Rare Diseases

FEBRUARY 2019 | FUTUREOFPERSONALHEALTH.COM

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Rare Diseases

Gaten Matarazzo, star of “Stranger Things,” shares how being different made him special.

DISCOVER one family’s journey struggling with a rare undiagnosed genetic disease

LEARN about the research of Pompe disease as we look back on 20 years of treatment

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in this issue

One doctor shares how growing up with a rare disease inspired her to build a community that helps others.

Page 8

Genetic counseling provides support to help patients and caregivers improve their quality of life.

Online

Years of advocacy has finally brought attention to the power of precise and personalized treatments.

Page 10

Rallying Public Support for Awareness of Rare Diseases A new campaign seeks to engage and inform the general public about rare diseases.

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ach year on the last day of February, the National O rg a n i z a t i o n f o r R a re Disorders (NORD) highlights the impact of rare diseases on the lives of approximately 350 million people worldwide. The goal of Rare Disease Day is to increase awareness around rare diseases and to bring to the forefront the many issues rare disease patients, their families and caregivers face every day. Drawing attention to disorders that may not be as familiar to the general public as more commonly known illnesses can be a challenge, even on a national awareness day.

Peter L. Saltonstall President and CEO, National Organization for Rare Disorders (NORD)

Rare diseases The unfortunate reality is that rare diseases are actually not so rare.

More than 7,000 medical conditions

are now recognized as rare (affecting less than 200,000 people) by the National Institutes of Health.

They affect between 25-30 million Americans, more than half of whom are children. Approximately 90 percent of these conditions are still without an FDA-approved treatment or therapy.

For more than 36 years, NORD has been committed to the identification, treatment and cure of all rare diseases.

Awareness campaign This year NORD has introduced a new call to action, “Show Your Stripes!” The idea is to raise awareness through creative, collaborative and fun activities that capture the public’s attention leading up to Rare Disease Day on February

28. Why stripes? The zebra is the symbol of rare diseases in the United States and is noted for its distinctive black and white stripes.

Just as zebras are unique, so are the members of our community.

Show your support Wearing stripes on Rare Disease D a y i s a sy mb ol of soli da r i ty with the rare disease community.

Companies and organizations can collaborate on a concept for Rare Disease Day. This could be as elaborate as wrapping a car in stripes, or as simple as encouraging employees to wear stripes for the day. Take a photograph and post it on social media with the hashtags #ShowYourStripes and #RareDiseaseDay to help spread the message. Together we can make an impact. n

Publisher Lindsay Waldman Business Developer Mac Harris Managing Director Luciana Olson Designers Tiffany Pryor, Marie Coons Copy Editor Juliana Burkhart Director of Sales Shannon Ruggiero Director of Business Development Jourdan Snyder Director of Product Faye Godfrey Lead Editor Mina Fanous Production Manager Josh Rosman Content Strategist Vanessa Rodriguez Cover Photo Nathaniel Taylor All photos are credited to Getty Images unless otherwise credited. This section was created by Mediaplanet and did not involve USA Today.

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Why It’s So Important to Diagnose Rare Diseases SPONSORED

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ore than 300 million people worldwide have a rare disease and experts say there may be more than 6,000 identified rare diseases.1,2 More than 50 percent of rare diseases affect children and it takes an average of nearly five years to get diagnosed.3 Now a major effort is underway to speed up those diagnosis times.

The Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease (the Global Commission), comprised of Takeda, Microsoft and EURORDIS-Rare Diseases Europe, and working with technology innovators, patient advocates, health care providers, researchers, family members and other experts from around the world, has created a strategic alliance to address this diagnostic challenge for rare disease patients.

Difficulty in diagnosis Here’s why it’s challenging to get rare diseases diagnosed: often patients, their families and doctors have limited awareness of rare diseases; rare disease symptoms aren’t always obvious to doctors and nurses who haven’t seen the disease before; and symptoms that may seem minor at first are often associated with common illnesses.

“Many of these children get the wrong diagnosis at least once, 40 percent of the time, at the beginning,” says Dr. Hartmann Wellhoefer, vice president of medical affairs, rare disease and internal medicine, and global research and development at the pharmaceutical company Takeda.4 “If you get the wrong diagnosis, you’ll probably get the wrong treatment, get the wrong care.

That might make things worse for a child.”

The sooner patients can get diagnosed, the sooner they can get the right treatments.

“These patients don’t have time to wait five years,” says Dr. Wellhoefer. “They need the right care now.”

Developing a roadmap The Global Commission is developing an actionable roadmap to help shorten the time it takes to diagnose rare diseases. The goal is to help patients with rare diseases live longer, healthier lives.

“Working together to put rare diseases on the map is a health care priority equal to cancer or HIV or diabetes,” says Dr. Wellhoefer.

Those commission’s roadmap recommendations are as follows: 1. Empowering patients and families by providing tools to connect seemingly unrelated symptoms; helping them ask the right questions and get the answers they need; and sharing their medical records — quickly, efficiently and securely — with multiple doctors and specialists to expedite diagnosis.

2. Giving frontline providers like doctors and nurses the awareness and tools

needed to quickly and effectively identify patients who may have a rare disease; helping them with next steps like using artificial intelligence to identify symptoms; and developing a platform for doctors to consult with genetic experts.

3. Standardizing reporting methods, streamlining genetic consultations and utilizing telemedicine so medical geneticists can see more patients in general and work with priority patients more quickly.

Fostering community Mike Porath’s now 12-year-old daughter Annabel was diagnosed with a rare disease, Dup15q Syndrome — a neurodevelopmental disorder, caused by the partial duplication of Chromosome 15 — when she was a toddler. Annabel is autistic and has cognitive delays.

Porath says a rare disease diagnosis can feel lonely and isolating for patients and families. He and his wife received support in an online group for other parents whose kids have Dup15q.

“Finding that community was so important for us,” says Porath, founder and CEO of

TheMighty.com, a digital health community the couple started in 2014 for people facing health challenges and disabilities.

Porath, a committee member of the Global Commission, knows the patient and family perspective on rare diseases.

“We want to provide a playbook for parents so the right questions get asked and you get on a path to getting diagnosed much faster,” he says.

