Kristi Rosa

Twenty-five to 30 million patients in the United States are living with a rare disease; this staggering number underscores a simple, yet little-known fact: the incidence of rare diseases is low, but prevalence remains high.

Despite many advances made in the fight against rare diseases, gaps remain when it comes to improving patient care—for some conditions, there are no safe or effective treatments available to patients to improve their quality of life.

The US Food and Drug Administration (FDA) Office of Orphan Products Development is dedicated to advancing the evaluation and development of products—drugs, biologics, or devices&mdash;that demonstrate potential in the diagnosis and/or treatment of rare diseases.

The following is a list of recent designations granted by the FDA from this past week that is working to further expand the collective arsenal against rare diseases:

A4250 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC) & Alagille Syndrome

On October 17, 2018, the FDA granted Fast Track designation to Albireo Pharma, Inc.’s 

, a rare, life-threatening liver disease. On the same day, the product was also granted an orphan drug designation for the treatment of Alagille syndrome, specifically, which is a genetic disorder known to affect the liver, heart, skeleton, eyes, and kidneys.

“A4250 is a highly potent, selective inhibitor of the ileal bile acid transporter (IBAT) that has minimal systemic exposure and is currently in development at Albireo,” Ron Cooper, president, and chief executive officer of Albireo told 

 in a past interview. “IBAT inhibition decreases intestinal bile acid absorption, thereby reducing high concentrations of liver and circulating bile acids, which are believed to play a key role in the development of pruritus, liver damage, and liver failure.”

The product is currently being evaluated in a 

On October 17, 2018, the FDA granted Axsome Therapeutics, Inc.’s AXS-12—a novel, oral, highly selective and potent norepinephrine reuptake inhibitor&mdash;orphan drug designation for the treatment of the symptoms associated with narcolepsy, a rare, neurological condition.

This came on the heels of the clinical-stage biopharmaceutical company’s announcement that they will be launching a phase 2 trial of AXS-12 for the treatment of patients with narcolepsy in the fourth quarter with top-line results expected in the first half of next year.

The potential use of AXS-12 in narcolepsy is supported by positive pre-clinical and preliminary clinical results as well as a positive clinical safety record, according to Axsome. For one, the active agent used in AXS-12, reboxetine, has been found to reduce narcoleptic episodes in animal models; it was also found to improve excessive daytime sleepiness and reduce cataplexy in patients with narcolepsy in an open-label pilot trial.

KD025 for the Treatment of Chronic Graft-Versus-Host Disease

On October 17, 2018, the FDA granted a breakthrough therapy designation to Kadmon Holdings, Inc.’s candidate, KD025, for the treatment of patients with chronic graft-versus-host disease after failure of 2 or more lines of systemic therapy.

KD025 is a selective oral inhibitor of Rho-associated coiled-coil kinase 2, according to Kadmon.

The company is currently in the process of enrolling participants for a 

“We are pleased that the FDA has recognized the therapeutic potential of KD025 for chronic graft-versus-host disease, a serious condition for which new treatments are urgently needed,” Harlan W. Waksal, MD, president and CEO of Kadmon, said in a recent statement. “This designation is a key regulatory milestone and we look forward to working closely with the FDA to expedite the development of KD025.”

PRN1008 for the Treatment of Immune Thrombocytopenic Purpura

On October 19, 2018, the FDA granted an orphan drug designation to Principia Biopharma Inc.’s PRN1008 for the treatment of patients with immune thrombocytopenic purpura, a rare, and often chronic, autoimmune disease that is described by a decreased number of circulating platelets.

The clinical-stage biopharmaceutical company is the midst of a phase 2 trial that has been designed to assess the safety and effectiveness of the oral, reversible covalent Bruton’s Tyrosine Kinase inhibitor, in patients with immune thrombocytopenic purpura.

Previous to this announcement, in June 2017, PRN1008 was granted an orphan drug designation for the treatment of patients with pemphigus vulgaris.

