Spotlight January 2016

BPI Staff

January 13, 2016

8 Min Read

Niche Disease: CAPS

by Cheryl Scott

Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited, autoinflammatory diseases with similar genetics and overlapping symptoms. The group includes three subtypes: familial cold autoinflammatory syndrome (FCAS); Muckle-Wells syndrome (MWS); and neonatal-onset multisystem inflammatory disease (NOMID), also called chronic infantile neurologic cutaneous articular (CINCA) syndrome. The cryopyrin protein is critical to production of the inflammatory cytokine interleukin-1β (IL-1β), which triggers inflammatory response when it binds to inflammatory cells. Genetic alterations in cryopyrin cause IL-1β overproduction, resulting in an inflammatory response and the symptoms of CAPS.

FCAS symptoms can develop when patients are exposed to even a mild degree of cold temperature. A systemic inflammatory response usually ensues within a few hours with rash, fever/chills, arthralgia, conjunctivitis, and fatigue. Most flares last <24 hours. MWS has similar inflammatory symptoms, but they are more chronic and have random, unknown triggers. Known triggers include stress, exercise, and cool temperatures. Patients may develop hearing loss or reactive amyloidosis with renal dysfunction. NOMID is the most severe form of CAP syndrome and usually diagnosed shortly after birth. In addition to having other CAPS symptoms, NOMID patients have significant disabilities: optic nerve abnormalities (papilledema), chronic aseptic meningitis, mental impairment, facial malformation, and arthropathy with aberrant ossification (especially in the knees and elbows).

Epidemiology: Many CAPS patients are diagnosed very late or not at all, so it’s believed that other people may have a CAP syndrome without realizing it. All CAPS are very rare, found in about one in 360,000–1,000,000 people. Usually arising in the first year of life, FCAS is more common in the United States; MWS is more common in Europe and typically starts later in life. NOMID is least common but present around the world. Males and females are both affected, as are all ethnic groups.

Treatment Options: Until 2005, there was no effective CAPS treatments. Patients received antiinflammatory drugs, steroids, or methotrexate to reduce symptoms. But research has shown that medications targeting IL-1 are effective for treating CAPS, but with no known cure, treatment must continue throughout a patient’s life.

In summer of 2015, BPI’s Leah Rosin spoke with Spencer Fisk (global head of biologics process research and development at Novartis) in anticipation of his turn as a BPI Conference keynote speaker. She asked him about orphan-disease programs at his company. One prominent example is canakinumab, an anti–IL-1β monoclonal antibody (Ilaris), which was approved in 2009 for treatment of two CAPS: MWS and NOMID.

“Addressing significant unmet medical need is a cornerstone of Novartis’s strategy and why we spend a lot of time and energy researching rare diseases,” Fisk said. “Novartis works to improve the understanding of many rare diseases. In doing so, we’re not only helping patients who often have few treatment options, but also deepening knowledge of the molecular pathways that control multiple diseases. This may in time lead to new treatments for larger numbers of patients. Novartis has investigated treatments for more than 40 rare diseases. The US Food and Drug Administration has granted us dozens of ‘orphan drug’ designations, and we have more than 15 medicines approved for such conditions.”

Organizations: The Autoinflammatory Alliance ( was formerly known as the NOMID Alliance, but it still focuses primarily on CAPS disorders. Two biopharmaceutical companies involved in CAPS treatment also offer online information portals: Novartis’s CAPS Family Network ( and Regeneron’s CAPS Community ( The latter produces Arcalyst (rilonacept) IL-1 blocker, which was approved in 2008.

IL-10 Homodimer Chemically Synthesized

Last fall, French company Provepep (the peptide business unit of Provence Technologies Group) synthesized several milligrams of bioactive interleukin 10 (IL-10) cytokine in its homodimer form. The company’s solid-phase peptide synthesis using proprietary peptide ligation technology is based on bis(2-sulfanylethyl)amido (SEA) thiol groups to build on the synthesis of different parts to complete a peptide sequence. The resulting monomer of 160 amino acids contains two disulfide bridges.

Provepep holds an exclusive SEA license from the French National Centre for Scientific Research (CNRS) and Lille University, claiming that it reduces production costs by up to 40%. The chemical synthesis is performed under good manufacturing practice (GMP) in a reproducible process touted as an alternative to recombinant technologies. It can create high-purity proteins that include nonnatural amino-acids, something living organisms cannot do. The company seeks to apply the technology toward producing affordable biological therapies, such as fusion proteins and polyepitope vaccines.

“This should offer as many uses as recombinant technologies and facilitate the use of new biological therapies in immunoregulation and inflammation,” said Michel Feraud, CEO of Provence Technologies Group. His company’s peptide business unit (formerly known as Synprosis) specializes in chemical synthesis of large peptides and small proteins for research or GMP use.