He knows the importance of a proper diagnosis, explaining, “Once you have a diagnosis, you can create a plan.” n Kristen Castillo

1 RARE Facts. Global Genes. https://globalgenes.org/ rare-facts/. Accessed February 6, 2019.

2 Orphan Medicines in the EU. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/ document_library/Leaflet/2017/12/WC500240710.pdf 3 The Global Challenge of Rare Disease Diagnosis.

Shire. https://www.shire.com/-/media/shire/ shireglobal/shirecom/pdffiles/patient/shire-diagnosisinitiative-pag-leaflet.pdf 4 Rare Disease Epidemiology: Update and Overview.

Posada de la Paz M et al eds. Advances in Experimental Medicine and Biology. 1031. 2017.

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Emerging Breakthroughs in Personalized Medicine Improve Care for Patients With Rare Diseases New tests and therapies may help doctors diagnose rare diseases faster and lead to more effective treatments.

Although scientists have long understood that most rare diseases are caused by harmful genetic mutations, it often takes several years for doctors to identify which gene is causing a patient’s specific

symptoms. These years take a toll on patients and their families, who watch loved ones suffer despite dozens of costly tests and visits to various doctors and specialists.

Even after the disease is diagnosed, existing daily maintenance medications can sometimes prove woefully inadequate.

Fortunately, new tests and therapies emerging in an era of personalized medicine are helping physi-

cians use diagnostics to determine which medical treatments will work best for each patient.

Genetic testing A new technology called nextgeneration sequencing (NGS) can test for thousands of genetic mutations at one time. Scientists hope NGS tests may someday replace the battery of single-gene tests that doctors often use to

understand the potential causes of a patient’s symptoms. The use of NGS tests may help shorten the diagnostic odysseys that many rare disease patients must endure before receiving an accurate diagnosis, thereby reducing associated expenses and improving patients’ lives.

pects for patients with rare diseases after they are diagnosed, the biopharmaceutical industry is developing an emerging group of personalized medicines known as gene therapies. Gene therapies promise to deliver lasting benefits for patients with rare diseases by reversing the genetic causes of diseases. The U.S. Food and Drug Administration approved the first gene therapy, called Luxturna (voretigene neparvovec), in 2017. By revising a harmful genetic mutation, Luxturna can restore vision to patients with Leber congenital amaurosis, a rare genetic retinal disease.

Researchers studying the benefits of NGS tests, gene therapies and other personalized treatments hope that their work will help advance a new era in health care that quickly targets more effective treatments to patients who will benefit from them. n

Personalized medicine Meanwhile, to improve the pros-

Edward Abrahams, President, Personalized Medicine Coalition

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Patient Data Helps Doctors Develop New Treatments for Rare Diseases Our experts share how health care professionals are using new technologies to develop cutting-edge treatments for patients.

What are the important emerging trends in rare disease research?

Oodaye Shukla Chief Data and Analytics Officer, HVH Precision Analytics

Dr. Cindy Jackson DO, F.A.A.P., Vice President and General Manager, Rare Disease and Pediatric Team, Covance Inc.

Oodaye Shukla: Advances in analytical techniques, the integration of health care data and genome sequencing are accelerating drug discovery and development. These factors in turn are creating demand to drive the development of rare-disease therapies that can help patients.

Cindy Jackson: Over the last three years, the interest in funding gene- and cell-based therapies has increased rapidly. In 2017, we received the first approval for a

gene-therapy compound for the treatment of Leber hereditary amaurosis and retinitis pigmentosa, which are both inherited rare retinal diseases.

How can the general public help support the rare-disease community?

OS: There are between 25 and 30 million people in the United States suffering from rare diseases, which equates to about 1 in 10 Americans. Awareness, education and support of patient advocacy groups are the most effective ways to support the rare-disease community.

CJ: The first thing for the public to realize is that rare diseases are really not that rare. With more than 7,000 disorders being defined as rare, it is likely that virtually everyone knows someone who is affected by a rare disease. Education and awareness are key to providing support to these individuals.

How have new technological developments helped improve treatment of rare-diseases?

OS: As health technology becomes more powerful, we are beginning to leverage vast amounts of col-

lected patient data to proactively find undiagnosed patients and shorten the time to diagnosis.

This has been accomplished by applying scalable analytics such as artificial intelligence and machine learning on data sources such as health care claims, genomics and prescription data.

CJ: The increasing number of approvals for therapeutic genetic modification is making a significant impact on the treatment of a number of rare diseases. For the first time, there are drugs and biological compounds that can positively affect the lives of people living with these diseases. n

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“Stranger Things” Star Gaten Matarazzo on Living With a Rare Genetic Condition Gaten Matarazzo shares his struggles with CCD and talks about raising awareness for the disorder.

CCD on the small screen According to the U.S. National Library of Medicine (NLM) Genetics Home Reference, people with CCD often have underdeveloped or absent collarbones and poorly

developed skulls, and they are usually shorter than relatives of the same age. Brothers Ross and Matt Duffer, who created “Stranger Things,” wrote the condition into the role of Dustin.

There’s a scene on the show where the character faces bullies who make fun of him for his teeth, which haven’t come in all the way. “Before they (the Duffer brothers) even wrote [the scene] in, they wanted to make sure I was comfortable and I am,” he said. “I always thought of it as a way to improve my character, so the minute they asked me, I said, ‘Yes.’” CCD, which can run in families and is also called cleidocranial dysostosis, affects an estimated 1 in 1 million people, though the condition likely affects even more people because the severity of symptoms ranges so widely, notes the NLM. The condition can be hereditary, but many cases are spontaneous, meaning there’s no genetic link. Matarazzo said the condition doesn’t run in his family, and the majority of other people whom he’s met with the condition also have spontaneous cases of CCD. Raising CCD awareness In 2018 Matarazzo attended the CCD Smiles Conference, where he met other individuals with CCD

“It’s not a fatal condition, but that doesn’t mean it doesn’t affect people’s lives negatively.”

of various degrees of severity. The youngest person at the conference was 16 weeks old; the oldest was an 85-year-old, Matarazzo said. It was the first time he ever met anyone with CCD. With the third season of “Stranger Things” en route and a growing fan base, Matarazzo has no doubt helped raise awareness of CCD due to his sheer celebrity.

He didn’t take issue with the idea

of being the face of CCD, but was quick to point out that his case of the condition is not the norm.