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Here’s a round-up of recent designations granted by the FDA to products developed to treat rare diseases.

FDA Grants Fast Track Designation to A4250 for Progressive Familial Intrahepatic Cholestasis

Retrotope, Inc. released new data at the Nationals Organization of Rare Diseases’ Rare Diseases & Orphan Products Breakthrough Summit (

) pertaining to their candidate RT001, which demonstrated arrest of disease progression in 2 patients with infantile neuroaxonal dystrophy (INAD).

“INAD is a very rare disease—there are probably less than several hundred patients worldwide with the condition&mdash;and it’s a genetic disorder in which infants develop normally initially and then they begin to lose developmental milestones,” Mark G. Midei, MD, clinical and regulatory consultant for Retrotope, told 

“A baby who may have been able to roll over or crawl suddenly loses that ability and it can happen a little bit later in their life, too,” he added. “A child that’s walking and maybe even talking begins to lose those abilities and then once that happens, it generally progresses rather unremittingly until, usually, the child will die an untimely death.”

To date, there is no treatment available for this disease that is effective in either arresting the progress of the disease or reversing its consequences, he added, and so, new, effective treatments are needed. Enter RT001.

 is a first-in-class, deuterated polyunsaturated fatty acid, a new category of drugs, that works by integrating into mitochondrial and cellular membranes and stabilizing them. In our interview, Dr. Midei explained why the treatment is so unique (

Through expanded access programs, 2 patients with INAD have been treated with RT001 thus far; the first patient began treatment in March 2017, while the second patient began in November 2017. Data pertaining to the first patient was previously presented at the American Academy of Neurology.

The data, according to Dr. Midei, has investigators enthusiastic about the treatment.

“First of all, we found that when it comes to the progress of the disease in these children—which is usually inexorably downhill&mdash;we’ve seen that RT001 has arrested some of the deterioration.,” he said. “We’ve also seen some actual improvements which is almost never seen with INAD; once the condition begins to accelerate we rarely see any kind of regression in the disease under normal circumstances.”

Specifically, improvements in bulbar function were noted by the investigators. The patients’ ability to swallow saliva strengthened, they were more interactive, and there was less spasticity in their limbs. Dr. Midei said that the team hopes that these advances will translate into improvements in other functional areas.

As for next steps, Dr. Midei and his team want to evaluate RT001 in a larger cohort of patients with INAD. As such, he told us that a more rigorous clinical trial will be launched within the next few weeks to see if the positive data observed in the 2 patients who received the treatment will translate to a larger group of patients.

“There are a lot of different conditions we think that this drug may be useful in and the problem with treating rare diseases is finding the patients and then trying to analyze the results of that because there’s not a lot of data on the natural history of some of these diseases,” he added. “Some of them have only been recognized for a few years.”

To this end, Dr. Midei pointed out that his team will also be using the treatment in other expanded access programs for other rare diseases, such as amyotrophic lateral sclerosis and Tay-Sachs disease (

Previously, the US Food and Drug Administration granted an orphan drug designation to RT001 for the treatment of PLAG26-associated neurodegeneration, which includes INAD.

RT001 has demonstrated arrest of disease progression in 2 patients with infantile neuroaxonal dystrophy.

RT001 Demonstrates Arrest of Disease Progression in 2 Patients with INAD

On July 9, 2012, officials signed the Food and Drug Administration Safety and Innovation Act (FDASIA) which had a section within it that established a new designation—the 

—which allows for expedited development and review of drugs to treat serious or life-threatening diseases if substantial evidence is provided.

The concept for the designation was first initiated at an annual meeting held by 

, an organization that has been instrumental in the development and implementation of policies dedicated to ensuring that safe and effective treatments are available to patients who need them most as quickly as possible.

At the National Organization of Rare Diseases’ Rare Diseases & Orphan Products Breakthrough Summit (

 sat down with Ellen Sigal, PhD, the chair and founder of Friends, to discuss how she and her organization were able to turn an ambitious concept into reality and what this designation did for the rare disease community as a whole.

