Promising Drug Puts Focus on Rare Condition That Can Lead to Growth of Tumors, Cysts

CURECURE® Fall 2020 Issue
Volume 19
Issue 4

The FDA is reviewing what could become the first-ever medication specifically for kidney cancer associated with von Hippel-Lindau disease.

A recent promise by the Food and Drug Administration (FDA) to give an expedited review to the experimental drug MK-6482 as a treatment for renal cell carcinoma (kidney cancer) associated with von Hippel-Lindau (VHL) disease was an exciting development for people with VHL.

Granted a breakthrough therapy designation from the FDA, the HIF-2a inhibitor is the first medication specifically indicated for people with VHL, which causes masses, some of them malignant, to grow in any of 10 organs. The disease is caused by a mutation to the VHL gene.

MK-6482 interferes with the activity of the HIF-2a protein, which — in the absence of a properly working VHL gene — accumulates, leading to the formation of tumors.

Because it’s a rare condition that affects about 10,000 people in the United States and 200,000 worldwide, VHL is not widely understood or recognized. CURE® spoke with Joshua Mann, director of engagement and outreach for the nonprofit VHL Alliance (, to learn more.

CURE®: Please tell us a little bit about VHL.

Mann: Von Hippel-Lindau disease is a rare hereditary tumor predisposition syndrome. It’s caused by a mutation in the VHL gene, which normally prevents tumor growth. This mutation can cause tumors to grow and develop in up to 10 different organs repeatedly throughout a patient’s lifetime. There’s no cure, and the best practices for treatment involve invasive surgeries that can be dangerous, painful and expensive. VHL runs in families, but it’s not restricted or predominant to any particular demographic. Its prevalence is about 1 in 36,000.

Is this always an inherited condition?

Not strictly. Approximately 80% of people who have the disease inherited it from a parent. Every child of a parent with VHL has a 50% chance of inheriting the disease. The other 20% of people with VHL have it as a result of a random genetic mutation that occurred soon after fertilization during the early human cell- division process.

Which cancers are associated with VHL?

In people with VHL, tumors may develop in up to 10 different parts of the body, including the brain, spine, eyes, ears, kidneys, adrenals, pancreas, lungs, liver and reproductive organs. All of these tumors involve the abnormal growth of blood vessels. Most of the tumors are benign, meaning they won’t spread to nearby organs. However, VHL tumors in the kidneys, adrenals and pancreas can grow to a stage where they become malignant, which is when the cancer can spread to other parts of the body.

It’s also important to mention that just because some of the tumors associated with VHL are benign does not mean that they aren’t serious or dangerous. Brain and spinal lesions can lead to extreme pain and permanent disability, and retinal tumors can lead to blindness. VHL is different in every patient, even in the same family. Since it’s impossible to predict exactly which VHL manifestations each person will have, and at what age, it’s important to continue to check for all the possibilities throughout a patient’s lifetime.

How can people find out they have VHL if no one else in their family has it?

Oftentimes, it happens that a manifestation of the disease comes out that’s unexplained any other way, and then the patient is sent for genetic testing. The rule of thumb is that, when any of the features of VHL are found, a diagnosis of VHL should be considered and a full diagnostic evaluation of all the other areas of the body should be carried out.

The only conclusive way to diagnose VHL is through a genetic test. Anybody who thinks they might have VHL in their family should see a genetic counselor. It is estimated that no DNA mutation or deletion can be found in approximately 10% of people who are clinically diagnosed with VHL. These people still have VHL and should begin a surveillance protocol.

Are there any preventive measures people can take if they know they have the disease?

To prevent some of the worst outcomes associated with the disease, the best thing people can do is be vigilant about active surveillance and always work with VHL-experienced specialists. Other than that, having a healthy diet and an active lifestyle, not smoking and moderating alcohol intake are things that can be done to contribute to overall good health.

What does active surveillance look like throughout an affected person’s lifetime?