“Some people suffer a lot more,” said Matarazzo, who has a lisp and can make his shoulders touch in front due to his underdeveloped collarbone, but otherwise leads a relatively normal life.

“It’s not a fatal condition, but that doesn’t mean it doesn’t affect people’s lives negatively,” he said,

PHOTO: NATHANIEL TAYLOR

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ometimes, the thing that makes you different can be the thing that makes you shine. If you want proof, look no further than Gaten Matarazzo, who for years struggled to land an acting role due to a rare condition, only to stand out in an audition for Netflix’s “Stranger Things” in part because of it.

Matarazzo, who plays the loveable nerd Dustin Henderson on the hit ’80s-nostalgic sci-fi thriller, lives with cleidocranial dysplasia (CCD), a rare condition that affects bone and teeth development.

“I did my best in the auditions, but it always came down to stuff I couldn’t control, and honestly, that was one of the most frustrating things on the planet,” said 16-year-old Matarazzo, who said he was turned down for roles due to his physical differences from ages 7-9. “I’m very, very grateful it did take as long as it did because people who do work with me [now] accept me and work with me even though I do have these differences in my voice and my stature.”

explaining that some people need procedures such as dental, back or knee surgery in order to function well in daily life. With CCD Smiles, Matarazzo is hoping to raise awareness of CCD and aid people living with the condition get the health care they need. “Any help that the organization can get will help a lot of people,” he said. n Melinda Carter

POLYCYTHEMIA VERA (PV) IS A RARE, CHRONIC BLOOD CANCER Unless you or a loved one has been diagnosed with PV, you may not have heard about it. PV is part of a group of diseases called “myeloproliferative neoplasms” or MPNs. With PV, a person’s body makes too many red blood cells, white blood cells, and platelets. Too many red blood cells can cause the blood to thicken. Thicker blood doesn’t flow normally through arteries and veins.

I S Y O U R P V U N D E R C O N T R O L? Check off the information below that applies to you.

It’s important to keep your PV under control to help reduce the risk of complications such as heart attack or stroke.

Regular monitoring and medical care can help detect changes in your condition. Keeping your blood counts—particularly your hematocrit (a measure of red cells in the blood)—at the right levels is an important goal in managing PV. By tracking your symptoms and blood counts, you and your healthcare team can work to control your disease and reduce the risk of complications.

START THE CONVERSATION WITH YOUR HEALTHCARE PROFESSIONAL It is important to tell your Healthcare Professional about any symptoms you have, even if you are not sure they are related to your PV. Talking to your Healthcare Professional about your symptoms helps you both: • Understand how PV is affecting you • Follow how your PV is changing over time

Get more information about PV. Visit PVvoices.com today.

If you checked any of the boxes above, it is important to talk to your Healthcare Professional to understand if your PV is under control.

Voices of MPN is a registered trademark of Incyte Corporation. © 2016, Incyte Corporation. All rights reserved. UPM-1093 01/16

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One in a Million: Living with a Rare Disease One doctor shares the story of how she was diagnosed with an uncommon bone disorder, and how her journey inspired her to help others.

At my birth it was obvious something was wrong, but no one knew what.

The entire top of my head was sunken in and bone was missing. The immediate assumption was that I had a brain defect, but at three months of age, when my doctor noticed I had no collarbones, the diagnosis came shortly after: cleidocranial dysplasia (CCD). This rare condition is caused by a gene mutation that affects bone formation, mainly the skull, collarbones and teeth.

Growing up different From ages 8-19, I had all of my baby teeth pulled, extra teeth removed, impacted teeth brought down, plates and screws, gum grafts, braces, headgear, dental implants and jaw surgery.

I had a dent in my forehead, my eyes were wide set, my chin was large, my knees were knocked, my feet turned in, my nose was crooked and my fingers were too short. Bullies, even my fifth grade teacher, would attack my appearance and call me names. To this day I have nightmares about my teeth.

Gathering a community I never met another individual with CCD until I was 33 years old. My life was changed when I connected with other people who understood my story. In 2017 I started a nonprofit organization, CCD Smiles, to help connect those with CCD to dental resources, raise awareness and assist with medical costs. Last summer was the first CCD Smiles conference in Salt Lake City, Utah. About 125 people with CCD from 28 states and four countries gathered together. We are no longer alone.

Dr. Kelly Wosnik, Founder, CCD Smiles

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The Past and Future of Treatment for Pompe Disease The 20th anniversary of the first trials to treat Pompe disease is a chance to look back at how far we have come, and forward to where we hope to go.

Tiffany House

President, Acid Maltase Deficiency Association

T

his year marks the 20th anniversary of the first successful enzyme replacement therapy (ERT) trials for Pompe disease (also known as acid maltase deficiency, and glycogen storage disease type 2). These trials ultimately culminated in the approval of a treatment for Pompe in 2006 that has reached most patients worldwide. While this treatment is not a cure, it is an important step in the treatment of Pompe disease.

Progress over the years When I was diagnosed in 1995, Pompe was terminal. The only thing patients could do was try to treat the symptoms of Pompe and buy time by staying as healthy as possible. We dreamed that one day a treatment would be discovered, and we fought to survive long enough to see that day.

We have not stopped looking for ways to improve the quality of life for Pompe patients.

In 1999, ERT trial treatments began at Erasmus University in the Netherlands, and later that year at Duke University in the United States. It quickly became clear that these trials were working. The hope of a treatment was becoming a reality, but it would take another seven years before that reality was here.

Most patients diagnosed after 2006

will never have to live in a reality where Pompe is untreatable.

The future of treatment While treatment was new and exciting in 2006, today it has become a part of life for most patients, and our focus has shifted.

We are all grateful for a treatment — most rare diseases don’t have one. But we are also aware that it isn’t the final answer. We have not stopped looking for ways to improve the quality of life for Pompe patients. We have an excellent medical community that is continually working to design more effective treatments and diagnose patients sooner. Our new reality is one in which we can look forward to better treatment, gene therapy, muscle regeneration and other technologies that are still over the horizon. n

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Learn more at pompe.com Reference: 1. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267-288.

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or decades, doctors, patients and caregivers have fought to bring attention to rare conditions.

Now it finally seems as if all stakeholders — including industry and academia — are turning their attention to rare disease. As a mother to two children with a rare genetic condition, I’m heartened to see the interest. It is my great hope that all of us can work together towards progress.

