condition poorly understood?
We understand quite a lot about the disease process and about the genetics, but Alport syndrome is not a very common disease and there are no approved therapeutic interventions for these patients.
Basically, patients are diagnosed and monitored, perhaps initially by a pediatric endocrinologist, and then referred to major centers.
For example, in the UK, I think you'll find the Great Ormond Street has a lot of experience because teenagers diagnosed with the condition are looked after there. The teenagers are monitored and eventually their renal function declines to the point where they need dialysis or a kidney transplant.
However, one of the ways that we understand disease in our industry is to study it in detailed controlled clinical studies. In Alport disease, therapeutics haven't been available to support those studies, meaning we're missing a lot of that type of data – the sort that would be generated in the study of other well-known diseases.
What are the main renal function markers and why is it important to study how they decline in Alport syndrome patients over time?
There are a number of different markers that we generally follow to assess kidney function. The kidney is an important organ in the body for filtering waste products and you can actually just measure the levels of those, both in the blood and the urine.
One good examples is creatinine, a by-product of muscle metabolism. The levels of creatinine are generally well established in a healthy body with normal kidney function.
Creatinine is actively excreted by the kidney into the urine, but as the kidney function declines, the creatinine level in the blood goes up. Creatinine is therefore a good marker of kidney function and requires just a simple blood test.
Another waste product that is relatively simple to test for is blood urea nitrogen (BUN). This is the level of nitrogen in the blood that comes from urea, the breakdown product of protein. Urea is excreted through the kidney and as kidney function declines, the BUN level in the blood rises.
We can also assess kidney function fairly accurately using something called the glomerular filtration rate (GFR), which assesses the function of the glomerulus, a structure which is primarily involved in handling the excretion of waste from the body.
There are different ways of testing the GFR. You can estimate it by looking at levels of certain other markers in the blood or urine or you can perform what is referred to as a “measured GFR.”
For that test, you administer either orally or intravenously, a chemical that you know is excreted by the kidney in a certain way. Then, you assess the levels of that chemical in both the blood and the urine over time. That information can then be used to generate a very accurate measure of kidney function – the so called “measured GFR”.
In addition, there are other biomarkers one can look at such as beta-2 microglobulin. As we're working in the microRNA space and know that we can detect microRNAs both in blood and in urine, we'll also be looking at those microRNAs as part of our trials.
Finally, a renal biopsy can also be used to assess renal function. A needle is used to take a small sample of tissue from the kidney, which is then examined histologically with special stains to assess the amount of inflammation, fibrosis or whatever is in it.
However, this is an unpleasant procedure for the patient and it is often only performed to confirm diagnosis in cases of chronic kidney disease. A lot of the other markers I just described involve either a blood or urine sample, so they are used on a more routine basis.
What do you think will be the main challenges in increasing our understanding of Alport syndrome?
I think we have a good sense of the disease in terms of its inheritance pattern and exactly what happens to people who develop the disease.
In terms of therapeutic intervention, we need to establish the endpoints that could be used in a clinical study to assess the effects of the intervention on a given measure. Obviously, in this patient population the most desired outcome would be to arrest the disease and stop its progression.
If that is not possible, the aim could be to significantly slow disease progression so that instead of patients developing end-stage renal disease by their late 20s, it could be delayed until the late 30s, 40s, or even later.
We need to look at measures that we can reproducibly analyze as part of the clinical study, perhaps by examining the difference between a group receiving treatment and a group not receiving treatment.
That's basically what we want to try and do, but the formal process of getting a drug approved and establishing those endpoints needs to be agreed both in the US with the FDA and with the European Medicines Agency in Europe, so that regulators agree that the endpoints used in the clinical protocols are suitable for assessing the efficacy of the drug.
What do you think the future holds for Alport syndrome patients?
I think the good news is that, as new therapeutic interventions are introduced to these orphan disease populations, people will start paying more attention to the patients and to the disease.
There are some great patient support groups that are trying to educate people about how Alport syndrome is a genetic disease that may be considered as a possible diagnosis when there are even the earliest signs of kidney disease.
The tests used to diagnose Alport syndrome are relatively simple genetic tests, yet a number of healthcare systems in the US will not reimburse for those tests.
I think that as this patient group starts to make noise, it could push for earlier diagnosis. I think the doctors who look after these patients can really start to think about working with the patients and with companies like us, with regard to properly studying therapeutic interventions.
I think overall, people will pay more attention to the disease, which at the end of the day is a great thing in terms of the patients' outcome.
What are Regulus’ plans for the future?
We've started our Athena study, a natural history study that is currently enrolling patients into a formal clinical protocol. We are frequently testing these patients to monitor their renal function and a number of other things over time, so we can assess what the natural progression of the disease is in a prospective manner. That study has started now in the US.
We hope we can use the information from this study to talk with both the FDA and EMA regarding endpoints and possible designs for a Phase 2 study, which we would like to start about a year from now.
We're currently trying to gather all the right paperwork to put together an Investigational New Drug (IND) application. We will also be able to file all of that paperwork in Europe in the future. The IND will allow us to do some initial work in the US using healthy volunteers to help us better understand the kinetics of this drug. We want to examine different subcutaneous doses to see how much gets into the bloodstream and how much is excreted through the kidney.
We'll do some of that work over the first half of next year, and then continue to work on the Phase 2 design with a number of the key opinion leaders and with regulatory agencies. That's our plan for the future.
Where can readers find more information?
Users can find more information at the Regulus website, regulusrx.com.
At the bottom right hand corner of the homepage, there is information about the Athena clinical trial where people can also link to the alportstudy.com website.
That site is really useful to look at because, as we discussed, this is a patient population that hasn't really been involved in clinical study before. The website provides background information about being a patient in a clinical trial.
We need the patients' support and commitment to come to their clinic visits, agree to the blood tests, and other things.
We need the clinical study to be a partnership between us, the patients and the doctors looking after these patients, if we're going to be successful in moving the clinical program forward.
About Dr Paul Grint
Dr. Grint joined Regulus in June 2014 with over two decades of experience in biologics and small molecule development, including the successful commercialization of numerous commercial products in oncology, anti-infectives and immunology in both domestic and international markets.
Prior to joining Regulus, Dr. Grint was President of Cerexa, Inc., a wholly-owned subsidiary of Forest Laboratories, Inc., where he was responsible for the oversight of anti-infective product development.
Prior to that, Dr. Grint served as Senior Vice President of Research at Forest Research Institute, Inc., Chief Medical Officer at Kalypsys, Inc., and Senior Vice President and Chief Medical Officer at Zephyr Sciences, Inc., and he also served in similar executive level positions at Pfizer Inc., IDEC Pharmaceuticals Corporation, and Schering-Plough Corporation.
Dr. Grint received his bachelor’s degree from St. Mary’s Hospital in London and his medical degree from St. Bartholomew’s Hospital Medical College at the University of London.
Dr. Grint is a Fellow of the Royal College of Pathologists, a member of numerous professional and medical societies, and the author or co-author of over fifty scientific publications.