Surveillance is the first line of defense in preventing the worst aspects of the disease, and it should begin as soon as there’s a diagnosis, before symptoms appear, to make sure that any issues are found early and treated at the best time to ensure long-term health.

The VHL surveillance guidelines include an annual eye exam with a retinal specialist and a complete physical exam. At age 5 begins an annual urine collection or blood testing for pheochromocytomas, which are associated with tumors in the adrenal glands. Starting at age 11, patients will get an annual hearing test by an audiologist, as well as imaging of the brain and spine every two years.

Then around age 15, they will begin getting an MRI of the abdomen every two years to check their pancreas and kidneys. It’s certainly an ongoing endeavor. If anybody’s interested in learning about the specific details of the surveillance guidelines, you can find them here.

What are your thoughts on the development of MK-6482?

We are extremely excited by the designation of MK-6482 as a breakthrough therapy by the FDA. If approved, it would be the very first medication specifically for VHL. This offers a lot of hope to the VHL community, as it could mean, one day, an alternative to these repeated, dangerous and painful surgeries.

It’s also exciting because the VHL Alliance’s vision is curing cancer through VHL. Advanced treatments and a cure for VHL are going to have major implications not just for patients with VHL, but also for the general population. For example, renal cell carcinoma is a major disease that affects many people, and by finding a cure for VHL and improved treatments for its manifestations, we’re going to be able to cure renal cell carcinoma. It starts with research at the basic level, and that’s why supporting VHL research is so crucial.

In fact, the 2019 Nobel Prize in Physiology or Medicine was awarded to three doctors including Dr. William Kaelin Jr., a VHL researcher. The reason we have MK-6482 today is because of that research. I think the world is finally starting to see the importance of medical research with the VHL gene.

What were the origins of the VHL Alliance?

The VHL Alliance was founded in 1993 by three families affected by VHL. This was done in the pre-internet era when people had limited means to connect and share information, so this was a vital service for those who had this disease that not much was known about. Since then, we’ve grown significantly. We have an international network of VHL clinical care centers capable of providing coordinated care by VHL-experienced specialists, and we have an enormous reach online and via social media, engaging with thousands of patients and families annually from all over the world.

We’ve also put a major emphasis on research, developing an in-depth, longitudinal online patient registry called MyVHL, as well as awarding over $2.3 million in research grants. We are the largest provider of research grants specifically for VHL in the world. Recently, we have been active in lobbying Congress to support spending on rare diseases and have participated in FDA listening sessions to share firsthand the importance of VHL research, clinical trials and the development of non-invasive treatment alternatives.

Are there any special projects on the horizon for the group?

We are in the final stages of publishing an updated VHL handbook with information about research and best practices and details of the disease. And we recently had a task force of top VHL experts in different specialties that put together updated surveillance guidelines based on a literature review, from which a manuscript will be published soon. We’re also focusing on addressing the needs of marginalized populations to make sure that everyone in the VHL community has access to quality care.

In October, we’ll have two huge online events. One is our Annual Family Weekend Oct. 23-25, where we bring families impacted by VHL together to talk with doctors and each other for support and to learn what can be done to better support the community. Our biennial Research/Medical Symposium will be Oct. 29-31. We’ll bring together top VHL researchers and physicians from all over the world to discuss what’s going on in research and see where we can capitalize on improvements and things that we’ve learned. We’re very excited about the great things that are going to come out of it.

How has the COVID-19 pandemic affected your organization?

The biggest impact that the COVID-19 pandemic has had on our organization was transitioning our Annual Family Weekend and biennial Research/Medical Symposium from being large, well-attended, in-person events into remote, digital events. Over the past seven months, we’ve put a focus on bringing our community together digitally.

We created an initiative called Surviving and Thriving Together, which consisted of several dozen live videos on Zoom and Facebook where patients, family members and caregivers had a chance to interact and support each other. At other events, they had a chance to learn more about their doctors, advances in research and our staff. The end goal was to make sure that everybody felt a sense of community.

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