There is no question that years of steadfast work, and the attention of the National Institutes of Health (NIH) and U.S. Food and Drug Administration (FDA), have played a role in creating this surge in interest. It is also true that pharmaceutical business practices have begun to look beyond the mass-production models that once buoyed them up. We now know a one-size-fits-all approach to treatment doesn’t work. We can do better with precise and personalized medicines.

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Public Attention Focused on Rare Disease After decades of advocacy and cooperation with federal organizations, it finally seems that patients with rare diseases are getting the attention they need.

The sequencing of the human genome has provided a more nuanced understanding of all diseases. Understanding the genetic underpinnings of disease enables accurate, individually relevant treatments. As we advance in developing therapies for rare conditions, we hope lessons learned

Understanding the genetic underpinnings of disease enables accurate, individually relevant treatments.

will be shared throughout the process, catapulting the field into a future of treatments for many more diseases.

Single-condition solutions are not the answer. It is essential that robust data-sharing occur in all sectors of rare disease research, particularly genetic

information, natural history data and even negative results.

Rare disease research could, and should, be a model for sharing data from completed clinical trials.

Importance of advocacy The disease-advocacy foundations that have invested so much time and effort in growing and engaging communities of affected individuals and initiating research will continue to be an important part of the ecosystem in which these advances take place. These are the exemplars of sharing and people-centered research. Once somewhat marginalized, those rare-disease organizations, research systems and researchers now feed our vision. They are our answer to alleviating the suffering of individuals and families. n Sharon F. Terry, President and CEO, Genetic Alliance

We’re proud to support Rare Disease Day. February 28, 2019.

At BioMarin, we are inspired and driven by the patients who receive our therapies, and we will continue our efforts to help more patients living with rare conditions who have unmet medical needs.

We are dedicated to making a meaningful impact in the lives of patients affected by rare genetic disorders who are often underserved and ignored.

BioMarin Pharmaceutical Inc. For more information, please go to www.biomarin.com BMRNCORP 0219

For the rarest of rare genetic conditions, a one-of-a-kind mouse could light a path to new treatments Caroline has a rare and severe form of Charcot-Marie-Tooth (CMT) disease, a neurodegenerative disorder that is deteriorating her muscles. The disease keeps her from walking or using her hands, and she relies on a ventilator at night.

Scientists at The Jackson Laboratory (JAX) took on the challenge to create a cure for Caroline, testing a novel gene therapy on a mouse model they made specifically to mimic Caroline’s disease. The mouse improved, showing the promise of the new gene therapy.

Now an expert team at Nationwide Children’s Hospital is seeking FDA approval for Caroline to use this experimental treatment.

Our approach, while tailored to patients like Caroline and Talia, may also be applied to other diseases.

At JAX, we’re tackling rare disorders and other diseases like cancer, Alzheimer’s and diabetes through our genetics and genomics research.

JAX research has also led to the development of Spinraza®, the first FDA-approved drug to treat spinal muscular atrophy (SMA), a rare neurodegenerative disease that affects children.

The cure begins with JAX Learn more and make an impact today. www.jax.org/rare-disease-info 1-800-474-9880

By the age of three, Talia was still not able to walk on her own.

Years later, she was finally diagnosed with CMT4J, a very rare form of Charcot-Marie-Tooth disease. There is no cure — yet.

JAX scientists tested a new therapeutic on mouse models of Talia’s disease, and saw notable improvements. Now, JAX is working with the FDA on the design of a clinical trial, which holds lifesaving potential for Talia and others.

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Hope for Patients With Uncommon Disorders

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Living With an Undiagnosed Disease

Personalized treatments for patients with very rare diseases point to a brighter future.

Promising results At The Jackson Laboratory, a nonprofit biomedical research institute, our team of scientists develops models to test therapeutics and inform clinical trials for patients like Talia.

We tested a new gene therapy on mouse models that mimic Talia’s disease. We have made great progress — the mice survived longer, and all of their fine motor functions improved. Now, we’re working with the FDA on a clinical trial design. Talia is 13 years old, and time is of the essence.

An approach that works This approach is personalized especially for Talia, but it also holds promising implications for other forms of CMT, other rare conditions and more common diseases.

The approach is working. Our past research and mouse models supported the development of Spinraza, the first FDA-approved drug to treat spinal muscular atrophy, a rare neurodegenerative disease that affects children.

Today, many more therapies for the treatment of rare diseases are in clinical trials, with promising results, and are on the verge of FDA approval. I believe there are many victories that lie ahead for patients with rare diseases.

Cat Lutz, Ph.D., MBA, Senior Research Scientist, The Jackson Laboratory

PHOTOS: SEASON ATWATER

By the age of three, Talia Duff was still not able to walk on her own, and her family noticed her strength was declining. After years of failed treatments, surgeries and unanswered questions, she was finally diagnosed with CMT4J, a very rare form of a neurological disorder called Charcot-Marie-Tooth (CMT) disease. There are only about 30 other known cases worldwide, and no cure yet. But we have hope.

I am the mother of three children who have an undiagnosed rare disease.

I am also undiagnosed.

Our family continues to endure a diagnostic odyssey times four.

In 2012, when I first heard our neurologist say the word “undiagnosed,” I was overwhelmed by confusion.

She explained that they may never find the root cause of our children’s diseases, but offered to help treat the symptoms going forward. I went home that night from the hospital and cried myself to sleep. How does a doctor not continue to find a diagnosis, a treatment and a cure?

lyzed eight times. We have had our whole genome sequenced and analyzed five times. We still live in the world of the unknown.

We begin every single day at the starting line of another marathon.

There is not one day that I do not spend some moment in time looking for the next steps to help my children and to help myself. We are still suffering from an undiagnosed rare disease with no hope for a treatment or a cure.

A long journey This was the first step in a long diagnostic odyssey that continues to this day. Our family has had our whole exome sequenced and ana-

Raising awareness In 2016, the Rare and Undiagnosed Network started the awareness campaign for an annual Undiagnosed Rare Disease Day on April 29.

The main objective of this day is to raise awareness for the undiagnosed rare-disease community among the general public about the emotional, physical and financial impact on the lives of patients and their families.

