A recent paper in nature highlighted that women with rare disease face higher risks of diagnostic delays, particularly after entering the health care system.
Based on data from the EURORDIS Rare Barometer program, an initiative that collects the experiences and opinions of people living with a rare disease and their close family members, it found that in France each step of the diagnostic process for 22 different rare diseases took longer for women than for men, even when accounting for gender-related prevalence.
Similarly, an analysis of health data from nearly seven million individuals in Denmark over 21 years revealed that women were diagnosed later than men in over 700 conditions.
A 2020 scoping review published in the International Journal for Equity in Health indicated that gender disparities in specialized health care could be mitigated or even eradicated through improved adherence to clinical guidelines. However, there is a significant gap in research addressing gender bias in primary health care, where its reduction could yield more substantial benefits. Further investigation is required to ascertain whether these disparities are influenced by specific diseases or vary by country.
Jennifer Schranz, head of rare diseases at Ipsen, believes that the future medical community can address this elongated “diagnostic odyssey” for women with rare diseases, if provided with sex-specific training on the sexual biology, gender biology, and gender science in the medical school resident curriculum, something not done in the past.
The fix, however, is multi-pronged she said, with socioeconomic advances also needed as described by the World Health Organization (WHO) in its gender structural determinants of health literature. WHO recognizes the “social stratification of women having lower education, lower paying jobs, having higher rates of poverty and more familial responsibilities and other discriminatory practices can affect health outcomes in women,” said Schranz.
While the double jeopardy of women with rare disease is part of a much wider conversation, Ipsen is working with patients in the rare liver disease space to counter this unseen gender bias within primary biliary cholangitis (PBC).
The PBC Community
PBC is a rare autoimmune cholestatic liver disease, predominantly affecting women at a ratio of nine to one compared to men, and most commonly diagnosed between 35-55. The condition is characterized by the accumulation of bile and toxins (cholestasis) and chronic inflammation, leading to irreversible liver fibrosis and bile duct destruction.
PBC can progressively worsen without effective treatment, potentially resulting in liver transplantation or premature death. Patients with PBC often endure debilitating symptoms such as pruritus and extreme tiredness and, as with many other rare diseases, these symptoms can be confused with other conditions such as, in the case of PBC, perimenopause or fatigue because of the daily strains of familial responsibility.
Ipsen has been working closely with patients to learn about their experiences of disease onset, and this patient-centric approach has culminated in the approval of the first-in-class PPAR agonist Iqirvo (elafibranor).
Licensed from Genfit in 2021, Iqirvo is a second line treatment option taken with ursodeoxycholic acid (UDCA) in patients for whom UDCA alone does not work well enough, and on its own in patients who cannot take UDCA. Up to 40% of patients don’t adequately respond to existing first-line treatments, putting them at increased risk of liver failure, liver transplantation or even death.
The FDA granted accelerated approval in June 2024, while the EMA granted conditional marketing authorization (CMA) in September 2024 on the basis of less comprehensive data than are normally required because it fulfils an unmet medical need.
The EU’s removal of the second-line treatment Ocaliva means that unmet need will be felt more keenly by the PBC community, and will undoubtedly benefit uptake of Iqirvo, although Gilead’s PPAR agonist Livdelzi (seladelpar) is following hot on its heels, with EMA approval expected early in 2025.
Advanz Pharma and Intercept Pharmaceuticals Inc’ FXR agonist Ocaliva (obeticholic acid) is given in conjunction with UDCA and works by reducing the levels of alkaline phosphatase, a live enzyme often elevated in PBC patients. It received accelerated approval in the US and CMA in Europe in 2016. However, it was thought that the drug’s benefits no longer outweighed its risks, and the premature termination of confirmatory studies in 2021 resulted in the European regulator revoking the CMA in September 2024.
Despite the General Court of the European Union temporarily suspending that decision, the drug’s future remains uncertain due to insufficient clinical trial data supporting its efficacy. A retrospective study showed some positive real-world outcomes, but its impact on regulatory decisions is yet to be determined.
So as not to repeat history, Ipsen must conduct a study to investigate the long-term clinical benefits in patients treated with Iqirvo, an oral once-daily medicine. Every year, the EMA will review any new information that becomes available.
The Impact Of AI In Rare Disease
Of course, it is not just women that face a staggered time to diagnosis in rare disease. Analysis conducted by Rare Diseases International and EURORDIS show that 72% of rare diseases, which impact around 300 million people globally, are genetic and 70% begin in childhood.
