Rare Diseases: Research, Development, and Commercialization

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Denise Myshko

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PV0615_ResearchDevCommercializationIn the past few years, significant progress has been made in rare diseases; in 2014, orphan drugs constituted 17 of the 41 new molecular entities approved by the Food and Drug Administration. An average of 140 drugs have been designated as orphan drugs by the FDA each year over the past decade, compared with 64 in the previous 10 years, according to the Pharmaceutical Research and Manufacturers of America.

The Orphan Drug Act, passed in 1983, was designed to provide incentives to manufacturers to research and develop drugs for rare diseases, defined as diseases that affect fewer than 200,000 people in the United States. The law has helped bring more than 450 new drugs to the market. During the decade before 1983, only 10 new treatments were developed for rare diseases. Since 1983, more than 3,000 products have been designated orphan drugs.

Driving recent approvals of rare diseases is the addition of the FDA’s breakthrough designation, says Maria Whitman, managing principal, at ZS.

“The breakthrough designation within the FDA in particular played a role in oncology where biomarkers have enabled targeting of an increasing number of subpopulations of patients even in larger cancers where therapies can target diseases at a more personalized level,” she says.

Robert Ryan, Ph.D., CEO at Scioderm, says the breakthrough designation provides a different level of engagement with regulators.
“We received a breakthrough designation in March 2013 when we were raising our Series A funding,” he says. “The breakthrough designation had a tremendous impact on our ability to sit down with the agency in a larger forum. It made a huge difference to be able to get everybody into the same room to discuss our IND.”

Scioderm’s lead product, Zorblisa, is in Phase III trials for treating skin effects associated with all subtypes of epidermolysis bullosa, a genetic connective tissue disorder.

Currently, America’s biopharmaceutical research companies are developing 452 medicines and vaccines to treat rare diseases, according to PhRMA. In particular, researchers are focusing on rare cancers, genetic disorders, neurological conditions, infectious diseases, and autoimmune disorders.

But despite these efforts, there is a huge unmet need in rare disease. In fact, about 95% of the estimated 6,000 to 7,000 rare diseases do not have a single FDA-approved drug treatment. At the current rate of approval, it will take more than 100 years to have therapies for all rare diseases, says Steve Smith, senior director, patient value, at Medidata.

The biggest unmet need in rare diseases — in addition to the inherent unmet medical need in most rare disease indications — has been the lack of multi-stakeholder alignment and collaboration, says Scott Schliebner, VP, scientific affairs, rare diseases, federal programs, at PRA Health Sciences.
“To make significant strides in these disease areas, we need stronger partnerships between industry and nonprofit patient advocacy groups; between regulators, payers, and drug developers; and between patients, families, and caregivers,” he says.

This, however, is beginning to change. An initiative that began last year within the U.S. Congress is aiming to understand how to advance innovative medical research and to accelerate the development of safe, effective medical treatments and cures, particularly for patients with unmet medical needs.

21st Century Cures Initiative

Many leaders in the rare disease space say while the Orphan Drug Act has been successful, enhancements and changes are needed to solve some of the challenges related to conducting trials in small patient populations.

“The Orphan Drug Act provided incentives for corporations to develop therapies, which many people have said is very effective,” says PV0615_FundingInnovationRareWendy White, senior VP, for rare diseases, at Dohmen Life Science Services. “Now we need a more coordinated effort and more directed support to move products to the market faster.”

That effort, the 21st Century Cures — an initiative within the House of Representatives — seeks to understand how to advance innovative medical research and to accelerate the development of safe, effective medical treatments and cures, particularly for patients with unmet medical needs.

In May, leaders from the Energy and Commerce Committee released a discussion draft of the 21st Century Cures initiative. The bipartisan initiative, led by Reps. Fred Upton (R-Mich.) and Diana DeGette (D-Colo.), began in April 2014 to look at ways to accelerate the pace of medical breakthroughs in the United States. The committee has held eight hearings, issued a number of white papers, and committee members have hosted more than two dozen roundtables across the country to generate ideas for this initiative.

John Crowley, CEO of Amicus Therapeutics, says the 21st Century Cures Initiative will go a long way to addressing the gaps in the Orphan Drug Act.

“It is the most patient-centered piece of legislation that I’ve seen proposed in Congress,” he says. “It addresses  a really important point: how do we develop medicines in the most patient-focused way,” he says. “The 21st Century Cure Initiative takes a pro-patient view, but it is also pro-science. It doesn’t put patients first at the expense of rigorous scientific evaluation of data. But it does approach the science in a much more flexible, responsive, and appropriate way.”