The campaign also seeks to raise awareness among policymakers, public authorities, industry representatives, researchers, health care professionals and anyone who has a genuine interest in undiagnosed rare diseases and the world of genetics. Since 80 percent of rare and undiagnosed diseases have identified genetic origins, it is imperative to emphasize the importance of genetics in the journey of patients with undiagnosed rare diseases.

Help us raise awareness for the undiagnosed rare-disease community by supporting Undiagnosed Rare Disease Day on April 29, 2019. n Gina Szajnuk, Co-Founder, Executive Director, RUN

This is a rare moment.

Patients living with advanced pheochromocytoma and paraganglioma have never had a proven treatment option. Until AZEDRA. AZEDRA® is the first and only FDA-approved treatment for patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

Learn more at www.AZEDRA.com/healthcare-providers Indication AZEDRA® (iobenguane I 131) is indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

Important Safety Information Warnings and Precautions: • Risk from radiation exposure: AZEDRA contributes to a patient’s overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of AZEDRA are greater in pediatric patients than in adults. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with AZEDRA consistent with institutional good radiation safety practices and patient management procedures.

• Myelosuppression: Among the 88 patients who received a therapeutic dose of AZEDRA, 33% experienced Grade 4 thrombocytopenia, 16% experienced Grade 4 neutropenia, and 7% experienced Grade 4 anemia. Five percent of patients experienced febrile neutropenia.

Monitor blood cell counts weekly for up to 12 weeks or until levels return to baseline or the normal range. Withhold and dose reduce AZEDRA as recommended in the prescribing information based on severity of the cytopenia.

• Secondary myelodysplastic syndrome, leukemia, and other malignancies: Myelodysplastic syndrome (MDS) and acute leukemias were reported in 6.8% of the 88 patients who received a therapeutic dose of AZEDRA. The time to development of MDS or acute leukemia ranged from 12 months to 7 years. Two of the 88 patients developed a non-hematological malignancy.

• Hypothyroidism: Hypothyroidism was reported in 3.4% of the 88 patients who received a therapeutic dose of AZEDRA. Initiate thyroid-blocking medications starting at least 1 day before and continuing for 10 days after each AZEDRA dose to reduce the risk of hypothyroidism or thyroid neoplasia. Evaluate for clinical evidence of hypothyroidism and measure thyroidstimulating hormone (TSH) levels prior to initiating AZEDRA and annually thereafter.

• Elevations in blood pressure: Eleven percent of the 88 patients who received a therapeutic dose of AZEDRA experienced a worsening of pre-existing hypertension defined as an increase in systolic blood pressure to ≥160 mmHg with an increase of 20 mmHg or an increase in diastolic blood pressure to ≥ 100 mmHg with an increase of 10 mmHg. All changes in blood pressure occurred within the first 24 hours post infusion. Monitor blood pressure frequently during the first 24 hours after each therapeutic dose of AZEDRA. • Renal toxicity: Of the 88 patients who received a therapeutic dose of AZEDRA, 9% developed renal failure or acute kidney injury and 22% demonstrated a clinically significant decrease in glomerular filtration rate (GFR) measured at 6 or 12 months. Monitor renal function during and after treatment with AZEDRA. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. AZEDRA has not been studied in patients with severe renal impairment.

• Pneumonitis: Fatal pneumonitis occurred 9 weeks after a single dose in one patient in the expanded access program. Monitor patients for signs and symptoms of pneumonitis and treat appropriately.

• Embryo-fetal toxicity: Based on its mechanism of action, AZEDRA can cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with AZEDRA and for 7 months after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.

• Risk of infertility: Radiation exposure associated with AZEDRA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative dose of AZEDRA is within the range where temporary or permanent infertility can be expected following external beam radiotherapy.

Adverse Reactions: The most common severe (Grade 3–4) adverse reactions observed in AZEDRA clinical trials (≥ 10%) were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Twelve percent of patients discontinued treatment due to adverse reactions (thrombocytopenia, anemia, lymphopenia, nausea and vomiting, multiple hematologic adverse reactions).

Drug Interactions: Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells and therefore interfere with dosimetry calculations or the efficacy of AZEDRA. These drugs were not permitted in clinical trials that assessed the safety and efficacy of AZEDRA. Discontinue the drugs listed in the prescribing information for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose.

For important risk and use information about AZEDRA, please see Brief Summary of Prescribing Information on adjacent pages.

To report suspected adverse reactions, contact Progenics Pharmaceuticals, Inc. at 844-668-3950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Reference: AZEDRA® prescribing information. New York, NY: Progenics Pharmaceuticals, Inc.; 08 2018.

AZEDRA® is a registered trademark of Progenics Pharmaceuticals, Inc. Trademarks, registered or otherwise, are the property of their respective owner. © 2019 Progenics Pharmaceuticals, Inc. PM-US-AZ-0141

Table 1: Absorbed-dose Threshold Values for Radiation Toxicity in Critical Organs Organ ~ 1%-rate: mortality Time to Threshold* or organ failure death or absorbed-dose associated organ for ~1%-rate with disease failure mortality or organ failure (Gy) Red marrow H-ARS mortality 1-2 months 12 Lungs Pneumonitis mortality 1-7 months 16.5 Kidneys Renal failure >1 year 18 Liver Hepatomegaly, ascites: possible organ failure 0.5-3 months 31 Small intestine GI-ARS mortality 6-9 days 40 * Threshold of ~0.5 Gy for both heart and carotid artery, derived from experience with external-beam radiotherapy and associated with fractionated exposure, has also been proposed to support an ~1% mortality rate of cardiovascular and cerebrovascular deaths in >10-15 years. Great uncertainty is associated with the value ~ 0.5 Gy cited for vascular disease (ICRP publication 118, p.300, Table 4.5), consider benefits/risks to patients.

The following is a Brief Summary; refer to the full Prescribing Information for complete information at www.AZEDRA.com INDICATIONS AND USAGE AZEDRA is indicated for the treatment of adult and pediatric patients 12 years or older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

DOSAGE AND ADMINISTRATION Important Safety Information AZEDRA is a radiopharmaceutical. Handle with appropriate safety measures to minimize radiation exposure. Use waterproof gloves and effective radiation shielding when handling AZEDRA. Radiopharmaceuticals, including AZEDRA, should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Recommended Dosage Administer thyroid blockade and other pre- and concomitant medications as recommended.