Working with families is part and parcel of the diagnostic odyssey, explained Schranz, and she is hopeful that access to genetic testing as soon as symptoms appear could be expedited further by the application of AI.
“AI in the future of science is at a precipice for further transforming and disrupting the treatment of patients with rare diseases.”
Jennifer Schranz
“Artificial intelligence, through structured algorithms like machine learning and deep learning, can help put a lot of this data together to create a differential diagnosis that will help health care providers to find the zebras,” she said. “AI in the future of science is at a precipice for further transforming and disrupting the treatment of patients with rare diseases.”
As such, contract research organizations (CROs) are accelerating targeted recruitment for rare disease clinical trials using AI, enriching the study population with patients that can show the value of the drug being trialed. While the use of AI within drug discovery and development is increasingly recognized, its use in rare disease patient finding is particularly necessary.
“You can use AI machine learning to find out where pockets of diseases could be from reviewing laboratory data or which centers of excellence are seeing patients for high alkaline phosphatase, for example. Artificial intelligence helps to develop algorithms to find where those patients are,” Schranz said.
Filling The Pipeline
As head of rare disease, Schranz leads one of the three therapeutic pillars Ipsen is built on, which include oncology and neuroscience.
The rare diseases portfolio is based around growth disorders, rare liver disease and bone conditions, with the ileal bile acid transporter (IBAT) reverse inhibitor Bylvay (odevixibat) its only other marketed liver disease product on the market for progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome, and in Phase III trials for biliary atresia.
“We have a novel model of partnering to bring scientific discovery into our organization, forming powerful partnerships that offer the best science and expertise in rare liver disease.”
Jennifer Schranz
With around 7,000 known rare diseases, of which only 4% have a treatment, the choice of which unmet need to develop therapies for, is vast. Ipsen has no internal innovation engine and makes a choice on which external assets to develop based on a disease modification criteria, strong preclinical data, an identified target, and a biological positive plausibility that the asset can make an impact on the disease.
“We have a novel model of partnering to bring scientific discovery into our organization, forming powerful partnerships that offer the best science and expertise in rare liver disease,” explained Schranz. “We complement these partnerships through our 30 years of experience in rare disease and our extensive access to world-wide markets, extensive know-how and global resources. Our partnership model is focused and fast, and has allowed us to bring in over 20-best- or first-in-class programs across our pipeline at every stage of development, with plans to acquire more,” she said.
Ipsen has one other asset in Phase II for primary sclerosing cholangitis (PSC), a chronic liver disease characterized by inflammation and scarring of the bile ducts. Ritivixibat “brings a different and complementary mode of action to Ipsen’s other program in PSC with elafibranor”, said Schranz, by targeting the intestinal bile acid transporter (IBAT), aiming to reduce bile acid levels in the liver and bloodstream, potentially alleviating symptoms and slowing disease progression.
The primary focus of the ongoing study is to assess the safety and tolerability of ritivixibat following repeat doses. A secondary goal is to evaluate the pharmacokinetic properties of ritivixibat with and without clinically relevant bile duct strictures and impact of removing bile acids through the kidney.
“By targeting three points in the body where bile acid transporters are present, we are gathering information in patients with PSC to determine whether ritivixibat may be an appropriate drug for people living with PSC,” she said. The study is estimated to be completed in the second quarter of 2025. While the combination of ritivixibat and elafibranor has the potential to benefit patients with PSC, Ipsen’s primary focus at this stage is to evaluate the benefits of each treatment alone, Schranz added.
Health Is Wealth
While Schranz is generally optimistic about the state of innovation within the rare diseases space, incentives for pharma companies remain critical to encourage reinvestment in pipelines, she said. And with that innovation, the more drugs that are approved increases disease prevalence because options become available for patients.
“Understanding the value of the medicines and what they bring long term is really critical. Sometimes it’s just short-term thinking about treating a disease, but if you can diagnose and treat people earlier their natural history can be changed such that they can function at a higher level within their family unit and within their community. Health is wealth and that is a critical message,” she said.
Schranz began her career as a clinician in infectious diseases during the AIDS epidemic. “That was a vulnerable population at the time, where patient advocacy was critical to move the needle, to demand that access to treatment was there,” she recalls.
This passion for patient advocacy led her to rare disease therapies, a part of medicine where a close connection is built between physician and patient. “Ninety six percent of rare disease patients don’t have treatment. As a clinician, you can make a difference for them and their families,” she said.