Amicus is conducting two Phase III global studies of migalastat HCl monotherapy in Fabry disease and a late-stage preclinical study of  AT-B200 for treating Pompe disease. Mr. Crowley’s two youngest children have Pompe disease, a lysosomal storage disease (LSD) that interferes with the body’s ability to break down molecules inside the lysosomes. He founded Novazyme Pharmaceuticals, a specialty biopharmaceutical company, to research enzyme replacement therapies for Pompe. Since then the company was sold to Genzyme.

(Editor’s Note: Mr. Crowley’s journey to find therapies for his children was profiled in PharmaVOICE in January 2009, as well as in a movie Extraordinary Measures.)

The 21st Century Cures draft includes provisions to: incorporate the patient perspective in the discovery, development, and delivery process, as well as increase funding for the National Institutes of Health, both through reauthorization and $10 billion over five years in mandatory funding, starting in fiscal year 2016. The draft also looks at how to break down barriers to increased collaboration and data sharing among patients, researchers, providers, and innovators, and help the development of personalized and precision medicines so the right patient can receive the right treatment at the right time.

“This initiative is charged with examining what is wrong with drug development,” Mr. Smith says. “We needed all stakeholders to have a consolidated discussion with Congress so Congress can pass new laws to change the FDA’s clinical trial process. This is historic; we haven’t had this sort of collaboration before.”

One of the biggest components of the draft, Mr. Smith says, is that it puts patients at the center of drug development.
“It will do this by compelling the FDA to take patients’ own assessment of risk and benefit into account and using risk vs. benefit in a methodological way,” he says. “It’s also important for clinical trial protocols that allow for small patient populations and allows us to use the data we do generate to prove whether the drug is working or not. This relates to endpoints and biomarkers. Using genetic biomarkers as an endpoint can bring us faster and better trials. The new legislation would mean that the FDA develops guidance so that biomarkers can be used more often.”

PV0615_SteveSmithAnother critical element of the draft is an increase in funding for both the NIH and the FDA.

“The 21st Century Cure legislation will restore America’s ability to lead in the 21st century of drug development,” Mr. Smith says. “We are a country that has traditionally led in medicine, but our leadership is in danger of being eroded by the weakening of the NIH and by inference, the weakening of the FDA.”

Mark Rothera, chief commercial officer, PTC Therapeutics, says an analysis of the risk-benefit trade offs that patients and families are prepared to make in order to have access to an effective therapy is important for a better understanding of the patient and family perspective, especially in the regulatory process.

“The European Medicines Agency is willing to provide approvals based on a single trial where it believes that the evidence is sufficient in terms of efficacy and safety,” he says. “The agency is prepared to give early approval subject to a subsequent confirmatory trial. This is a compelling approach when dealing with progression and devastating disorders. It would be beneficial to patients if the FDA adopted a similar approach when looking at rapidly progressing and deadly diseases, because time is of the essence.”

In February 2015, the Senate’s Health Committee began its effort to look at how to improve biomedical innovation. Led by Sens. Lamar Alexander (R-Tenn.) and Patty Murray (D-Wash.), the committee is holding hearings to examine the process for getting products to the market.

Researching Rare Diseases

Phil Vickers, Ph.D., global head of R&D, Shire, says the research of rare diseases is different from more common diseases.
“With rare diseases we are not following a well-trodden path; we’re making the path,” he says. “There is usually no effective standard of care and no drug has gone through the regulatory process.”

PV0615_MarkRotheraShire has been active in the rare disease space since the acquisition of Transkaryotic Therapies (TKT) in 2005 and most recently established a three-year research agreement with the Cincinnati Children’s Hospital Medical Center for rare diseases. In February 2015, the company also acquired NPS Pharma, a company focused on rare diseases.

Dr. Vickers says rare diseases are not fully understood and so companies in rare disease research often have to do natural history studies. They have to work closely with key opinion leaders to try to understand the disease.

“As this research then transitions into clinical and regulatory, we need to work very carefully with physicians to understand what biomarkers may be relevant to disease, and we need to engage with regulators early in the process to ensure that we are aligned on the appropriate biomarkers and clinical endpoints to focus on,” he says.

Understanding the basic biology of disease is a challenge, Mr. Crowley agrees.

“But we are understanding more about the genetic mutations that lead to these diseases and how those result in different severities of disease, different onsets, different organ involvement, and different responses to various medicines and technologies that might be applicable to treat the disease,” he says.