Dosimetric Dose The recommended AZEDRA dosimetric dose administered as an intravenous injection is: • Patients weighing greater than 50 kg: 185 to 222 MBq (5 or 6 mCi) • Patients weighing 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg) Dosimetry and Biodistribution Assessment Following the AZEDRA dosimetric dose: • Acquire anterior/posterior whole body gamma camera images within 1 hour of the AZEDRA dosimetric dose and prior to patient voiding (Day 0; Scan 1).

• Acquire additional images on Day 1 or 2 following patient voiding (Scan 2).

• Acquire additional images between Days 2-5 following patient voiding (Scan 3).

For each individual patient, calculate the radiation dose estimates to normal organs and tissues per unit activity [D (organ)] of administered dose using data extracted from these 3 images. Calculate in accordance with the Medical Internal Radiation Dose (MIRD) schema or related methodology. Whenever possible, use patient-specific organ masses (e.g. estimated from imaging).

Therapeutic Dosage The recommended AZEDRA therapeutic dose is based on body weight and reduced, if necessary, based on the dosimetry data. Administer a total of 2 therapeutic doses intravenously a minimum of 90 days apart.

Weight Based Dose per Therapeutic Cycle • Patients weighing greater than 62.5 kg: 18,500 MBq (500 mCi) • Patients weighing 62.5 kg or less: 296 MBq/kg (8 mCi/kg) Determine if Dose Reduction Needed Based on Critical Organ Limits • Calculate the estimated critical organ absorbed-dose by multiplying the dosimetry-derived radiation absorbed-dose per unit activity [D (organ)] by weight based therapeutic total activity (Aw).

• If resulting estimated critical organ absorbed-dose is less than threshold absorbed-dose (T) shown in Table 1, no dose adjustment is necessary.

• If resulting estimated critical organ absorbed-dose exceeds threshold absorbed-dose (T) shown in Table 1, calculate the reduced therapeutic total activity (i.e., the cumulative activity that would be administered in 2 therapeutic cycles) using the following equation: Reduced Therapeutic Total Activity= Aw × [T ÷ {Aw × D (organ)}] • Example: A 75 kg patient qualifies for a therapeutic total activity of 1000 mCi (Aw). For the kidneys, the dosimetry yields an estimated critical organ absorbed dose per unit activity of 0.027 Gy/mCi [D (kidney)]. Thus, the estimated critical organ absorbed-dose to the kidney is 27 Gy [Aw x D (organ)], which exceeds the threshold absorbed-dose for the kidneys (T) of 18 Gy (Table 1). Using the equation above the reduced therapeutic total activity to be administered to this patient is 666.7 mCi. 1000 mCi × [18 Gy ÷ {1000 mCi × 0.027 Gy/mCi }]

Thyroid Blockade and Other Pre- and Concomitant Medications Thyroid Blockade Administer inorganic iodine starting at least 24 hours before and continuing for 10 days after each AZEDRA dose.

Hydration Instruct patients to increase fluid intake to at least two liters a day starting at least 1 day before and continuing for 1 week after each AZEDRA dose to minimize irradiation to the bladder.

Drugs that Reduce Catecholamine Uptake or Deplete Stores Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose.

Antiemetic Administer antiemetics 30 minutes prior to administering each AZEDRA dose.

Dose Modifications for Adverse Reactions Recommended dose modifications of AZEDRA for adverse reactions are provided in Table 2 and the recommended dose or dose reduction for the second therapeutic dose of AZEDRA for myelosuppression are provided in Table 3.

Table 2: Recommended Dose Modifications of AZEDRA for Adverse Reactions Adverse Reaction Dose Modification Myelosuppression Do not administer the first therapeutic dose for platelet counts less than 80,000/mcL or absolute neutrophil counts (ANC) less than 1,200/mcL. Do not administer the second therapeutic dose until platelets and neutrophils return to baseline or to the normal range. Reduce the second therapeutic dose for the following: • platelet count less than 25,000/mcL, ANC less than 500/mcL, or life-threatening anemia for more than 7 days • febrile neutropenia • platelet count less than 50,000/mcL with active bleeding Pneumonitis • Do not administer the second therapeutic dose if pneumonitis is diagnosed after the first therapeutic dose.

Table 3: Recommended Dose or Dose Reduction for Second Therapeutic Dose of AZEDRA for Myelosuppression Patient Population

If first therapeutic dose was weight based,

Patients weighing Reduce the second greater than 62.5 kg therapeutic dose to 425 mCi Patients weighing Reduce the second 62.5 kg or less therapeutic dose to 7 mCi/kg

If first therapeutic dose was reduced based on critical organ limits, Reduce second therapeutic dose to 85% of the first dose Reduce second therapeutic dose to 85% of the first dose

DOSAGE FORMS AND STRENGTHS Injection: 555 MBq/mL (15 mCi/mL) as a clear, colorless to pale yellow solution in a single-dose vial.

WARNINGS AND PRECAUTIONS Risk from Radiation Exposure AZEDRA contributes to a patient’s overall long-term radiation exposure.

Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of AZEDRA are greater in pediatric patients than in adults.

Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with AZEDRA consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression Severe and prolonged myelosuppression occurred during treatment with AZEDRA. Among the 88 patients who received a therapeutic dose of AZEDRA, 33% experienced Grade 4 thrombocytopenia, 16% experienced Grade 4 neutropenia, and 7% experienced Grade 4 anemia. Five percent of patients experienced febrile neutropenia. In Study IB12B following the first therapeutic dose, patients who experienced Grade 4 neutropenia reached neutrophil nadir at a median of 36 days (27 – 55 days) and

remained at nadir for a median of 12 days (8 – 22 days) until recovery to less than or equal to Grade 3. Following the second dose, patients who experienced Grade 4 neutropenia reached nadir at a median of 43 days (38 – 47 days) and remained at nadir for a median of 18.5 days (8 – 31 days) until recovery to less than or equal to Grade 3.

Monitor blood cell counts weekly for up to 12 weeks or until levels return to baseline or the normal range. Withhold and dose reduce AZEDRA as recommended based on severity of the cytopenia.

Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies Myelodysplastic syndrome (MDS) or acute leukemias were reported in 6.8% of the 88 patients who received a therapeutic dose of AZEDRA. The time to development of MDS or acute leukemia ranged from 12 months to 7 years.