: Can you tell us more about the expedited FDA development program?

We always have a conference every year that includes the US Food and Drug Administration, the National Cancer Institute, and other stakeholders, and Rick Pazdur, MD, suggested to us that we should look at—we didn’t call it breakthrough&mdash;what we should do in the regulatory environment when we see substantial evidence early?

It seemed like an easy question, but the answer was very complicated. We worked with many stakeholders, companies, statisticians, and scientists, and we came up with a whitepaper on it—but it wasn’t easy, because the questions were hard. For example, what does substantial evidence mean? Because in every disease setting, it’s very different.

But in any event, we reached a consensus and then we put it through legislation. And at that point, we thought that maybe there would be 1 or 2 drugs per year, and we thought they would all be for cancer, so we were pretty shocked at the outcome; it was unexpected.

What we’re very pleased about, is it created this new pathway that is built on evidence and many diseases have benefitted from it. I think it’s still 55% to 60% cancer, but there’s a large percentage of rare diseases and other diseases that have benefitted from this designation.

What was the process of turning that concept into a reality?

The process was first deciding what ‘substantial evidence’ means; every disease setting is different—what this means in breast cancer is different than what it means in glioblastoma or pancreatic cancer. We were trying to look for definitions and it was very complicated. But we knew that the processes had to change, so when we brought it to legislation a lot of members of Congress thought, ‘Well, they can already do this’ and the answer is, ‘Maybe, but not so quickly.’

So what Breakthrough did, was it changed the way the FDA handled it, it changed the way academics and others handled it, it changed the culture among companies and among people because they started doing better, smarter trials that would really look for evidence earlier on.

And, of course, everybody thought they had a Breakthrough—it was like everyone’s children are brilliant and beautiful&mdash;but it was really game changing and part of it was because it was a better process that defined but it was because it really meant substantial evidence and all-hands-on-deck.

How has this law impacted patients and providers in the rare disease space?

Breakthrough changed cultures—companies, FDA, NCI&mdash;but cancer is a rare disease, so 30 years ago when we started the war on cancer it was 1 disease; now, we know it’s hundreds and hundreds of diseases and within subsets of cancer there are rare diseases. For example, we have some in lung cancer with squamous cell, which may be 2% of a population.

So clearly, we’re really looking to affect those populations in or outside of cancer whether there are no obvious large trials necessary or possible. And so, that was really a major impact on rare diseases—many of them in cancer, but many of them outside of cancer.

Ellen Sigal, PhD, discusses how she helped make the concept of the expedited FDA development program a reality.

How FDA's Breakthrough Therapy Designation Program Changed the Rare Disease Space

In an effort to meet the Blue Ribbon Panel recommendation of establishing a network to facilitate direct patient involvement, the National Cancer Institute (NCI)’s Center for Cancer Research has launched the 

Funded by Cancer Moonshot, the overall aim of the project is to build a national network to evaluate rare pediatric and adult tumors and create a network of clinical trials. The project has 2 central arms: the NCI-CONNECT arm, which aims to advance understanding of central nervous system cancers, and the MyPART arm, which will focus on pediatric, adolescent, and adult rare solid tumors.

In an exclusive interview at the National Organization of Rare Diseases’ Rare Diseases & Orphan Products Breakthrough Summit (

 sat down with Karlyne Reilly, PhD, director of the NCI’s Rare Tumor Initiative, and head of the MyPART arm of the network, to discuss the project and the importance of patient involvement in cancer research.

: What is the Rare Tumor Patient Engagement Network?

The Blue Ribbon panel of the Beau Biden Cancer Moonshot recommended as one of its first recommendations that patients be more engaged in research, that they have better access to their own data, that they have a better understanding of what it means to be involved in cancer research, and that they feel more like a team player.

I heard a patient say, ‘He doesn’t feel like a guinea pig; he feels like a test pilot,’ and that’s what we really want. We want patients to understand how critical they are in the process. Because at the Center for Cancer Research, where I work, we feel we have an opportunity in rare tumors that may be difficult to address in other parts of the country, we purposed a Rare Tumor Patient Engagement Network.