Perspectives on HHS Forum on Access and Affordability of Prescription Drugs

On 20 November 2015, the US Department of Health and Human Services held a pharmaceutical forum on the subject of “Innovation, Access, Affordability, and Better Health.” The invitation-only forum brought together a broad range of stakeholder groups to discuss ideas that will help foster a healthcare system that leads in innovation while providing affordable, high-quality medicines.

One speaker was Debra Whitman, chief public policy officer of AARP. Speaking on a panel entitled “Patient Access and the Affordability of Prescription Drugs,” Whitman focused on rapidly escalating prescription drug prices and how the trend is making it increasingly difficult for people (particularly older Americans on fixed incomes) to afford medications they need.

“An AARP study out today found that the average cost of one specialty drug cost over US$53,000, more than the median household income of just over $52,000. This price is twice the median income of $23,500 for people on Medicare and almost three-and-half times the average Social Security retirement benefit.

“No one should have to choose between paying for food or rent and paying for the prescription drugs they need to stay healthy. American taxpayers and consumers cannot and should not be asked to foot the entire bill for medical innovation. We cannot continue to give drug manufacturers a blank check to pay for prescription drugs.”

Whitman also discussed the importance of increasing the availability of research that compares new drugs with those on the market. Known as comparative effectiveness research, such information would increase competition in the pharmaceutical market.

“Right now,” she said, “we have no idea whether a new drug is better than similar treatments that are already on the market. Other countries already require drug companies to provide such information, so why don’t we?” AARP believes that drug companies need to be more transparent about how they price their drugs. “We cannot and should not continue to simply accept ‘what the market will bear.’”

After the forum, the Biotechnology Industry Organization (BIO) released a public statement. “We welcome the opportunity to have a robust dialogue with all stakeholders in the healthcare system about what is needed to make sure that patients have access to our innovations and how we can speed the development of the next generation of cures and therapies, so that more patients can benefit from these breakthroughs. We appreciate HHS providing a venue for this discussion.”

The panel discussion explored the complicated issue of affordability. BIO highlighted the role that insurance companies play and encouraged “deeper examination of how insurance industry practices (e.g., out-of-pocket fees, high deductibles, changing formularies, the use of specialty tiers, industry consolidation) affect patient access and affordability.” BIO says stakeholders need to find ways to improve insurance-plan design for patients with chronic conditions.

“Another important issue was raised about spending in other areas of the healthcare system, including hospitals and doctor visits. New research shows that spending in these areas are out-pacing medical inflation. Innovation in biopharmaceuticals can help address this, and it should be a part of the conversation about managing overall healthcare costs.”

BIO claimed that some insurance-industry representatives engaged in obfuscation rather than dialogue. “We need to focus on challenges and opportunities. We have to use advances in science to better serve patients. This is an important conversation and we need all stakeholders engaged in it.

“America is the global leader in biotechnology innovation and investment, and today 70% of the biopharmaceutical industry’s clinical pipeline is attributed to small companies. Breakthroughs from these entrepreneurs will revolutionize the way we treat patients for a wide array of diseases. Making sure that our loved ones have access to these innovations is the top priority of our industry and why we look forward to continuing this discussion.”

Clinical Trials Need Automation Too

Late in 2015, San Francisco–based software company goBalto, Inc. announced preliminary findings of its 2015 Global Study Startup Survey. They identify significant gaps in the drug industry’s ability to manage document work flows and activities associated with starting clinical trials. Industry leaders are adopting cloud-based e-clinical solutions such as clinical trial management systems (CTMS), electronic data capture (EDC), and electronic trial master files (eTMFs). But such applications fall short when it comes to the inefficient and costly bottleneck of clinical study startup (SSU). Initiating trials is cumbersome and challenging, often behind schedule, and one of the poorest performing aspects of clinical testing.

Use of Microsoft Excel is omnipresent in the life-science industry. Over two thirds of product sponsors and contract research organizations (CROs) use it for clinical site selection and evaluation. Most use the spreadsheet program for site-feasibility assessment and tracking SSU processes.

Three top complaints for both sponsors and CROs were directly related to the limitations of that program: lack of operational oversight and real-time reporting on clinical trial status (or CRO performance); lack of project management standards, particularly related to milestones along the critical path; and lack of systems integration for site selection, feasibility, activation, and document management. Business-intelligence initiatives continue to be top priorities as executives demand faster and greater visibility of trial data. Manually prepared data often are too old to reliably represent a program’s status. Companies want interactive, real-time answers.

“True business intelligence is the ability to proactively identify and resolve bottlenecks in real time, instantly view statuses, quantify your team’s performance, and discover meaningful patterns in your clinical study startup data,” said goBalto CEO Sujay Jadhav. “Today’s industry leaders in clinical trials recognize that good data increasingly translates to a competitive advantage.”

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