Two of the 88 patients developed a non-hematological malignancy. One patient developed colon cancer at 18 months and one patient developed lung adenocarcinoma at 27 months following the first therapeutic dose.

Hypothyroidism Hypothyroidism was reported in 3.4% of the 88 patients who received a therapeutic dose of AZEDRA. The time to worsening of hypothyroidism was 4 months in one patient, and the time to development of hypothyroidism was less than one month in one patient and 18 months in one patient. Initiate thyroid-blocking medications starting at least 1 day before and continuing for 10 days after each AZEDRA dose to reduce the risk of hypothyroidism or thyroid neoplasia. Evaluate for clinical evidence of hypothyroidism and measure thyroid-stimulating hormone (TSH) levels prior to initiating AZEDRA and annually thereafter.

Elevations in Blood Pressure Eleven percent of the 88 patients who received a therapeutic dose of AZEDRA experienced a worsening of pre-existing hypertension defined as an increase in systolic blood pressure to ≥160 mmHg with an increase of 20 mmHg or an increase in diastolic blood pressure to ≥ 100 mmHg with an increase of 10 mmHg. All changes in blood pressure occurred within the first 24 hours post infusion. Monitor blood pressure frequently during the first 24 hours after each therapeutic dose of AZEDRA. Renal Toxicity Of the 88 patients who received a therapeutic dose of AZEDRA, 7% developed renal failure or acute kidney injury and 22% demonstrated a clinically significant decrease in glomerular filtration rate (GFR) measured at 6 or 12 months. Monitor renal function during and after treatment with AZEDRA. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. AZEDRA has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min).

Pneumonitis Fatal pneumonitis occurred 9 weeks after a single dose in one patient in the expanded access program for Study IB12B (n=11). Pneumonitis was not diagnosed among the 88 patients enrolled in Study IB12 or IB12B. Monitor patients for signs and symptoms of pneumonitis and treat appropriately.

Embryo-Fetal Toxicity Based on its mechanism of action, AZEDRA can cause fetal harm. There are no available data on the use of AZEDRA in pregnant women. No animal studies using iobenguane I 131 have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including AZEDRA, have the potential to cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Advise females and males of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AZEDRA and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.

Risk of Infertility Radiation exposure associated with AZEDRA may cause infertility in males and females. The recommended cumulative dose of 37 GBq of AZEDRA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Myelosuppression • Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies • Hypothyroidism • Elevations in Blood Pressure • Renal Toxicity • Pneumonitis Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in Warnings and Precautions reflect exposure to AZEDRA in 88 patients with iobenguane-scan positive recurrent or unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) who received a therapeutic dose of AZEDRA in one of two clinical studies (IB12 or IB12B). The Warnings and Precautions also include data from 11 patients enrolled in an expanded access program for Study IB12B. The safety data below was evaluated in two studies in patients with recurrent or unresectable, locally advanced or metastatic PPGL. Study

IB12 was an open-label, multi-center, single-arm dose-finding study in adult patients with malignant or recurrent PPGL. The study consisted of a 12-month efficacy phase with a 1 year follow-up. Twenty-one patients received a dosimetric dose (~5 mCi), followed by one therapeutic dose (~500 mCi) of AZEDRA. Study IB12B was an open-label, multi-center, single-arm study in 68 adult and pediatric patients age 12 years and older with recurrent or unresectable, locally advanced or metastatic PPGL. Patients with evidence of liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥ 2.5 times the upper limit of normal or total bilirubin > 1.5 times the upper limit of normal), a history of liver disease (including hepatitis and chronic alcohol abuse), or severe renal impairment (creatinine clearance < 30 mL/min) were excluded. Patients who had received external beam radiation to > 25% of bone marrow, received whole body radiotherapy, or who had received any systemic radiotherapy resulting in myelosuppression within 3 months of study entry, were also excluded. The safety data described below are based on pooled safety data from studies IB12 and IB12B. A total of 88 patients received at least one therapeutic dose of AZEDRA and 50 patients received two therapeutic doses (one patient received treatment in both studies).

Adverse reactions from studies IB12 and IB12B are presented in Table 4. The most common severe (Grade 3-4) adverse reactions were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Twelve percent of patients discontinued treatment due to adverse reactions (thrombocytopenia, anemia, lymphopenia, nausea and vomiting, multiple hematologic adverse reactions).

Table 4: Adverse Reactions Occurring in ≥10% of Patients with PPGL Receiving Therapeutic Dose of AZEDRA in Studies IB12B and IB12 Adverse Reaction Hematologicb Lymphopenia Anemia Thrombocytopenia Neutropenia Gastrointestinal Nausea Vomitingc Dry mouth Sialadenitisd Diarrhea Abdominal paine Constipation Oropharyngeal pain Dyspepsia General Fatiguef Pyrexia Injection site pain Hyperhidrosis Alopecia Infections Upper respiratory tract infectiong Urinary tract infection Investigationsb International normalized ratio increasedh Increased aspartate aminotransferase Increased blood alkaline phosphatase Increased alanine aminotransferase Metabolism and nutrition Decreased appetite Dehydration Decreased weight Musculoskeletal and connective tissue disorders Back pain Pain in extremity Nervous system Dizzinessi Headache Dysgeusiaj Respiratory, thoracic, and mediastinal disorders Cough Dyspnea Vascular Hypotension Hypertensionk Tachycardia a

All Gradesa, (%)

Gradesa 3 - 4, (%)

96 93 91 84

78 24 50 59

78 58 48 39 25 23 19 14 10

16 10 2 1 3 6 7 0 0

71 14 10 10 10

26 2 0 0 0

16 11

2 1

85 50 53 43

18 2 5 2

30 16 16

5 4 1

17 15

2 0

34 32 24

13 6 1

18 18

0 7

24 20 10

4 11 3

NCI CTCAE version 3.0.

Based on laboratory data.

Includes vomiting and retching. d Includes sialoadenitis, salivary gland pain, and salivary gland enlargement. b c

e

Includes abdominal pain, abdominal pain upper, and abdominal pain lower.

Incudes fatigue, asthenia. g Includes upper respiratory tract infection, sinusitis, rhinorrhea, upperairway cough syndrome, nasopharyngitis. h Only assessed in Study IB12B (N=68). i Includes dizziness and dizziness postural. j Includes dysgeusia, hypogeusia and ageusia. k Includes blood pressure increased and hypertension.