The challenges of developing drugs for rare diseases are often underestimated, says Kevin Lee, Ph.D., senior VP and chief scientific officer, Pfizer. He says partnering is the most effective way for drug discovery and the most rapid way in an area like rare disease. Pfizer’s current pipeline includes clinical and preclinical programs in sickle cell disease, hemophilia, muscular dystrophies, spinal muscular atrophy, cystic fibrosis, and other rare diseases.

Scientific collaboration is crucial, says Eric Althoff, head of global media relations, Novartis. Novartis has nine marketed drugs that have been designated orphan drugs as well as a robust clinical pipeline, including more than 40 active preclinical and clinical research projects in the rare diseases area.

“Researchers must work together toward the goal of creating a global knowledge base, a necessary step to tackling the challenges of these PV0615_RareDiseaseFactsdiseases where basic knowledge is limited and the small patient populations are dispersed across the globe,” he says. “Knowledge derived from the thorough analysis of a rare disease has high scientific and societal value, because insights into rare disorders may also provide scientists with a clear understanding of disease mechanisms that could be useful to treat more common disorders.”

Industry experts identify numerous challenges specific to each particular disease state, including investigator cultivation and site identification; patient identification, recruitment, and retention; understanding the patient pathway and selection of endpoints; and engaging and including various stakeholders to the drug development process.

“There are strategic and tactical considerations that can be used to address and overcome the various challenges to rare disease drug development,” Mr. Schliebner says. “We use an evidenced-based approach that leverages medical informatics to drive study design and trial positioning; natural history studies and registries can be developed to shed light on the disease state and the optimal selection of endpoints; early and transparent engagement with patient advocacy groups can help to build trust and collaboration to accelerate rare disease drug development.”

Rare disease studies are often restricted by the number of patients available. And while patient recruitment continues to be a challenge for all trials, it is even more so for trials of rare diseases. Every patient counts in a clinical study to drive statistical significance.Partnering with advocacy organizations can go a long way to helping pharmaceutical companies reach patients.

“Patientricity is becoming a buzz word and is especially relevant to the rare disease arena,” Mr. Schliebner says. “We are also seeing bigger industry players begin to enter the rare disease space, make acquisitions, and broaden their focus on orphan drug development. There are more agents in development and more awareness. This will continue.”

Dr. Vickers agrees that having strong links with patient associations is particularly important in the rare disease space.
“We are working in areas where there is no effective standard of care and in many cases, there have been no drugs that have gone through the regulatory path,” he says. “In fact, there is little published on some of the rare diseases that we work on, so just defining what are the appropriate factors to measure in clinical studies is something we spend a lot of time on.”

PV0615_JohnCrowleyYuval Cohen, Ph.D., CEO of Corbus Pharmaceuticals, says patient groups are important partners in helping companies develop and execute trials in the best possible way. Corbus is working with the Cystic Fibrosis Foundation Therapeutics Development Network on a Phase II trial for Resunab, which is being investigated for the treatment of cystic fibrosis. They are also launching a Phase II clinical trial in diffuse systemic sclerosis.

Dr. Vickers says working closely with patient advocacy groups is essential to understand the patient’s  and caregiver’s perspectives on the most significant unmet needs and the most devastating effects or consequences of these diseases on their daily lives in order to design studies to best meet patients’ needs.

In many rare diseases, however, there is no patient advocacy organization. In this case, biopharmaceuticals companies are working on their own to reach patients.

One such company is Catalyst Pharmaceuticals. The company’s lead program is Firdapse. An NDA for this product is expected to be submitted to the FDA in the third quarter of 2015 to treat patients with Lambert-Eaton Myasthenic Syndrome (LEMS). LEMS is a rare autoimmune disorder with the primary symptoms of debilitating muscle weakness. While this disease would fall under the Muscular Dystrophy Association, no specific LEMS organization exists. Catalyst recently worked with the National Organization for Rare Disorders (NORD) to set up a patient meeting this spring in Orlando for patients and caregivers and their physicians.

“This meeting gave us an opportunity to better understand the patient’s journey,” says Pat McEnany, CEO of Catalyst. He says this was the company’s first patient meeting and others are planned around the country for continued patient outreach.

Patient-to-patient connection is a powerful means of communications, says Dan Bobear, principal, managing director at The Patient Experience Project.

“In rare diseases, there is an interesting dynamic in that many patients have never, or rarely, spoken to someone else with the same condition,” he says. “So when patients speak to, hear stories, or get advice from someone in the same situation it has deep meaning and the potential for connection and engagement is incredible.”