The idea behind this is to set up a patient portal where rare tumor patients can come, have their own little piece of portal, which has a place where they can provide data for research, they can keep track of their informed consents, and they can then get results back—either their own individual results or finding out what’s going on with a study, what are we learning about the kind of cancer they have. And so, the idea is to really make the patients feel like they’re an important part of the process and this is their little place as part of it.

The Rare Tumor Patient Engagement Network, right now, has 2 major arms; one is for neurooncology because all brain cancers are rare, and the other is a pediatric and young adult branch because all pediatric tumors are also rare. And so, that’s where we’re starting, but we’re hoping that we’ll build infrastructure that can be used across all rare cancers.

The one that I’m working on most closely is this Pediatric and Young Adult Rare Solid Tumor Network.

Can you tell us more about the My Pediatric and Adult Rare Tumors (MyPART) Network?

MyPART is one of the arms of the Rare Tumor Patient Engagement Network and it is a network that is focused on patients who are pediatric adolescents or young adults—about 30 years or less&mdash;and have solid tumors. There’s a big focus on sarcomas and we’ve got a lot of neuroendocrine tumors that we’re looking at.

The idea is that young adults and adolescents have some unique challenges that they face when they receive a cancer diagnosis that’s sort of compounded by having a rare cancer diagnosis. There are feelings of isolation—not knowing anybody else like them with this kind of a disease. And so, there’s also a component to all of this, of trying to provide support, trying to learn how to support adolescents and young adults better, and pediatric patients and their families better.

We’ve also got a psychosocial aspect to the research that we’re doing, which I’m very excited about. And so, it’s sort of what I was saying, we’re having the patients come in, provide information about their experience, and provide samples. And then, try to compile all of that together and we’re hoping that we’ll find some patterns that haven’t been seen before that might lead to new therapeutics.

And in all of this, we’re going to be looking at whether these patients are also candidates for intervention trials because we do want to get these patients into trials that might provide a treatment as well. But this allows us a blanket protocol that anybody can join—even if they’re not eligible for a clinical trial, they can still participate in this.

When it comes to the development of new therapies for rare tumors, how is patient involvement so important?

We’re trying to work very closely with the advocacy organizations and NORD is a great example of that, of course. But in some cases, the patient may not have an advocacy organization for their particular kind of tumor; it may be so rare that there aren’t enough people to form a group.

And so, we’re looking into ways of taking advantage of social media—Twitter, Facebook&mdash;and Rare Disease Day and things like that where we can try and reach out and get the patients more involved without necessarily having to go through that advocacy group.

But I think the ways in which advocates and patients really help out researchers is participating in clinical trials. I think that there are ideas that don’t get tested because there aren’t enough people to test them in the trial and that’s a really sad thing, that there might be a therapy out there that never gets tested rigorously.

And so, participating in clinical trials is very huge and we want people to understand what that really means so that it’s not such a scary thing necessarily, and so that they understand the value that they’re providing us.

Another way that patients really help us is when they provide samples of their tumors so that we could study them. In many cases, we can try and use those tumor samples to make model systems that are able to be perpetuated so that we can test drugs on them over and over and over again. And so, that’s a huge opportunity.

And little things like going and talking to your congressman, going and talking to your government representatives about how even though rare tumors individually only affect a small number of people, as a group, they’re affecting a lot of people, and they’re an important thing to be funded and to be supported. One-quarter of all cancer deaths are people with rare cancers, so it’s an important issue and patients are the best spokesmen.

I also think just coming and being honest with us, contacting us and telling us what’s important. We get focused on what we think is the most important thing but it’s very, very important for the patients to come to us and say, ‘These are the issues that really affect my quality of life when I have this disease.’

Karlyne Reilly, PhD, discusses the Rare Tumor Patient Engagement Network and the importance of getting patients with rare conditions involved in cancer research.