The following clinically significant adverse reactions were observed in < 10% of patients treated with AZEDRA: Cardiac: palpitations (9%), syncope and presyncope (8%) Endocrine: decreased TSH (5%), hypothyroidism (3%) Gastrointestinal: dysphagia (7%), abdominal distension (6%), gastroesophageal reflux disease (6%), stomatitis (3%) General: insomnia (9%), chills (8%), chest pain (6%) Infections: candida infection (6%) Investigations: prolonged prothrombin time (9%) Musculoskeletal and connective tissue: arthralgia (8%), neck pain (8%), pain in jaw (7%), muscle spasms (6%) Renal and urinary disorders: proteinuria (9%), renal failure (7%), Respiratory: epistaxis (9%), nasal congestion (7%), pulmonary embolism (3%) Skin and subcutaneous tissue: dry skin (8%), rash (8%), petechiae (7%) Vascular: orthostatic hypotension (9%). f

DRUG INTERACTIONS Drugs that Reduce Catecholamine Uptake or Deplete Stores Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells and therefore interfere with dosimetry calculations or the efficacy of AZEDRA. These drugs were not permitted in clinical trials that assessed the safety and efficacy of AZEDRA. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores, such as those listed below, for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose.

• CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) • Norepinephrine and dopamine reuptake inhibitors (e.g. phenteramine) • Norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) • Monoamine oxidase inhibitors (e.g. phenelzine and linezolid) • Central monoamine depleting drugs (e.g. reserpine) • Non-select beta adrenergic blocking drugs (e.g. labetalol) • Alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) • Tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, buproprion, duloxetine, mirtazapine, venlafaxine) • Botanicals that may inhibit reuptake of norephinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St John’s Wort, or yohimbine) USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, AZEDRA can cause fetal harm. There are no available data on AZEDRA use in pregnant women. No animal studies using iobenguane I 131 have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including AZEDRA, have the potential to cause fetal harm. Advise pregnant women of the risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation Risk Summary There are no data on the presence of iobenguane I 131 in human milk or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with AZEDRA and for 80 days after the final dose.

Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Contraception AZEDRA can cause fetal harm when administered to a pregnant woman.

Females Advise women of reproductive potential to use effective contraception during treatment with AZEDRA and for 7 months following the final dose of AZEDRA. Males Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for 4 months following the final dose of AZEDRA. Infertility The recommended cumulative dose of 37 GBq of AZEDRA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.

Pediatric Use The safety and effectiveness of AZEDRA have been established in patients 12 years and older with unresectable and iobenguane scan positive, locally advanced or metastatic, pheochromocytoma and paraganglioma (PPGL) which require systemic anticancer therapy. Use of AZEDRA for this indication is supported by evidence from an adequate and well-controlled study in adults and pediatric patients 12 years and older.

The risks of radiation associated with AZEDRA is greater in pediatric patients than that in adult patients due to greater absorbed radiation doses and longer life expectancy. Ensure the therapeutic benefit of AZEDRA outweighs these greater risks prior to administration in pediatric patients.

The safety and effectiveness of AZEDRA have not been established in pediatric patients younger than 12 years old with unresectable and iobenguane scan positive, locally advanced or metastatic PPGL which require systemic anticancer therapy.

Geriatric Use Of the patients enrolled in all clinical studies of AZEDRA, 17% were 65 years or older and 1% were 75 years or older. Clinical studies of AZEDRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Renal Impairment The radiation dose to patients with renal impairment may be increased due to the delayed elimination of the drug. Adjust the therapeutic dose based on radiation exposure estimates from the dosimetry assessment.

The safety of AZEDRA in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease has not been studied.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with iobenguane I 131 have not been conducted; however, radiation is a carcinogen and a mutagen. No animal studies were conducted to determine the effects of iobenguane I 131 on fertility.

PATIENT COUNSELING INFORMATION Hydration Advise patients to drink at least 2 liters of liquid a day before and for one week following each dose of AZEDRA to minimize irradiation of the bladder.

Radiation Risks Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression Advise patients to contact their health care provider for any signs or symptoms of neutropenia, thrombocytopenia, or anemia.

Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies Advise patients of the potential for secondary cancers, including myelodysplastic syndrome, acute leukemia, and other malignancies.

Hypothyroidism Advise patients to take thyroid-blocking agents as prescribed. Advise patients of the need for life-long monitoring for hypothyroidism.

Elevations in Blood Pressure Advise patients to contact their health care provider for signs or symptoms that may occur following tumor-hormone catecholamines release and possible risk of increased blood pressure during or 24 hours following each therapeutic AZEDRA dose.

Pneumonitis Advise patients to contact their health care provider for signs or symptoms of pneumonitis.

Drug Interactions Advise patients that some medicines interact with AZEDRA and to contact their health care provider before starting any over the counter medicines or herbal or dietary supplements.

Embryo-Fetal Toxicity Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their health care provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with AZEDRA and for 7 months after the final dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for 4 months after the final dose.

Lactation Advise females not to breastfeed during treatment with AZEDRA and for 80 days after the final dose.

Infertility Advise females and males patients that AZEDRA may impair fertility.

Manufactured for: Progenics Pharmaceuticals, Inc. One World Trade Center, 47th floor, Suite J New York, NY 10007 AZEDRA® is a registered trademark of Progenics Pharmaceuticals, Inc.

We are proud to join others from around the world in recognizing Rare Disease Day 2019 to raise awareness of rare diseases.

We understand the impact that rare diseases have on the day-to-day life of patients and their caregivers, as well as the need for treatment options.

Currently, we have ongoing clinical trials for our investigational product, sparsentan, for patients with rare kidney diseases. Focal segmental glomerulosclerosis (FSGS) and immunoglobulin A nephropathy (IgAN) are rare kidney disorders defined by progressive scarring of the kidney that may lead to kidney failure. The DUPLEX Study and PROTECT Study are Phase 3 clinical trials evaluating the safety and efficacy of sparsentan on kidney function in patients with FSGS and IgAN, respectively.

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To learn more about the DUPLEX Study, visit fsgsduplex.com or call 877-659-5518.

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To learn more about the PROTECT Study, visit iganprotect.com or call 877-659-5518.

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