PV0615_DrPhilVickersBecause the understanding around rare diseases is often limited, patient registries and postmarketing studies play an increasingly important role in research.

Fewer than 20% of rare diseases have patient registries, and most are operated by patients’ organizations or academic researchers, according to the National Institutes of Health.

One such program is the Global Rare Diseases Patient Registry Data Repository/GRDR program from the NIH’s National Center for Advancing Translational Sciences. This program aims to develop a Web-based resource that aggregates, secures, and stores de-identified patient information from many different registries. NORD has been instrumental in helping set up a number of patient registries, the most recent is the Foundation for Prader-Willi Research, which launched in May. Prader-Willi is a rare genetic disorder that affects development and growth.

Patient registries are important to gather additional information about how a drug is performing in patients, says Stella Blackburn, VP of global risk management, in Quintiles’ real world and late-phase research division.

“All the evidence before registration is from clinical trials,” she says. “A lot of the patients who will get the drug will have more complex diseases and may be different age ranges or they may be taking other drugs as well. These registries aim to answer questions that couldn’tPV0615_MariaWhitman be answered pre-authorization.”

Commercializing Drugs for Rare Diseases

Sales of drugs designated as orphans by regulators in the United States, Europe, or Japan will grow at an annual rate of almost 11% per year through 2020, compared with only about 4% for drugs treating larger populations, according to a 2014 report from EvaluatePharma. In fact, orphan drug sales will constitute 19% of the total share of prescription drug sales by 2020, totaling $176 billion.

Launch strategies for products for rare diseases need to be different from other product launches, says Kristin Keller, executive VP, client engagement, Discovery USA. She says in the rare disease ecosystem, the stakeholders tend to be more connected and they tend to be communicating with each other more. This means pharma companies have make to sure brands have a very holistic and innovative strategy at a brand, commercial, and communications level.

“Typically there is a heavy burden put on the patients both by the disease and by the dynamics of the treatment,” Ms. Keller says. “Patients may be dealing with more intensive treatment regimens, and are typically dealing with life-long chronic diseases. It’s important to provide as much support and value at a high level of service to the patient community.”

Ms. Keller says these services make sure that patients are at the center of the treatment and can include anything from reimbursement, patient support, or nurse counselors who come to the home; patient mentors; or wrap around services that are designed to addressed the unmet needs of the patient and their family.

Physicians are challenged in dealing with patients with rare diseases. Physicians — both primary care and specialists — have limited resources and information to properly diagnose/manage patients with rare diseases as compared with the more common diseases they see. Frontline Medical Communications conducted a survey of healthcare professionals, and found that 88% of the HCPs surveyed agreed therePV0615_KristinKeller is a need for professional content around rare diseases. HCPs have an average of 12 patients who have either been diagnosed with, are being treated for, or are suspected to have and remain undiagnosed with a rare disease.

“A survey of our readers found physicians know they lack understanding of rare diseases and want more information,” says Elizabeth Katz, publisher of Neurology Reviews, Frontline Medical Communications.

Unless patients are seeing a key opinion leader in the disease area, they may not be receiving the highest standard of care, Ms. White says.
“Primary care physicians just don’t have the time to learn about diseases they may never see in their practice,” she says. “They are doing exactly the same thing that patients and caregivers do when a patient presents with something they don’t recognize — they look it up on the Internet. If we, on behalf of manufacturers, can help them know that there is a treatment available and how to get to the right diagnosis and provide that in a timely way, then we can help physicians be more effective.”

Ms. White says it’s important to bring payers into the discussions about new therapies for rare diseases early on.

“Bringing payers in as a company is developing its clinical trial and thinking about what kind of proof is going to be needed to cover costs is critically important,” she says.

PV0615_RareSoundBitesMs. Whitman says pharma companies have not had a high burden to communicate value in rare diseases so far. Communicating value to payers is becoming challenging with orphan and rare diseases as more products launch and budget impact goes up. More companies are launching products into rare indications, and while there is a limited breadth of patients and data, many drugs will expand into broader indications.

Ms. Whitman recommends companies consider constructing a cohesive value story for payers, physicians, and patients. While each of these stakeholders is making different decisions in the patient journey, in rare diseases there is much more collaboration among the stakeholders across the journey of a patient.

“We haven’t gotten to a point yet in most rare diseases where there are multiple products to determine if certain endpoints outweigh others,” she says. “With more rare approvals and comparators emerging impact is harder to prove. The value will be in demonstrating differentiation in disease modification and how this is going to make a difference to the patient. A rare disease is one of the areas where we can still truly change the course of a patient’s life.” (PV)

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